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SAGE KE Discussions

SAGE KE Discussions consisted of electronic letters discussing various aspects of articles posted on the SAGE KE site. We have reproduced all of these contributions available on the site at the time the site ceased pubilication in June 2006. (Most discussions can also be accessed via the "E-Letters" link available in the full-text view of the article being discussed.)

To see discussions posted on the SAGE KE General Bulletin Board, please visit the Bulletin Board home page.

List of E-Letters Posted for Specific Articles

Jump to Comments for citation
reports
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Kayed et al. (18 April 2003) [Abstract] [Full text]
Letters
Jump to Comment Alzheimer amyloid beta oligomers vs lipoprotein Ab ($)
Alexei R. Koudinov, neuroscientist and editor Russian Academy of Medical Sciences; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100, Israel   (1 May 2003)

Jump to Comments for citation
SAGE Perspectives
SENS and the Polarization of Aging-Related Research
Gray and Bürkle (5 April 2006) [Abstract] [Full text]
Letters
Jump to Comment Shunned cadres - a clarification
Rich Miller, Biogerontologist   (21 April 2006)
Jump to Comment SENS's detractors should not intimidate aging-related scientists
Aubrey D.N.J. de Grey, Research Scientist University of Cambridge   (13 April 2006)

Jump to Comments for citation
SAGE News Focus
Loose Chromosomes Sink Cells
Leslie (21 December 2005) [Abstract] [Full text]
Letters
Jump to Comment Lamins an chromatin organization during aging
Giuseppe Novelli, Lab director Tor Vergata University   (4 January 2006)

Jump to Comments for citation
SAGE News Focus
Shortchanged by Sir2
Leslie (23 November 2005) [Abstract] [Full text]
Letters
Jump to Comment We buy it
Valter Longo, Professor USC   (6 December 2005)

Jump to Comments for citation
SAGE Reviews
Mitochondrial Genetics of Aging: Intergenomic Conflict Resolution
Rand (9 November 2005) [Abstract] [Full text]
Letters
Jump to Comment secure transit of funds
Anthony Davies, research none   (16 November 2005)

Jump to Comments for citation
SAGE Tidbit of the Week
5 October 2005 Tidbit
(5 October 2005) [Full text]
Letters
Jump to Comment For openers, how about...
Anonymous   (5 October 2005)

Jump to Comments for citation
SAGE Neurodegenerative Disease Case Studies
Brain Tumor-Associated Dementia
Noble et al. (24 August 2005) [Abstract] [Full text]
Letters
Jump to Comment �Cognitive impairment associated with malignancy.�
Slawomir Michalak, neurologist Department of Neurochemistry and Neuropathology University of Medical Sciences, Poznan, Poland   (20 September 2005)

Jump to Comments for citation
SAGE Other Resources
Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
SantaCruz et al. (20 July 2005) [Abstract]
Letters
Jump to Comment Comment on SantaCruz et al.
Dietmar R. Thal   (25 July 2005)

Jump to Comments for citation
SAGE News Focus
Not Like the Other
Davenport (13 July 2005) [Abstract] [Full text]
Letters
Jump to Comment AGING CHROMOSOMES
ROBERT BELLIVEAU, PATHOLOGIST   (14 July 2005)

Jump to Comments for citation
SAGE Perspectives
The Longevity Gender Gap: Are Telomeres the Explanation?
Aviv et al. (8 June 2005) [Abstract] [Full text]
Letters
Jump to Comment Abstract of the 'telomere-gender gap' paper, published in January 2004
Reinhard Stindl, Research Scientist Medical University of Vienna   (20 June 2005)
Jump to Comment Tying it all together: telomeres, sexual size dimorphism and the gender gap in life expectancy
Reinhard Stindl, Research Scientist Medical University of Vienna, Austria   (10 June 2005)

Jump to Comments for citation
SAGE News Focus
Mopping Up Nuclear Waste
Leslie (30 March 2005) [Abstract] [Full text]
Letters
Jump to Comment Prior Evidence of Nuclear Proteasome Activity
David Goldfarb University of Rochester   (8 July 2005)

Jump to Comments for citation
SAGE Reviews
Microarrays as a Tool to Investigate the Biology of Aging: A Retrospective and a Look to the Future
Melov and Hubbard (20 October 2004) [Abstract] [Full text]
Letters
Jump to Comment Test
Anonymous   (31 January 2005)

Jump to Comments for citation
SAGE News Focus
Racing Against Time
Chen (23 June 2004) [Abstract] [Full text]
Letters
Jump to Comment Excellent Article
Anna E. Shethar   (1 July 2004)

Jump to Comments for citation
SAGE Tidbit of the Week
26 May 2004 Tidbit
(26 May 2004) [Full text]
Letters
Jump to Comment Re: tidbit
Gregory A. Petsko, Professor Brandeis University   (26 May 2004)

Jump to Comments for citation
SAGE Reviews
Androgens, ApoE, and Alzheimer's Disease
Raber (17 March 2004) [Abstract] [Full text]
Letters
Jump to Comment Discussion at Alz Forum
Kelly LaMarco   (26 May 2004)

Jump to Comments for citation
SAGE Noteworthy This Week
Protective Parents
Davenport (5 March 2003) [Abstract] [Full text]
Letters
Jump to Comment Daughters from old mothers
James Ryley UTHSC   (13 March 2003)

Jump to Comments for citation
SAGE News Synthesis
Dietary Drawbacks
Hopkin (26 February 2003) [Abstract] [Full text]
Letters
Jump to Comment We're not getting older, just fatter
Michael G Kurilla, MD-PhD   (10 March 2003)
Jump to Comment CR does not increase longevity in Drosophila
Eric Le Bourg, scientist CNRS, University Paul-sabatier, Toulouse, France   (27 February 2003)

Jump to Comments for citation
SAGE Noteworthy This Week
Lasting Without Fasting
Davenport (5 February 2003) [Abstract] [Full text]
Letters
Jump to Comment Life Extension
Edward J. Masoro   (6 March 2003)

Jump to Comments for citation
SAGE Other Resources
{alpha}-Synuclein Locus Triplication Causes Parkinson's Disease
Singleton et al. (5 November 2003) [Abstract]
Letters
Jump to Comment Familial DLB Cracked
John Q. Trojanowski   (5 November 2003)

Jump to Comments for citation
SAGE Noteworthy This Week
JNK-ing Cellular Poisons
Leslie (5 November 2003) [Abstract] [Full text]
Letters
Jump to Comment Response by the Authors
Dirk Bohmann, Prof. of Genetics U. of Rochester   (11 November 2003)

Jump to Comments for citation
SAGE Noteworthy This Week
Evolutionary Oxymoron
Beckman (6 August 2003) [Full text]
Letters
Jump to Comment Related work just published
Mary Beckman   (6 August 2003)

Jump to Comments for citation
SAGE News Focus
Mindful of Metal
Leslie (26 March 2003) [Abstract] [Full text]
Letters
Jump to Comment Putting the Al in METAL
Chris Exley, moribund scientist Keele University   (1 April 2003)

Jump to Comments for citation
SAGE Perspectives
Vitamin B1 Blocks Damage Caused by Hyperglycemia
Obrenovich and Monnier (12 March 2003) [Abstract] [Full text]
Letters
Jump to Comment Vitamin B1 to the Rescue of the Glucose-Mitochondrial Axis of Evil in Diabetes?
Vincent M. Monnier Case Western Reserve University   (25 August 2003)

Jump to Comments for citation
SAGE Viewpoint
Help Wanted: Physiologists for Research on Aging
Martin (6 March 2002) [Full text]
Letters
Jump to Comment Response to Walter Bortz
George M Martin, Pathologist University of Washington   (20 March 2002)
Jump to Comment Homeodynamics
Walter Bortz, MD Stanford Med   (19 March 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Random Acts
Davenport (18 December 2002) [Abstract] [Full text]
Letters
Jump to Comment Thank you
Koji Itahana, posdoc MD Anderson Cancer Center   (21 December 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Other Noteworthy Papers This Week
(4 December 2002) [Abstract] [Full text]
Letters
Jump to Comment psychosocial factors in aging
soeharno honggokoesoemo, physician health care   (18 December 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Strong Spirit, Weak Flesh
Beckman (30 October 2002) [Abstract]
Letters
Jump to Comment Scoring paralysis as death?
Matt Kaeberlein   (30 October 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Closing the Generation Gap
Beckman (25 September 2002) [Abstract]
Letters
Jump to Comment Is ATP2 really involved in aging?
Matt Kaeberlein   (26 September 2002)

Jump to Comments for citation
SAGE Classical Papers
The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis
Sapolsky et al. (25 September 2002) [Abstract]
Letters
Jump to Comment Need to investigate common biochemical link for stress related disorders
Pradeep Shukla, Research UIC, Chicago   (20 March 2006)

Jump to Comments for citation
SAGE Reviews
Subfield History: Caenorhabditis elegans as a System for Analysis of the Genetics of Aging
Johnson (28 August 2002) [Abstract] [Full text]
Letters
Jump to Comment kudos
Anonymous   (16 October 2002)

Jump to Comments for citation
SAGE Other Resources
Protecting the Brain While Killing Pain?
Helmuth (28 August 2002) [Abstract]
Letters
Jump to Comment Open letter to Public Citizen's Health Research Group on Alzheimer's disease research
Alexei R. Koudinov, neuroscientist and editor Russian Academy of Medical Sciences; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100, Israel   (21 February 2003)

Jump to Comments for citation
SAGE Reviews
Innate Immunity, Local Inflammation, and Degenerative Disease
McGeer and McGeer (24 July 2002) [Abstract] [Full text]
Letters
Jump to Comment Untitled
Vijendra K Singh, Associate Professor Utah State University   (2 August 2002)

Jump to Comments for citation
SAGE Viewpoint
No Truth to the Fountain of Youth
Olshansky et al. (15 December 2004) [Abstract] [Full text]
Letters
Jump to Comment Down With Dogma
Richard L. Bowen, Research Scientist Voyager Pharmaceutical Corp.   (13 April 2004)

Jump to Comments for citation
SAGE News Focus
Give Me Liberty or Give Me an Early Death
Leslie (3 July 2002) [Abstract] [Full text]
Letters
Jump to Comment Free mice! Free!
Richard A. Miller, researcher University of Michigan   (10 July 2002)

Jump to Comments for citation
SAGE Viewpoint
Insulin-Like Growth Factor 1 and Mammalian Aging
Bartke (24 April 2002) [Full text]
Letters
Jump to Comment Reply to the comments of Dr. Sonntag
Andrzej Bartke   (27 May 2002)
Jump to Comment WHAT DO DWARF MODELS REVEAL ABOUT MECHANISMS OF AGING
William E. Sonntag, Professor of Physiology Wake Forest University School of Medicine   (16 May 2002)

Jump to Comments for citation
SAGE Perspectives
Deciphering the Gene Expression Profile of Long-Lived Snell Mice
Becker (20 March 2002) [Abstract] [Full text]
Letters
Jump to Comment Comment on inferences from gene arrays
Rich Miller University of Michigan   (22 March 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Youth Beats Experience: Older parents hatch weaker offspring (Reproduction)
Leslie (20 March 2002) [Abstract]
Letters
Jump to Comment Maternal age effects in fruit fly aging
Nicholas K. Priest, graduate student University of Virginia   (22 April 2002)
Jump to Comment Parental Age and Human Longevity
Leonid Gavrilov, scientist Center on Aging, NORC/University of Chicago   (1 April 2002)
Jump to Comment Re: What age constitutes
Phyllis Wise, Researcher   (27 March 2002)
Jump to Comment What age constitutes "older/younger" and which lifestyles constitute aging?
, chem   (22 March 2002)

Jump to Comments for citation
SAGE News Synthesis
More Than a Hot Flash
Davenport (13 March 2002) [Abstract] [Full text]
Letters
Jump to Comment Male testosterone need not decline with age
Allan Mazur, professor syracuse university   (20 March 2002)

Jump to Comments for citation
SAGE Perspectives
Cancer and Aging: Yin, Yang, and p53
Campisi (9 January 2002) [Abstract] [Full text]
Letters
Jump to Comment Cancer curable, aging probably not
Charles R Fred   (22 February 2002)
Jump to Comment p53: The yin, the yang, and the universal
Charles Mobbs, Associate Professor Mt. Sinai School of Medicine   (23 January 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Reviving Biomedicine: New Basel institute tackles aging and aims to bolster Swiss research (Research funding)
Weiss (9 January 2002) [Abstract]
Letters
Jump to Comment A Welcome move worth emulating by other countries
Kalluri S Rao, Emeritus Professor University of Hyderabad, Hyderabad.India   (12 January 2002)

Jump to Comments for citation
SAGE Viewpoint
A Position Paper on Longevity Genes
Miller (28 November 2001) [Full text]
Letters
Jump to Comment We can add new genes as well as change existing ones
Aubrey de Grey   (2 December 2001)
Jump to Comment Using the term gerontogenes
Suresh Rattan, Professor Univesity of Aarhus   (30 November 2001)

Jump to Comments for citation
SAGE News Focus
Drugs Protect Mice From Pernicious Forms of Oxygen
Tuma (7 November 2001) [Abstract] [Full text]
Letters
Jump to Comment Meal frequency
Michael Gates, Physician   (11 November 2001)

Jump to Comments for citation
SAGE News Focus
Death and Aging, Together at Last
Hopkin (24 October 2001) [Abstract] [Full text]
Letters
Jump to Comment Cancer curable, aging probably not.
Charles R Fred   (22 February 2002)
Jump to Comment Cancer curable, aging probably not.
Charles R Fred   (22 February 2002)
Jump to Comment Cancer curable, aging probably not.
Charles R Fred   (22 February 2002)

Jump to Comments for citation
SAGE Noteworthy This Week
Faustian Bargain: Cellular senescence at first prevents, later promotes, cancer
Davenport (17 October 2001) [Abstract]
Letters
Jump to Comment A question about stoichiometry
Rich Miller, Gerontologist University of Michigan   (18 October 2001)

Jump to Comments for citation
SAGE Viewpoint
Realizing Wisdom
Olshansky (10 October 2001) [Full text]
Letters
Jump to Comment More kudos for our social science colleagues
George M Martin, Pathologist University of Washington   (11 October 2001)

Jump to Comments for citation
SAGE Viewpoint
Can Current Evolutionary Theory Explain Experimental Data on Aging?
Mitteldorf (19 December 2001) [Full text]
Letters
Jump to Comment Evolutionary theory is nicely compatible with experimental research on aging
Steve Austad, Professor University of Idaho   (12 November 2001)
Jump to Comment Discussion 3 Introduction
By Joshua Mitteldorf   (7 November 2001)

Jump to Comments for citation
SAGE Viewpoint
Identifying Differentially Expressed Genes in cDNA Microarray Experiments Authors
Bengtsson et al. (19 December 2001) [Full text]
Letters
Jump to Comment Re: lowess normalization
Henrik Bengtsson   (12 October 2001)
Jump to Comment lowess normalization
Kristen Carlberg   (10 October 2001)
Jump to Comment Re: False discovery rates and ease of use
Henrik Bengtsson Mathematical Statistics, Lund University   (9 October 2001)
Jump to Comment False discovery rates and ease of use
Richard Miller, Biogerontologist University of Michigan   (2 October 2001)

Jump to Comments for citation
SAGE Viewpoint
Is Life-Span the Best Measure of Aging?
Crawford (19 December 2001) [Full text]
Letters
Jump to Comment Segmental aging
George Martin   (2 October 2001)
Jump to Comment Life span as gerontometric - an asymmetric problem
Rich Miller, Bioigerontologist University of Michigan   (2 October 2001)

Jump to Comments for citation
SAGE Viewpoint
SAGE KE: An Intellectual Home for Scientists Who Seek to Understand Why and How Organisms Age
Martin (3 October 2001) [Full text]
Letters
Jump to Comment Plaudits and comments on SAGE KE
Dave Teplow, Protein chemist/neurologist/logophile Brigham and Women's Hospital and Harvard Medical School   (4 October 2001)
Jump to Comment Re: basic science or clinical science?
George M Martin, Pathologist University of Washington   (3 October 2001)
Jump to Comment basic science or clinical science?
Monroe King, Allergist immunologist U of South Florida   (3 October 2001)

Jump to Comments for citation
SAGE Viewpoint
A SAGE KE Primer
Davenport et al. (3 October 2001) [Full text]
Letters
Jump to Comment Re: More historic archived info on Human genome?
Paul Anthony Mazzuca, researcher/ caretaker Mom and Dad   (18 October 2001)
Jump to Comment More historic archived info on Human genome?
Paul Anthony Mazzuca, researcher/caretaker Mom and Dad   (18 October 2001)

Jump to Comments for citation
SAGE Perspectives
Biomarkers of Aging
Miller (3 October 2001) [Abstract] [Full text]
Letters
Jump to Comment near term solutions consistently ignored: alt-711
Michael L Murray, geneticist Reliagene Technologies   (11 November 2001)

Jump to Comments for citation
SAGE Perspectives
Using Yeast to Discover the Fountain of Youth
Kaeberlein et al. (3 October 2001) [Abstract] [Full text]
Letters
Jump to Comment Re: Re: Re: The sir2 overexpression and knockout
Charles R Fred, E.E. none   (19 November 2001)
Jump to Comment Re: The sir2 overexpression and knockout
Matt Kaeberlein, Grad Student Guarente Lab - MIT   (29 October 2001)
Jump to Comment The sir2 overexpression and knockout
Florian Muller   (28 October 2001)
Jump to Comment Re: comments on Yeast and the Fountain of Youth
Matt Kaeberlein, Grad Student Guarente Lab - MIT   (25 October 2001)
Jump to Comment comments on Yeast and the Fountain of Youth
David Gershon, Professor Technion   (11 October 2001)

Jump to Comments for citation
SAGE Noteworthy This Week
Aiming for Ames: Test promises to ease breeding task
Strauss (3 October 2001) [Abstract]
Letters
Jump to Comment Untitled
Jim Harper, Postdoc University   (2 October 2001)

Jump to Comments for citation
SAGE Noteworthy This Week
Protecting the Heart: Will studying the young save the old?
Strauss (3 October 2001) [Abstract]
Letters
Jump to Comment Untitled
Kathy Rosewell   (2 October 2001)

Jump to Comments for citation
SAGE News Synthesis
Life Extension--Our Salvation or Our Ruin?
Barinaga (3 October 2001) [Abstract] [Full text]
Letters
Jump to Comment The unpleasant necessity to discuss timescales
Aubrey de Grey   (10 October 2001)
Jump to Comment A Sage Discussion
Greg Fahy, Scientist 21st Century Medicine   (3 October 2001)

Jump to Comments for citation
SAGE Aging in the Arts
Reverse Living
Unknown (3 October 2001) [Full text]
Letters
Jump to Comment author
walter bortz, md stanford   (18 November 2001)

Jump to Comments for citation
Evolution
A test of evolutionary theories of aging
Hughes et al. (29 October 2002) [Abstract] [Full text]
Letters
Jump to Comment Comment on Recent Hughes et al. Paper
Daniel Promislow   (28 October 2002)

Jump to Comments for 701
Mild hypercholesterolemia is an early risk factor for the development of Alzheimer...
MA Pappolla, TK Bryant-Thomas, D Herbert, J Pacheco, M Fabra Garcia, M Manjon, X Girones, TL Henry, E Matsubara, D Zambon, B Wolozin, M Sano, FF Cruz-Sanchez, LJ Thal, SS Petanceska, and LM Refolo
Neurology 2003; 61: 199-205 [Abstract]
Letters
Jump to Comment Cholesterol and Alzheimer's: is amyloid beta a cause or consequence of the disease?
Alexei R. Koudinov, neuroscientist and editor Russian Academy Med Sciences; Neurobiology of Lipids   (10 August 2003)

Jump to Comments for 701
RecBCD enzyme is a bipolar DNA helicase.
MS Dillingham, M Spies, and SC Kowalczykowski
Nature 2003; 423: 893-7 [Abstract]
Letters
Jump to Comment Two heads are better than one!
Nancy Maizels   (2 July 2003)

Jump to Comments for 701
Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease.
C Hock, U Konietzko, JR Streffer, J Tracy, A Signorell, B Muller-Tillmanns, U Lemke, K Henke, E Moritz, E Garcia, MA Wollmer, D Umbricht, DJ de Quervain, M Hofmann, A Maddalena, A Papassotiropoulos, and RM Nitsch
Neuron 2003; 38: 547-54 [Abstract]
Letters
Jump to Comment Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure?
Alexei R. Koudinov, neuroscientist and editor Russian Academy of Medical Sciences; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100, Israel   (29 May 2003)

Jump to Comments for 701
Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of...
T Sunderland, G Linker, N Mirza, KT Putnam, DL Friedman, LH Kimmel, J Bergeson, GJ Manetti, M Zimmermann, B Tang, JJ Bartko, and RM Cohen
JAMA 2003; 289: 2094-103 [Abstract]
Letters
Jump to Comment Amyloid beta and Alzheimer's disease: an endpoint relation?
Alexei R. Koudinov, neuroscientist and editor Russian Acad Med Sci, Moscow Russia; Neurobiol Lipids   (13 July 2003)

Jump to Comments for citation
JOURNAL OF GERONTOLOGY: BIOLOGICAL SCIENCES
Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period
Walford et al. (1 June 2002) [Abstract] [Full text]
Letters
Jump to Comment Untitled
Steven Austad University of Idaho   (25 June 2002)
Jump to Comment Comment on Walford J. Gerontol (2002) paper
Richard M. Miller   (17 June 2002)

Jump to Comments for citation
Articles
Increased T cell reactivity to amyloid ß protein in older humans and patients with Alzheimer disease
Monsonego et al. (1 August 2003) [Abstract] [Full text]
Letters
Jump to Comment Amyloid beta road show
Alexei R. Koudinov, neuroscientist and editor Russian Academy Med Sciences, Neurobiology of Lipids   (13 August 2003)

 

Text of Posted E-Letters

reports
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Kayed et al. (18 April 2003) [Abstract] [Full text]
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Alzheimer amyloid beta oligomers vs lipoprotein Ab ($)
1 May 2003
Alexei R. Koudinov,
neuroscientist and editor
Russian Academy of Medical Sciences; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100, Israel

The recent impressive article on conformational antibodies to amyloid oligomers (Science 18 April, p. 486, also see SAGE KE) reminded me of a paper that came out a decade ago in Science on catalytic antibodies that mimic the conformation of an enzymatic reaction transition state [1]. Both papers illustrated the magnificent potential for antibody technology. With respect to the amyloid oligomer antibodies, however, there is an important consideration to bear in mind.

For a decade we have known that Alzheimer's (AD) amyloid-beta protein (Abeta) exists normally as a soluble, molecule and is associated in blood and CSF with high density lipoproteins (HDL) [detailed in 2].

Lipoproteins provide the proper thermodynamic environment for Abeta, which shares with other apolipoproteins the unique structural property of amphipathicity [2]. In the absence of lipids, such molecules easily cross- and self- aggregate and undergo oligomerization. Some also form amyloid fibrils, structures that are present in separate types of human amyloidosis (for ex., apoA-I, serum amyloid A). Previous reports have indicated that natural Abeta does not cross link with other apoliporoteins in normal cerebrospinal fluid (CSF) high density lipoproteins (HDL), but does crosslink with HDL apolipoproteins in CSF samples from Alzheimer's patients [2]. The AD condition thus may represent a pathological alteration of the lipoprotein structural integrity in a way that breaks monomeric Abeta-to-lipid interaction and favors the interaction of Abeta-to-apolipoprotein (shown for ApoE and ApoJ) [2] or Abeta-to-Abeta, which creates the oligomers that are the subject of the Science study (18 April, p. 486).

Of major importance for this report, in our view, is the potent inhibition by lipoproteins of the neural toxicity of Abeta [3, 4, 5]. Such inhibition of Abeta toxicity by lipoproteins was shown in SH-SY5Y cells [3]. These same cells were used in the Science study under different experimental conditions to prove Abeta oligomer toxicity; the effect of lipoproteins on oligomer toxicity was not tested in this report.

We also think that introducing a control of specificity (perhaps by pre-adsorbing anti-oligomer antibodies with Abeta oligomers) in an immunofluorescent staining of Alzheimer's brain tissue would add confidence that the structures detected are indeed Abeta oligomers. This is especially important, because the micellar Abeta used for production of the anti-oligomer antibodies may mimic the conformation of lipid-bound Abeta (and of other membrane-bound proteins [6]), which was similarly shown to have distinct immunoreactivity [7].

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org

Footnote: This 300 word letter was first submitted to Science magazine (online submission no. 30545, April 21, 2003; rejected on May 1, 2003).

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience Guidelines for Responsible Conduct Regarding Scientific Communication. Discussed herein Science report (18 April, p. 486) and earlier Science viewpoint article on oligomeric Ab by Dennis J Selkoe (25 Oct 2002, p. 789) lack appropriate competing interest declaration. Such interests are disclosed in Forbes magazine and in Science (Corrections and clarifications. Science 27 Sept 2002, 297: 2209), respectively. For further details please see my Open letter to Public Citizen's Health Research Group on Alzheimer's disease research (SAGE KE, 21 Feb 2003).

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:

1. Shuster AM, Gololobov GV, Kvashuk OA, Bogomolova AE, Smirnov IV, Gabibov AG. DNA hydrolyzing autoantibodies. Science 256: 665-7 (1992) [ PubMed ].

2. Koudinov AR, Berezov TT, Koudinova NV. The levels of soluble Ab in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. 314: 115-118 (2001) [ PubMed ][ Author Related Articles and Scientific Correspondence ].

3. Cedazo-Minguez A, Huttinger M, Cowburn RF. Beta-VLDL protects against A beta(1-42) and apoE toxicity in human SH-SY5Y neuroblastoma cells. NeuroReport 12: 201-206 (2001) [ PubMed ].

4. Farhangrazi ZS, Ying H, Bu G, Dugan LL, Fagan AM, Choi DW, Holtzman DM. High density lipoprotein decreases beta-amyloid toxicity in cortical cell culture. NeuroReport 8: 1127-1130 (1997) [ PubMed ].

5. Koldamova RP, Lefterov IM, Lefterova MI, Lazo JS. Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits Abeta aggregation and toxicity. Biochemistry. 40: 3553-3560 (2001) [ PubMed ].

6. Soreghan B, Pike C, Kayed R, Tian W, Milton S, Cotman C, Glabe CG. The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties. Neuromolecular Med. 1: 81-94 (2002) [ PubMed ].

7. Yanagisawa K, McLaurin J, Michikawa M, Chakrabartty A, Ihara Y. Amyloid beta-protein (Abeta) associated with lipid molecules: immunoreactivity distinct from that of soluble Abeta. FEBS Lett. 420: 43-46 (1997) [ PubMed ].

SAGE Perspectives
SENS and the Polarization of Aging-Related Research
Gray and Bürkle (5 April 2006) [Abstract] [Full text]
SENS and the Polarization of Aging-Related Research
Shunned cadres - a clarification
21 April 2006
Rich Miller,
Biogerontologist

Friday, April 21, 2006

Dear Dr. Gray and Dr. B�rkle:

I enjoyed your article in SAGE-KE about the recent SENS-II conference, which gave a nice overview of the meeting and the areas of controversy around Aubrey�s ideas and activities.

As one of the authors of the EMBO Reports article, I thought I ought to respond to your speculation about an area of apparent ambiguity. You write:

[quotation] Positing that the SENS agenda is 'so far from plausible that it commands no respect at all within the informed scientific community,' these authors wish to 'dissociate themselves from the cadre of those impressed by de Grey's ideas in their present state.' This statement is both forceful and ambiguous. It can be read as the relatively benign wish to be placed in a nonoverlapping circle on the Venn diagram of who believes what in aging-related research, or it can be read as a more sinister threat of shunning the apostates. If the authors intended the latter, what are the requirements for admission into the shunned cadre? It could not be attendance at one SENS conference, for some of the signatories have attended. Would attendance at both suffice? Further, is it not possible to express interest in or contribute to some of the scientific objectives of SENS without being judged a SENS acolyte? [end quotation]

I am very sorry that the article may have left the misimpression of its cosignators as sinister and threatening bullies, the kind of people who take attendance at meetings and make lists of evil-doers destined to be confined to some scientific Guantanamo, where they are denied access to their copies of Rejuvenation Research, and from which much-needed shipments of liquid nitrogen and telomerase are diverted to other purposes. It was intended, as you speculated, to express a fully benign wish, inviting comrades to see the light and step into the part of the Venn diagram where people support aging research, do some of it themselves, go to any conferences they want to attend, and talk to and be friendly with anyone they wish, but are careful to try to distinguish fact from speculation, and speculation from fantasy.

I don�t see any need to define a shunned cadre, with or without admission requirements. Nearly all of the scientific objectives on the SENS menu are interesting, and people working on them are likely to make discoveries of great importance. But when colleagues, like Aubrey, feel a need to exaggerate the speed with which biogerontology will produce practical advances, or exaggerate the likelihood that old people can be converted into spanking new ones, I think this is in general bad for society and harmful to the scientific enterprise. I think it�s important for scientists to do their part to help administrators, journalists, and interested laypersons distinguish strategy from wish-fulfillment, and critical thought from advertising. Your SAGE-KE article is, in my view anyway, a fine example of how to approach this kind of knotty issue.

Rich Miller

SENS and the Polarization of Aging-Related Research
SENS's detractors should not intimidate aging-related scientists
13 April 2006
Aubrey D.N.J. de Grey,
Research Scientist
University of Cambridge

Gray and Buerkle's commentary [1] on SENS's evaluation by scientists is most welcome, not only for what it gets right but also for the serious factual errors that it contains. These errors are probably widespread in the biogerontology community, because they result from misleading statements that have been made, both in print and off the record, by others. I am therefore grateful to Gray and Buerkle for giving me this opportunity to correct those errors.

First, I have never remotely suggested that participation in my SENS conferences constitutes tacit agreement with me as to SENS's feasibility. (It is not clear from Gray and Buerkle's text whether they think I have been doing this, but a reader might easily form such an impression.) That would be a ludicrous inference, given that I am on abundant record as knowing full well how radical SENS is, and also that I have repeatedly taken a decidedly more established approach when I seek to determine whether other scientists support a component of SENS, namely, first to expose them to it for a whole day and then to ask them to co-author a paper on it [2-5]. (It is notable that only one of my co-authors on any of these papers signed Warner et al.'s recent denunciation of SENS [6]; one can draw one's own conclusions from the fact that her name was mis-spelled in the list of authors.) There is no reason whatever for a SENS conference participant to be concerned that his or her opinions regarding SENS will be misrepresented either by me or by any other SENS advocate. If some of my more energetic detractors seek to make such a link, it is those detractors who should be condemned for impugning the reputations of eminent scientists in an attempt to marginalise me, and if anything, scientists should resist that intimidation by attending SENS conferences in greater numbers than ever. Perhaps this was Gray and Buerkle's point, but if so, I fear that some readers might have missed it.

The converse point also merits a slight correction. While attendance at the SENS conferences means nothing about support for SENS, it does confer at least circumstantial authority to opine on the matters that were presented there. Gray and Buerkle point out that some of the 28 signatories to the recent denunciation of SENS [6] attended, but this may give an exaggerated impression; in fact, and as I pointed out in my response to Warner et al. [7], not one of them attended SENS 2 and only five attended its altogether less SENS-centric predecessor, IABG10, in 2003 (when SENS had less notoriety).

Gray and Buerkle quote the "Position Statement on Human Aging" [8] out of context: the comment there about humans living forever referred to literally that, i.e. no death from age-independent causes either. My agreement with that paper's main thrust, the present non-existence of any true life- extending products, is the reason I endorsed it. I and some other endorsers lobbied the authors vigorously to remove assertions about the probability of such products arriving within our lifetime, but without success; but that was not the paper's main theme, so I judged that an endorsement was still appropriate.

I am perplexed at Gray and Buerkle's implication that I have in some way been tarred with the Hwang brush as a result of his participation in a conference that I organised. If I have, all I can say is that I am in very good company.

Finally, I must take sharp exception to Gray and Buerkle's assessment of the SENS Challenge. When scientists disagree as to the plausibility of a hypothesis or the feasibility of an experiment, they generally do so in cautious terms, and in such circumstances it is entirely proper to be able to express one's view without being required to justify it rigorously. When they express their opinion of a colleague's work using words like "fantasy" and "pretence," however, the object of their derision is entitled to ask for an explanation - and, if years pass with no explanation being forthcoming, to bring his critics' reticence to public notice. Gray and Buerkle say that the terms of the Challenge mean that it allows me to taunt my detractors "baselessly," but that is not true at all: rather, the conclusion that a submission must persuade a panel of independent experts of in order to win (namely, that SENS is so absurd that it should not be dignified with learned debate) is precisely the view that my critics have been expressing off the record for some years and more recently (though only after my strong criticism of their public silence [9]) in print. It is public knowledge [10] that Technology Review began the search for a mainstream gerontologist's demolition of SENS entirely on its own initiative, as a result of having been given a strongly negative but non- specific evaluation of it by experts whom they consulted during 2004, and that the SENS Challenge was begun (with input from the Methuselah Foundation, yes) only after a number of experts declined to write such an article and Technology Review began to wonder whether they had been misled. Thus, Gray and Buerkle are absolutely wrong to suggest that "[t]he TR Challenge serves no purpose but to attract attention to Aubrey de Grey and the increasingly bitter dispute with his detractors" -- rather, it serves the wholly legitimate purpose of testing the hypothesis that my detractors have formed their negative opinions of SENS without the attention to its details that their audience will tend to presume that they have paid. If Gray and Buerkle know of a better way to distinguish that hypothesis from the competing one, advanced by my detractors, that no such commentary has been written simply because experts are too busy to ridicule something so ridiculous, they should suggest it.

In conclusion, my high media profile results from the coherence of the SENS agenda and the incoherence of the criticism that SENS has so far received [7]. This is demonstrated by the fact that SENS has been accorded an almost uniformly positive media treatment (Technology Review's articles in February 2005 being almost the only exception). I am not a soundbite expert, nor am I fond of them. The SENS conferences will thus continue to bring together the world's best science in areas that I consider relevant to extreme life extension, and participants will continue to be able to make up their own minds as to whether that science adds up to a viable approach to greatly postponing aging.

1. D. A. Gray, A. Buerkle, SENS and the Polarization of Aging-Related Research. Sci. Aging Knowl. Environ. 2006 (7), pe8 (2006).

2. de Grey ADNJ, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJM, Stock G. Time to talk SENS: critiquing the immutability of human aging. Annals NY Acad Sci 2002; 959:452-462.

3. de Grey ADNJ, Baynes JW, Berd D, Heward CB, Pawelec G, Stock G. Is human aging still mysterious enough to be left only to scientists? BioEssays 2002; 24(7):667-676.

4. de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers. Annals NY Acad Sci 2004; 1019:147-170.

5. de Grey ADNJ, Alvarez PJJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age- related diseases. Ageing Res Rev 2005; 4(3):315-338.

6. H. Warner, J. Anderson, S. Austad, E. Bergamini, D. Bredesen, R. Butler, B. A. Carnes, B. F. Clark, V. Cristofalo, J. Faulkner et al., Science fact and the SENS agenda. What can we reasonably expect from ageing research? EMBO Rep. 6, 1006-1008 (2005).

7. de Grey ADNJ. Like it or not, life extension research extends beyond biogerontology. EMBO Reports 2005; 6(11):1000.

8. S. J. Olshansky, L. Hayflick, B. A. Carnes, Position statement on human aging. J. Gerontol. A Biol. Sci. Med. Sci. 57, B292-B297 (2002).

9. de Grey ADNJ. Resistance to debate on how to postpone ageing is delaying progress and costing lives. EMBO Rep 2005; 6(S1):S49-S53.

10. Pontin J. Cynthia Kenyon declines. http://www.technologyreview.com/ Blogs/wtr_15021,291,p1.html (2005).

SAGE News Focus
Loose Chromosomes Sink Cells
Leslie (21 December 2005) [Abstract] [Full text]
Loose Chromosomes Sink Cells
Lamins an chromatin organization during aging
4 January 2006
Giuseppe Novelli,
Lab director
Tor Vergata University

The work described by M. Leslie it is interesting since further supports a key role of lamins in chromatin organization and mechanical integrity of the nucleus, crucial to maintain cell and tissue integrity during aging and confirm previous reports on the involvement of heterochromatin disorganization in laminopathies. In particular, I would like to stress that we have documented the presence of nuclear envelope and chromatin alterations in primary cultured fibroblasts from patients carrying a missense mutation in the LMNA gene (R527H) resulting in MADA phenotype, the first progeroid syndrome caused by a lamin mutation. We demonstrated accumulation of prelamin A, altered stability of heterochromatin proteins HP1alpha and Me9H3 and a redistribution of the nuclear envelope protein LBR in MADA cells. These cells showed evident alterations of the nuclear periphery at the interface between peripheral heterochromatin and the nuclear envelope. Interestingly, the degree of morphological alterations correlated with patient�s age (see Filesi et al., 2005 fo details). We suggest that because the regulation of gene expression requires a fine compartmentalisation which is supported by chromatin architecture, mutations in different lamin sites could generate alteration in gene transcription. Our results provide further support to the hypothesis of a regulatory pathway connecting, in sequence, cellular morphometry/nuclear architecture/chromatin structure/gene expression.

SAGE News Focus
Shortchanged by Sir2
Leslie (23 November 2005) [Abstract] [Full text]
Shortchanged by Sir2
We buy it
6 December 2005
Valter Longo,
Professor
USC,
Paola Fabrizio

I think Leonard Guarente is referring to an earlier version of our Cell paper. In our published study the controls lacking the mating- type gene are included in virtually all the experiments. Although we cannot exclude a pro-aging role for HMRa, our results indicate that the effect of Sir2 in blocking stress resistance and extreme longevity extension is largely independent of the expression of both mating-type genes. We agree with Leonard Guarente that we have shown that the lack of SIR2 deacetylase activity must be combined with mutations that reduce Sch9 or adenylate cyclase activity to cause extreme life span extension. However, the deletion of SIR2 also extends the chronological life span of calorie restricted S. cerevisiae, which is the opposite of what previously shown by the Guarente lab in replicative life span studies but in agreement with results from the Kennedy lab. Notably, we have performed our experiments in 3 different genetic backgrounds.

SAGE Reviews
Mitochondrial Genetics of Aging: Intergenomic Conflict Resolution
Rand (9 November 2005) [Abstract] [Full text]
Mitochondrial Genetics of Aging: Intergenomic Conflict Resolution
secure transit of funds
16 November 2005
Anthony Davies,
research
none,
none

I cannot comment, the SAGE KE 'pay per article' does not display a 'padlock' symbol alongside the 'internet zone' symbol, indicating that my Visa debit card details are not secure in transit.

I would be happy to pay the fee, and very much wish to study this work, I understand it's importance, however there must be some way of obtaining this article without the possibility of breaching my Visa security.

It's puzzling, as the other 'Science' subsciption sites do display the padlock symbol. It may just be an oversight.

Yours sincerely, Anthony Davies

SAGE Tidbit of the Week
5 October 2005 Tidbit
(5 October 2005) [Full text]
5 October 2005 Tidbit
For openers, how about...
5 October 2005
Anonymous

Bob Hope ? George Burns ?

SAGE Neurodegenerative Disease Case Studies
Brain Tumor-Associated Dementia
Noble et al. (24 August 2005) [Abstract] [Full text]
Brain Tumor-Associated Dementia
�Cognitive impairment associated with malignancy.�
20 September 2005
Slawomir Michalak,
neurologist
Department of Neurochemistry and Neuropathology University of Medical Sciences, Poznan, Poland

In the 309 volume of Science (26th August 2005) the SAGE KE section published a paper by James McC. Noble et al. entitled �Brain Tumor- Associated Dementia�. For general readers this paper needs some comments regarding the case, its clinical interpretation as well as some statements made by the authors.

First of all, the title of the paper is misleading. The authors describe the impairment of cognitive functions, however the neuropsychological examination performed was incomplete and not consistent with the diagnosis of dementia. Mini-Mental State Examination showed decreased score (27/30), nevertheless it is not sufficient to diagnose dementia (MMSE score should be in such cases below 24). MMSE is the screening test and for the diagnosis of dementia, particularly if the authors like to differentiate it with Alzheimer disease there are more precise neuropsychological tests, to mention ADAS-cog (Alzheimer�s Disease Assessment Scale) as the most adequate one. DSM IV criteria for the diagnosis of Alzheimer disease exclude brain tumor as pathology involved in etiology for dementia of such a kind (1).

The patient clinically manifests frontal lobe syndrome (change in behavior and personality, social withdrawal). Among the symptoms indicating the lesion of frontal lobe, depression is very frequent, so there exists a strong clinical need for psychological examination of the mood of the patient. The differentiation of depression � associated cognitive impairment and dementia requires further testing (e.g. Cornell scale).

Cognitive function impairment in the course of malignancy, which is an important clinical question, needs to be recognized at two levels. One is dementia associated with brain tumor (besides neoplastic brain tumor, the abscess, subdural hematoma, arterio-venous malformation should be also taken into consideration), and the other is cognitive dysfunction as paraneoplastic syndrome (remote effect of cancer). Paraneoplastic limbic encephalitis (2,3,4) may manifest with dementia as it is also the case for subacute cerebellar degeneration (5,6). The last two syndromes of high clinical importance, however not common, should be taken into consideration during differential diagnosis of dementia.

The authors have undertaken an important question of cognitive impairment associated with malignancy, however the case presented is not consistent with contemporary diagnostic standards and clinical knowledge and needs elucidation as a local effect of tumor, manifesting more likely as frontal lobe syndrome rather than dementia. 1. American Psychiatric Association, Desk Reference to

Diagnostic Criteria from DSM-IV. DC:APA, Washington

(1994). 2. S. Alamowitch, F. Graus, M.Uchuya, R.Ren�,

E. Bescansa, J. Y. Delattre, Limbic encephalitis and

small cell lung cancer. Clinical and immunological

features. Brain 120, 923�928 (1997). 3.R.Voltz, S. H. Gultekin, M.R. Rosenfeld, E.Gerstner,

J.Eichen, J.B. Posner, J. Dalmau, A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med 340,1788-95 (1999). 4. J. Kassubek, E.U. Nitzsche, F.D. Juengling,

C.H.L�cking, Limbic Encephalitis Investigated by 18FDG-

PET and 3D MRI. J Neuroimaging 11, 55�59 (2001). 5. N.E.Anderson, J.B.Posner, J.J.Sidtis, J.R.Moeller,

S.C.Strother, V.Dhawan, A.Rottenberg, The metabolic

anatomy of paraneoplastic cerebellar degeneration. Ann

Neurol 23(6), 533-40 (1988).

6. J.B.Posner, Paraneoplastic syndromes in Neurology in

Clinical Practice, Bradley W.G. et al. (eds),

Butterworth-Heinemann, Boston, 1299-1307 (2000).

Slawomir Michalak

Department of Neurochemistry and Neuropathology

Chair of Neurology, University of Medical Sciences,

Poznan, Poland

SAGE Other Resources
Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
SantaCruz et al. (20 July 2005) [Abstract]
Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function
Comment on SantaCruz et al.
25 July 2005
Dietmar R. Thal

SantaCruz et al. describe a transgenic mouse model that expresses a repressible human tau variant that is linked to hereditary tauopathies. Repression of tau is in these mice regulated by a tretracycline-operon responsive element. These mice develop neuronal tau changes in a similar sequence as seen in Alzheimer�s disease (AD) starting with �Pre-tangles� and finally resulting into severe neuronal loss. When repressing tau by application of doxycyclin tau levels decreased and progression of neuronal loss stopped. However, the progression of tangle formation continued after repression of tau. The authors conclude that tau may be capable of inducing neuronal death in a neurofibrillary tangle independent pathway and that neurofibrillary tangles not necessarily induce neurodegeneration.

This study points out that the generation of neurofibrillary tangles once initiated does not require overexpression of abnormal tau variants. Moreover, neurofibrillary changes can be present without altering neuronal function for a long time. This result is in line with neuropathological studies that have shown that neuronal function of tangle-bearing neurons prevails for years before tangle formation leads to neuronal cell death (1 -3). Neurofibrillary independent mechanisms of cell death in tau transgenic mice can be discussed as a similar mechanism as in AD. However, several arguments may favor alternative explanations for this type of neurodegeneration in this mouse model. 1) In the tau transgenic mice a mutant form of tau is overexpressed that leads to fronto-temporal dementia but not to AD. 2) Tau overexpression in neuronal cells blocks the intracellular kinesin-dependent transport (4) and may, in so doing, lead to neurodegeneration. 3) In AD the amyloid beta-protein is present and it has an additional neurotoxic capacity that can alternatively explain neurodegeneration of non-tangle-bearing neurons.

1. C. Bancher, C. Brunner, H. Lassmann, H. Budka, K. Jellinger, G. Wiche, F. Seitelberger, I. Grundke-Iqbal, K. Iqbal, H. M. Wisniewski, Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res 477, 90 (Jan 16, 1989). 2. E. Braak, H. Braak, E. M. Mandelkow, A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87, 554 (1994). 3. I. Sassin, C. Schultz, D. R. Thal, U. Rub, K. Arai, E. Braak, H. Braak, Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert. Acta Neuropathol (Berl) 100, 259 (2000). 4. A. Ebneth, R. Godemann, K. Stamer, S. Illenberger, B. Trinczek, E. Mandelkow, Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J Cell Biol 143, 777 (Nov 2, 1998).

SAGE News Focus
Not Like the Other
Davenport (13 July 2005) [Abstract] [Full text]
Not Like the Other
AGING CHROMOSOMES
14 July 2005
ROBERT BELLIVEAU,
PATHOLOGIST

The article on twins chromosomes reminded me of the fact that paternal age correlates with achondroplasia in the offspring. It would seem logical that is a similar reflection of a change in the DNA of the father over time.

Robert Belliveau

SAGE Perspectives
The Longevity Gender Gap: Are Telomeres the Explanation?
Aviv et al. (8 June 2005) [Abstract] [Full text]
The Longevity Gender Gap: Are Telomeres the Explanation?
Abstract of the 'telomere-gender gap' paper, published in January 2004
20 June 2005
Reinhard Stindl,
Research Scientist
Medical University of Vienna

The classic explanation that women outlive men solely due to hormonal and lifestyle differences, does not withstand a critical analysis. In developed countries, the average gap in life expectancy between the sexes is 7 years. It has widened over the last decades, despite the trend of women copying the 'unhealthy' lifestyle of men. Estrogen levels in postmenopausal women are virtually identical to estrogen levels in males and can hardly explain the discrepancy. Furthermore, testosterone got its bad reputation from one study on mentally retarded men, which has to be interpreted with caution. However, sexual size dimorphism with men being the larger sex in conjunction with the limited replication potential of human somatic cells might account for higher mortality rates in males, especially at old age. The hypothesis, as presented here, is based on the well-known concept of a cellular mitotic clock, which was discovered by Leonard Hayflick almost half a century ago. The underlying counting mechanism, namely the gradual erosion of chromosome ends (telomeres) due to the end replication problem of linear DNA molecules, was first described by Alexey Olovnikov in 1971 and with minor modifications has become a widely accepted paradigm. In a recent Lancet study, an inverse correlation between mean telomere length and mortality in people has been found. In this and two other studies, it was confirmed that males do have shorter telomeres than females at the same age. This is almost certainly a consequence of men being usually taller than women, although nobody has done an investigation yet. Clearly, a larger body requires more cell doublings, especially due to the ongoing regeneration of tissues over a lifetime. Accordingly, the replicative history of male cells might be longer than that of female cells, resulting in the exhaustion of the regeneration potential and the early onset of age-associated diseases predominantly in large-bodied males. Inherited telomere length variation between unrelated individuals might have obscured a clear correlation between body height and mortality, leading to conflicting results in some studies. Finally, I propose that the secular height increase over the last decades, of about 2.5 cm per generation in the western world, has to be blamed for the widening of the gender gap in life expectancy. Med Hypotheses. 2004;62(1):151-4. Tying it all together: telomeres, sexual size dimorphism and the gender gap in life expectancy.
The Longevity Gender Gap: Are Telomeres the Explanation?
Tying it all together: telomeres, sexual size dimorphism and the gender gap in life expectancy
10 June 2005
Reinhard Stindl,
Research Scientist
Medical University of Vienna, Austria

The authors provide just two explanations for the phenomenon of longer telomeres in women, oestrogen and somatic cell selection. In January 2004 I published a third one, namely sexual size dimorphism.

Stindl R. Tying it all together: telomeres, sexual size dimorphism and the gender gap in life expectancy. Med Hypotheses 2004;62(1):151-154.

www.stindl.info

Reinhard Stindl

SAGE News Focus
Mopping Up Nuclear Waste
Leslie (30 March 2005) [Abstract] [Full text]
Mopping Up Nuclear Waste
Prior Evidence of Nuclear Proteasome Activity
8 July 2005
David Goldfarb
University of Rochester

I wish to provide additional background on this work by mentioning a 1999 paper by Ullrich et al. (Proc. Natl. Acad. Sci. USA 96, 6223-6228). There is abundant evidence that the proteasome controls cell function by degrading regulatory proteins in both the nucleus and cytoplasm. This study concludes that the proteasome also functions as a protein quality control mechanism to rid nuclei of damaged proteins. By treating K562 leukemia cells with hydrogen peroxide, the authors conclude that oxidized histones are degraded in the nucleus by the proteasome. The authors correlate the increased degradation of oxidized histones following hydrogen peroxide treatment with an induction of proteasome activity. A link between the proteasome and the degradation of oxidized histones was shown using a specific proteasome inhibitor (lactacystin). The induction of proteasome activity following hydrogen peroxide treatment was dependent on poly-ADP ribosylation activity, which is catalyzed by the enzyme PARP. These experiments suggest the possibility that nuclear protein quality control may be regulated by PARP. This interesting hypothesis warrants more attention. A direct link between the ADP-ribosylation of the proteasome and the selective degradation of damaged proteins would be a significant advance. In conclusion, this study shows that oxidized histones are likely degraded by the proteasome, and that the degradation probably occurs in the nucleus. These early results support the conclusion that mammalian nuclei contain a system for targeting damaged proteins for degradation by the proteasome.

The paper by Gardner, Nelson, and Gottschling is the first to reveal an ubiquitin-conjugating enzyme (San1p) and ubiquitin-protein ligases (Ubc1p and Ubc3p/Cdc34p) that target the ubiquitination of specific damaged (mutant) proteins for proteasome-dependent degradation in nuclei. A number of neurodegenerative diseases are associated with the accumulation of nuclear protein aggregates. These aggregates can be ubiquitinated and some have also been shown to associate with proteasomes. The description of the San1p-mediated targeting pathway is a significant advance in the quality of proof that damaged proteins are degraded in nuclei, and provides opportunities to identify similar factors that function in mammalian nuclei and, perhaps, in human diseases.

SAGE Reviews
Microarrays as a Tool to Investigate the Biology of Aging: A Retrospective and a Look to the Future
Melov and Hubbard (20 October 2004) [Abstract] [Full text]
Microarrays as a Tool to Investigate the Biology of Aging: A Retrospective and a...
Test
31 January 2005
Anonymous

Test

SAGE News Focus
Racing Against Time
Chen (23 June 2004) [Abstract] [Full text]
Racing Against Time
Excellent Article
1 July 2004
Anna E. Shethar

To Whom It May Concern: I just wanted to say taht the article that you wrote is extremely inspiring and I think it is one of the best articles I have ever read. Thank you for your time.

Yours Respectfully, Anna Shethar

SAGE Tidbit of the Week
26 May 2004 Tidbit
(26 May 2004) [Full text]
26 May 2004 Tidbit
Re: tidbit
26 May 2004
Gregory A. Petsko,
Professor
Brandeis University

As an ex-classics major, I was delighted to see the quote from Homer as this week's tidbit: "The gods envy us because we are mortal." There is, however, another viewpoint. Shakespeare says ( in King Lear): "As flies to wanton boys are we to the gods. They kill us for sport."

SAGE Reviews
Androgens, ApoE, and Alzheimer's Disease
Raber (17 March 2004) [Abstract] [Full text]
Androgens, ApoE, and Alzheimer's Disease
Discussion at Alz Forum
26 May 2004
Kelly LaMarco

A discussion on this Review has taken place at the Alzheimer Research Forum Web site. To access this resource, click here.

SAGE Noteworthy This Week
Protective Parents
Davenport (5 March 2003) [Abstract] [Full text]
Protective Parents
Daughters from old mothers
13 March 2003
James Ryley
UTHSC

Dear Dr. Davenport,

In your article you state that "Daughters have a normal life span even when they come from older moms..." However, Kennedy et al. (1994) states the opposite. And, the current paper which you are discussing, "Asymmetric Inheritance of Oxidatively Damaged Proteins During Cytokinesis," comes to the conclusion that asymmetry of oxidized proteins does break down with increasing mother cell age (which would support Kennedy's findings, if you believe that oxidized proteins are causative to the aging process and not just correlated).

Perhaps I have missed something in the literature refuting Kennedy. Could you explain the basis for the statement that daughters of old mothers have a normal lifespan?

Sincerely, James Ryley

SAGE News Synthesis
Dietary Drawbacks
Hopkin (26 February 2003) [Abstract] [Full text]
Dietary Drawbacks
We're not getting older, just fatter
10 March 2003
Michael G Kurilla, MD-PhD

Aging and life extension research has been stuck in the CR mode for quite some time without delving into an real understanding of the biochemical, hormonal, and physiological bases for the effects of CR. In addition, human beings are biased with notions of aging that are being overturned almost daily by an advancing baby boom generation that is providing fresh data to shed some light on antiquated concepts. For example, how long ago was tooth loss considered an inevitable consequence of aging, but now is regarded as a chronic disease process (periodonditis) with an infectious component?

One does not need to look too hard to identify other 'dogmas' of aging that are being revised in light of new data. Most textbooks cite reductions in growth hormone (GH) as a consequence of aging, yet recent evidence suggest that increases in visceral adipose tissue and fasting insulin levels are better predictors, independent of age. In addition, glucose homeostasis has long been thought to deteriorate with aging, yet again, visceral adipose tissue mass appears more signficant. The basis for the former mistake is simple, adipose tissue mass and visceral adipose tissue mass typically accumulates with aging. Unless one can indentify all the relevant variables and statistically control for them, age may appear predictive, but only because it is highly correlated with increasing overall adiposity.

Adipose tissue is gradually coming into its own as an important tissue. Again, older textbooks simply relegated adipose tissue to an energy storage site. Today, adipose tissue is regarded as a true endocrine organ involved with many systems that clearly can derange and contribute to chronic diseases that shorten lifespan. In addition, current imaging techniques are now able to quantitate different adipose tissue stores. Discrete anatomical sites of adipose tissue accumulation manifest different effects, such as leptin secretion by subcutaneous adipose tissue and insulin resistance with increasing visceral adipose tissue.

Thus, we can view CR as a means to restrict adipose tissue and promote leaness, rather than limit energy expenditure. In this light, perhaps rather than an overall caloric reduction, a carbohydrate limitation would demonstrate better glucose homeostasis and prevent the host of chronic disease where hyperinsulinemia is believed to play a role (hypertension, dyslipidemias, diabetes, etc.). In fact, the recent work by Donald Layman on altered protein to carbohydrate ratios during dietary restriction provides for a sound physiological basis with regards to carbohydrate restriction effects on glucose homeostasis. Exercise in this light can also be seen as contributory since exercise would serve to create another source for carbohydrate utilization.

The question to address is if better control and regulation of body composition would have an impact on overall homeostasis by balancing adipose - lean tissue masses. CR under this model would simply be a crude, but somewhat effective means to achieve this, but not necessarily the optimal manner. Obviously, most of the drawbacks to CR mentioned in the article would not be an issue in an otherwise lean animal. Unfortunately, with ever increasing numbers of overweight and obese adults in the world, there may not be sufficient controls to evaluate alternatives.

Dietary Drawbacks
CR does not increase longevity in Drosophila
27 February 2003
Eric Le Bourg,
scientist
CNRS, University Paul-sabatier, Toulouse, France

This review states that "unlike Drosophila melanogaster", CR does not work in the fly Ceratitis capitata. The first part of this sentence is not true, because CR does not seem to work in Dm (David, van Herrewege & Fouillet, Exp. Geront. 6: 249-257, 1971; Le Bourg & M�dioni, Age & Nutr. 2: 90-94, 1991). "Positive" effects in mated females (Chippindale et al., J. Evol. Biol. 6: 71-193, 1993) were due to a strongly decreased egg-laying (egg-laying decreases longevity in Dm), but no increased longevity has been observed in virgin females, which lay less than mated ones (Le Bourg & Minois, J. Geront. Biol. Sci. 51A: B280-B283, 1996). In males, the only study of both mated and virgin males (Le Bourg & Minois, 1996) did not report any positive effect of CR. Clancy et al (Science 296: 319, 2002) reported that increasing the concentration of food decreases longevity in virgin females (-10 days) while decreasing concentration increases longevity (+5 days), and we can hope that they will next publish results on both sexes with virgin and mated flies in order to clarify the issue. For the time being, the cautious conclusion is that CR does not increase longevity in Dm.

SAGE Noteworthy This Week
Lasting Without Fasting
Davenport (5 February 2003) [Abstract] [Full text]
Lasting Without Fasting
Life Extension
6 March 2003
Edward J. Masoro

�Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue� (Jan.24, pp. 572-574) by Bluher et al. is an exciting report. It is the first demonstration that maximal length of life of a mammalian population can be significantly increased by a manipulation that does not decrease caloric intake on a per animal basis. Moreover, the fact that the life extension is due to the knockout of the insulin receptor specifically in the adipose tissue (FIRKO mouse) provides a potentially valuable new approach to the study of mammalian aging.

However, the authors also infer that their findings indicate that the increased life span in both the FIRKO mouse and in calorie-restricted rats and mice is due to the decrease in body fat. This inference dismisses the findings in the literature that strongly indicate that extended longevity induced by caloric restriction is not due to a reduction in fat mass. In calorie-restricted rats, for example, fat mass and life span are positively correlated; in ad libitum-fed rats, there is no correlation (1). Also, calorie-restricted ob/ob mice (48% body fat) have a life span that is longer than the ad libitum-fed, highly congenic C57BL/6J mice (22% body fat), and as long a life span as the very lean (13% body fat) calorie-restricted C57BL/6J mice (2). Even in the case of the FIRKO mouse, the reduction in fat mass may well be adventitious in regard to the increased longevity. Indeed, Bluher et al. point out that the insulin receptor loss-of-function and the metabolic sequelae thereof may be responsible for the increase in life span. In summary, the author�s implication that reduction of fat mass plays a causal role in life extension in calorie-restricted rodents is not in accord with currently available facts.

EDWARD J. MASORO
Department of Physiology, University of Texas Health Science Center, San Antonio, TX 78229, USA

References
1. H. A. Bertrand et al., J. Gerontol. 35, 827 (1980).
2. D. E. Harrison et al., Proc. Natl. Acad. Sci. USA 81, 1836 (1984).

SAGE Other Resources
{alpha}-Synuclein Locus Triplication Causes Parkinson's Disease
Singleton et al. (5 November 2003) [Abstract]
{alpha}-Synuclein Locus Triplication Causes Parkinson's Disease
Familial DLB Cracked
5 November 2003
John Q. Trojanowski

This duplication of genetic material that includes the alpha-synuclein gene solves the mystery of what causes familial DLB in the Iowa kindred, and the exciting findings should prompt others to look for similar explanations of other familial neurodegenerative diseases in which linkage has been established to a gene, but no mutation has been found in the putative disease gene. Examples of this include familial frontotemporal dementia kindreds with linkage to chromosome 17 where the tau gene resides, but wherein no tau gene mutations have been discovered. Thus, by analogy with Down syndrome (DS), excess copies of the region of chromosome 4 that contains the wild-type alpha-synuclein gene also can lead to neurodegeneration. This is the first instance of familial alpha-synucleinopathy or other neurodegenerative disease that is shown to be caused by duplication of the gene encoding the wild-type protein rather than a mutation leading to the generation of a mutant protein. Presumably, in the Iowa DLB kindred and DS, it is the overproduction of the wild-type protein throughout the life span, rather than production of a mutant form of the protein, that results in the onset of disease, although the exact mechanisms by which disease onset occurs in DS and familial DLB remain to be elucidated. However, we do know that in familial DLB and in related diseases caused by mutations in the alpha-synuclein gene, the underlying neuropathology is an abundance of cortical Lewy bodies and Lewy neurites formed by filamentous aggregates of alpha-synuclein that impair neuronal function, viability and survival over the life span.

SAGE Noteworthy This Week
JNK-ing Cellular Poisons
Leslie (5 November 2003) [Abstract] [Full text]
JNK-ing Cellular Poisons
Response by the Authors
11 November 2003
Dirk Bohmann,
Prof. of Genetics
U. of Rochester,
Heinrich Jasper, Meng C. Wang

We are pleased that SAGE decided to highlight our paper with a commentary. M. Leslie accurately describes the first part of the paper in which we discuss evidence for JNK signals protecting fruitflies against oxidative stress. We feel, however, that the second main conclusion of the paper (i.e. that JNK signaling can extend lifespan) is dismissed based on a misrepresentation or misunderstanding of the experimental evidence. Citing John Tower from USC, Leslie implies that the conclusion that JNK signaling extends lifespan is wrong and derived by flawed experimentation. The text indicates that in the critical experiments we compared an inbred strain to a cross between two genetically diverse strains and that therefore the results that we see are due to alleviation of inbreeding depression (i.e. heterosis; hybrid strains being fitter than inbred strains) and not to changes in JNK signaling. This is not how the experiment was done and thus the implication is quite erroneous. Specifically,

- by backcrossing the puc strain 10 times into its parental background (ry506), we have generated isogenic controls where no heterosis effects can be expected.

- the rescue of the observed longevity of puc heterozygotes by crossing in the hypomorphic JNKK mutation hep1 demonstrates that JNK signaling is required for increased lifespan in puc heterozygotes

- the lifespan extension observed in flies that over-express Hep in neurons (compared to the same strain without Hep) independently demonstrates that higher JNK signaling levels extend lifespan.

These experiments are clearly described in the publication (see Fig. 3 in Wang et al., 2003), and, in our opinion (and that of the reviewers and editors of Developmental Cell), support the drawn conclusions.

We are concerned about the way our data were represented and hope that this clarification will help the reader to appreciate the relevance of the findings not only for stress defense but also for the biology of aging.

SAGE Noteworthy This Week
Evolutionary Oxymoron
Beckman (6 August 2003) [Full text]
Evolutionary Oxymoron
Related work just published
6 August 2003
Mary Beckman

A related paper was published this week. Using slightly different sequencing techniques, Ethylin Jabs of Johns Hopkins University in Baltimore, Maryland, and colleagues determined how much higher the Apert syndrome birth rate was than the sperm mutation rate. Unlike Wilkie's group, Jabs's group found a slightly higher mutation rate in younger men who had fathered Apert children compared with men of the same age who hadn't fathered Apert children. The inconsistency between the two reports could "depend on the methodology," says Jabs.
--Mary Beckman
R. L. Glaser et al., The paternal-age effect in Apert syndrome is due, in part, to the increased frequency of mutations in sperm. Am. J. Hum. Genet., 31 July 2003 [e-pub ahead of print]. [Abstract] [Full Text]

SAGE News Focus
Mindful of Metal
Leslie (26 March 2003) [Abstract] [Full text]
Mindful of Metal
Putting the Al in METAL
1 April 2003
Chris Exley,
moribund scientist
Keele University

I am always pleased to find that the scientific community are prepared to adopt new thinking and to judge such hypotheses on their scientific credentials (merit). This has been done for the research of Ashley Bush and colleagues who have, rightly, pioneered the idea of a role for copper and zinc in the aetiology of Alzheimer's disease.

However, such hypotheses should not be built through the discrediting of other equally viable hypotheses. For some reason, Bush and colleagues seem to like nothing more than to pooh-pooh the possible role of aluminium in AD as if their own hypothesis involving zinc and copper actually requires the Al hypothesis to be discredited ? This has all the makings of great politics but very poor science. It is equally disappointing that Science has taken up Bush's cudgel in ridiculing the Al hypothesis. Flippant remarks in this weeks hard copy of Science advertising the Sage article refer to aluminium pots and pans being 'exonerated' of causing AD !

I am not aware of pots and pans being aetiological factors in AD though I am aware of a burgeoning amount of high quality scientific research which does, if nothing else, describe the link between Al and AD (see; Exley C (Editor) (2001) Aluminium and Alzheimer�s Disease: The Science that Describes the Link. Elsevier Science, Amsterdam, The Netherlands. 441p.)

Whilst Bush and colleagues actively ignore the question of Al this ignorance should not be a substitute for science and it certainly should not be perpetuated in the pages of Science.

Unlike Bush and colleagues I do not know whether Al is a contributory factor in AD. However, if needs be I can tell a story with at least the scientific content of that told by Bush and colleagues for copper and zinc which does implicate Al in AD and does not require me to ridicule any possible role of any other aetiological factor such as copper and zinc.

This is the difference between doing science and pandering to the whims and fashions of science. Bush elucidates upon the opposition that he initially faced in implicating copper and zinc in AD. He even goes so far as to blame the Al hypothesis for this opposition ! and yet he is quite prepared to make life equally difficult for researchers who would like to test the Al hypothesis scientifically.

In the UK, the comments by individuals such as Bush have now made it impossible to do research on Al and AD. There is not a single grant of any substance from any funding body to any individual anywhere to do research in this area. This is in spite of the fact that the scientific case for an involvement of Al in AD is stronger today than at any other previous time.

Spurious comments made by irresponsible people cannot be avoided. What can be avoided is that such comments are not carried and thus perpetuated (without any form of peer review) by the leading scientific journals of the day.

I hope that Bush and colleagues continue to strongly support their notion of a role for copper and zinc in AD. They should do, but what they should not be allowed to do is to build their argument on their ignorance of another equally viable and equally scientifically sound field, the role of aluminium in Alzheimer's disease.

SAGE Perspectives
Vitamin B1 Blocks Damage Caused by Hyperglycemia
Obrenovich and Monnier (12 March 2003) [Abstract] [Full text]
Vitamin B1 Blocks Damage Caused by Hyperglycemia
Vitamin B1 to the Rescue of the Glucose-Mitochondrial Axis of Evil in Diabetes?
25 August 2003
Vincent M. Monnier
Case Western Reserve University,
Mark E. Obrenovich

A key question in the pathogenesis of diabetic complications is whether it is possible to uncouple pathways of metabolic and glycemic damage, i.e. glycation, oxidation and activation of gene expression, from hyperglycemia with the help of an orally absorbable agent. Recent evidence suggests Vitamin B1 and its lipid soluble homologue may do just that.

Focusing on diabetic nephropathy as an endpoint, Thornalley and colleagues, at the University of Essex (United Kingdom), demonstrated that treatment of diabetic rats with high doses of thiamine (vitamin B1), or its lipid soluble derivative benfotiamine, can normalize abnormal cell signaling and molecular tissue damage by oxidation and reactive carbonyl compounds of the Maillard/glycation reaction, thus preventing early diabetic nephropathy (1). The central mechanism of action of Vitamin B1 appears to involve the activation of transketolase, an enzyme that is at the branching point between glycolysis and the reductive pentose pathway.

The authors first showed in vitro that supplementation of thiamine to human mesangial cells incubated under hyperglycemic conditions lead to a decrease in the formation of intracellular advanced glycation endproducts (AGEs) derived from methylglyoxal. They also demonstrated that the vitamin decreased protein kinase C (PKC) activation. In vivo, high-dose vitamin B1 and benfotiamine also increased transketolase activity in renal glomeruli, inhibited the diabetes-induced hyperfiltration, decreased activity of PKC, decreased glycation and oxidation of glomerular protein without a change in elevated plasma glucose concentration and glycated HbA1c, in the diabetic state. High-dose thiamine prevented microalbuminuria and proteinuria. Interestingly, thiamine dosing increased glomerular transketolase activity but only in diabetic rats.

The impairment of transketolase activity in experimental diabetes appears to be in part linked to renal loss of thiamine due to excessive diuresis and decreased thiamine resorption. By supplementing the vitamin, the reductive pentosephosphate pathway is activated, leading thereby to decreased accumulation of glycolytic intermediates which pile up upstream of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Partial inactivation of the latter is thought to be mediated by superoxide originating from mitochondrial. According to Brownlee�s �Unifying Hypothesis of Glycemic Damage� in diabetes (2), impairment of this enzyme is critical for the activation of multiple forms of glycemic damage in diabetes, i.e. increased methyglyoxal AGE formation, activation of PKC via de novo diacylglycerol synthesis, activation of the �hexosamine pathway� which mediates increased transcription of various genes, and activation of aldose reductase.

These results of Thornalley�s group are complementary to the recent study of Hammes et al. (3), which demonstrated beneficial effects of benfotiamine on diabetic retinopathy, as recently reported in SAGE-KE (4). Taken together, these data are extremely interesting to scientists engaged in understanding the role of the glucose-insulin axis in aging and the role of dietary restriction in prolonging life span, because transketolase was found to be the enzyme whose mRNA was most highly upregulated in muscle from dietary restricted mice (5). GAPDH activity was indeed found decreased in certain muscles of aging rats (6). Thus, not only are clinical studies on the effects of high dose vitamin B1 in diabetic complications urgently needed, but studies on the life span enhancing effects of thiamine and benfotiamine in aging animals are eagerly awaited. These compounds now hold promise for preventing the development and progression of diabetic complications without acting on glycemia itself.

1. R. Babaei-Jadidi, N. Karachalias, N. Ahmed, S. Battah, P. J. Thornalley, Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 52, 2110-2120 (2003).

2. M. Brownlee, Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813-820 (2001).

3. H. P. Hammes, X. Du, D. Edelstein, et al., Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat. Med. 9, 294-299 (2003).

4. M. E. Obrenovich, V. M. Monnier, Vitamin B1 blocks damage caused by hyperglycemia. Sci. SAGE KE 2003, pe6 (12 March 2003).

5. T. A. Zainal, T. D. Oberley, D. B. Allison, L. I. Szweda, R. Weindruch, Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J. 14, 1825-1836 (2000).

6. D. A. Lowe, H. Degens, K. D. Chen, S. E. Always, Glyceraldehyde-3-phosphate dehydrogenase varies with age in glycolytic muscles of rats. J. Gerontol. A Biol. Sci. Med. Sci. 55, B160-B164 (2000).

SAGE Viewpoint
Help Wanted: Physiologists for Research on Aging
Martin (6 March 2002) [Full text]
Help Wanted: Physiologists for Research on Aging
Response to Walter Bortz
20 March 2002
George M Martin,
Pathologist
University of Washington

I am most grateful to Walter Bortz for making me aware of the type of integrative physiology exemplified by the work of Ewald R. Weibel and colleagues (The concept of symmorphosis: A testable hypothesis of structure-function relationship. PNAS 88:10357, 1991). The name Weibel immediately brought to mind the famous Weibull distribution, which engineers use to estimate time to failure and which therefore is of interest to gerontologists. But Professor Ewald Weibel is Swiss, whereas Wallodi Weibull (1887-1979) was Swedish (http://www.bathtubsoftware.com/weibull_bio.PDF).

Help Wanted: Physiologists for Research on Aging
Homeodynamics
19 March 2002
Walter Bortz,
MD
Stanford Med

Dear DR. Martin, Kudos on content and policy implications of your submission. The case is building for a systems approach to aging and frailty. A helpful corollary constuct is " Symmorphosis" PNAS 1991, 88:10357-10361.

Walter Bortz

SAGE Noteworthy This Week
Random Acts
Davenport (18 December 2002) [Abstract] [Full text]
Random Acts
Thank you
21 December 2002
Koji Itahana,
posdoc
MD Anderson Cancer Center

Dear Dr. Davenport,

Thank you very much for your nice comment at SAGE-KE. Since our paper may be complicated for the people who are not familiar with the cellular senescence, I appreciate the way you introduced our paper.

Sincerely yours,

Koji Itahana

SAGE Noteworthy This Week
Other Noteworthy Papers This Week
(4 December 2002) [Abstract] [Full text]
Other Noteworthy Papers This Week
psychosocial factors in aging
18 December 2002
soeharno honggokoesoemo,
physician
health care

Dear sir inequality in health, in diseases incidences, in mortality, mean there are inequality in aging, the lower one get in social-economic position the shorter one's life expectancy, or the faster one get older.

SAGE Noteworthy This Week
Strong Spirit, Weak Flesh
Beckman (30 October 2002) [Abstract]
Strong Spirit, Weak Flesh
Scoring paralysis as death?
30 October 2002
Matt Kaeberlein

It may seem silly, but if muscle cells selectively degrade and the nervous system stays intact, couldn't it be possible that what people have been calling "dead" worms aren't really dead at all - at least metabolically? Since the phenotype used to score a worm as "dead" in the life-span assay is lack of movement, perhaps muscle degradation causes people to score living worms that are paralyzed or partially paralyzed as dead. While it may not seem like this is an important distinction, we certainly wouldn't consider a paralyzed person to be dead. Is there any evidence that non-moving worms in a life-span assay are metabolically inactive?

SAGE Noteworthy This Week
Closing the Generation Gap
Beckman (25 September 2002) [Abstract]
Closing the Generation Gap
Is ATP2 really involved in aging?
26 September 2002
Matt Kaeberlein

After reading the paper by Lai et al., I can't help but wonder whether ATP2 is really relevant to the normal aging process in wild type yeast. The authors have most likely already thought about these issues and I'd be interested to hear their reasoning.

My first reason for questioning the validity of this mutant as a model for aging is the change in shape of the viability curves for atp2 mother and daughter cells grown at the restrictive temperature and transferred to the permissive temperature after 6 generations (Fig 2B). Unlike wild-type (Fig 2C), the mutants no longer show Gompertz-Makeham kinetics. The change in the shape of the curve can't simply be explained by a 6 generation shifting of the curves (the length of incubation at the restrictive temperature), as the slope is quite different from wild type. In fact, the mutant viability curves strongly suggest a large stochastic component to mortality that is not present in wild type cells. I would interpret this to suggest that some sort of unrepaired damage persists in atp2 cells after the switch back to 30C, which results in a fixed probability of death with each generation. When a high rate of stochastic death is combined with Gompertz-Makeham kinetics, the result is a curve very similar to those present in Fig 2B (McVey et al., 2001).

I am also forced to question the selection scheme for differentiating between a mutant that makes a "vital substance" and a true segregation mutant. First of all, I don�t think these are the only two possibilities. What about a mutant that results in some sort of persistent, unrepaired damage at the restrictive temperature? If the damage results in an increased probability of terminal arrest or cell lysis, you might expect to get a viability curve with a large stochastic component � which is exactly what the data show. I would predict that many clonal senescence or weak ts mutants would behave exactly the same way as this allele of ATP2. Was a control experiment performed on other ts clonal senescence mutants (hdf1 for example)?

I don't think it's necessarily true that a segregation-defective mutant would result in clonal senescence. In the case of rDNA circles, a mutation that results in no segregation bias should cause an increase in the steady-state level of ERCs (assuming negligible reintegration of ERCs into the rDNA array) in the population, but wouldn�t necessarily cause clonal senescence, due to dilution of the ERCs among mothers and daughters.

I also have a few questions that perhaps the authors would be willing to answer:

I may have missed it, but what is the life span of the atp2 mutant strain (CS16) when grown at 30C for the entire experiment? What does the viability curve look like? This seems like an important piece of information.

What is the explanation for the increase in ERCs in the ATP2 deletion mutant at 37C (Fig5)?

Why was the YPK9 strain background chosen for these experiments? If I remember correctly, this was the only strain out of 4 where petite mutants had an extended life span (Kirchman et al., 1999). Were these results verified in any other strain background? Given that YPK9 behaves differently from every other yeast strain tested for petite life span extension, this may be important information. It is stated in the paper that deletion of ATP2 results in clonal senescence in W303. Since it's pretty well established that ERCs are limiting for life span in W303 (Defossez et al., 1999, Kaeberlein et al., 1999, Sinclair et al., 1997), this also suggests to me that the clonal senescence phenotype of ATP2 mutants is unrelated to normal (wild-type) aging.

SAGE Classical Papers
The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis
Sapolsky et al. (25 September 2002) [Abstract]
The Neuroendocrinology of Stress and Aging: The Glucocorticoid Cascade Hypothesis
Need to investigate common biochemical link for stress related disorders
20 March 2006
Pradeep Shukla,
Research
UIC, Chicago

Finding was well correlated with aging in male subjects. After 9/11 another major public health concern is on post traumatic stress disorder (PTSD) which persist much longer and may induce aging, helplessness, depression and suicidal behavior. Serotonin, calcium and cAMP dependent kinases are well correlated with stress related disorders. There is need to investigate a common biochemical links for all stress related disorders and Its pharmacological interventions which might be more useful for society specially after war and incidence like 9/11.

SAGE Reviews
Subfield History: Caenorhabditis elegans as a System for Analysis of the Genetics of Aging
Johnson (28 August 2002) [Abstract] [Full text]
Subfield History: Caenorhabditis elegans as a System for Analysis of the Genetics...
kudos
16 October 2002
Anonymous

Nice piece!

SAGE Other Resources
Protecting the Brain While Killing Pain?
Helmuth (28 August 2002) [Abstract]
Protecting the Brain While Killing Pain?
Open letter to Public Citizen's Health Research Group on Alzheimer's disease research
21 February 2003
Alexei R. Koudinov,
neuroscientist and editor
Russian Academy of Medical Sciences; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100, Israel



Dear Colleagues,

I read with great interest two recent News focus stories by Laura Helmuth on a developing spectrum of Alzheimer's disease therapeutic approaches (Science 23 Aug. 2002, p. 1260, p. 1262 ; SAGE KE 28 Aug. 2002, or9, or10 ). One report by L. Helmuth is entitled "Protecting the brain while killing the pain?" and discusses possible prevention of Alzheimer's disease by NSAIDS, a nonsteroidal anti-inflammatory drugs.

"An NIA-funded prevention trial that aims to determine whether NSAIDs do indeed protect against Alzheimer's disease" was the subject of the recent letter of the Public Citizen's Health Research Group addressed to Health and Human Services Secretary Tommy Thompson [1].

The group letter urged "the NIA to immediately stop this unethical trial" and particularly stated [1]:

"In the current amyloid hypothesis, the inflammatory reaction is a secondary response, not the primary event.[19] NSAID effect is now thought to be due to an effect on gamma-secretase, not to an anti-inflammatory reaction. Although some NSAIDs inhibit the gamma-secretase, the two chosen for the ADAPT trial (naproxen and celecoxib) have never been shown to have such activity. They showed no lowering of amyloid levels in model systems[20], no benefit in a population-based cohort study,[21] nor any benefit in a recent clinical trial of AD that used naproxen and rofecoxib, another COX-2 inhibitor.[22]"

"The NSAID hypothesis, however, has turned out to be more complicated than this, and it is now felt that the inflammatory response is secondary to amyloid deposition and not the cause of it.[7]"

"Even if there was a basis when the ADAPT trial was first proposed for believing that naproxen or celecoxib might have worked in preventing AD, there is no longer a scientific basis to support that hypothesis..."

Public Citizen claimed that "there is no longer any biological basis for this [ADAPT] trial". Their preference was the amyloid hypothesis. The major support for the amyloid hypothesis in the group letter come from the Science magazine review article by Hardy and Selkoe [2].

What the letter missed is the fact that the key reference for the article by Hardy and Selkoe [2] is red flaged by Science magazine erratum [3]. This is because of the competing financial interest by Dennis J. Selkoe, MD. Dr. Selkoe is not only a Harvard Professor and a recent member of the governmental NIH National Advisory Council on Aging [4]. He also serves as a director for Elan, a company, involved in developing amyloid hypothesis based Alzheimer's therapy. Moreover, Howard L. Weiner, M.D., a co-inventor and co-author of Dr. Selkoe nasal amyloid vaccine [5] serves as a member of the Federal Drug Administration (FDA) Peripheral and Central Nervous System Drugs Advisory Committee [6].

The most eye-catching is the following journalist message [7, also see Ref. 8]:

"Elan director and world renowned authority on Alzheimer's disease, Dennis Selkoe MD, sold 2,800 Elan shares for $120,000 indicating a price of $43.65 in "early December 2001" the company has stated to The Sunday Business Post. This was shortly before the pharmaceutical company announced poor results from its major Alzheimer's tests on January 18, 2002. The share price subsequently collapsed to a recent price of around $2. Selkoe also sold 20,000 shares for just over $1 million on February 6, 2001. Elan directors' sales, in all, came to over $43.5 million in February 2001..." [7].

Moreover, shortly after D. Selkoe sale of his Elan shares in February 2001 [7] American Academy of Neurology (AAN) Potamkin Prize Selection committee (chaired since 1999 by Dennis Selkoe) awarded the Prize 2001 to Elan scientist Dr. Dale Schenk [9, 10]. As CNN stated, "The Potamkin -- seen by some as a potential precursor to Nobel consideration -- is a peer award, and the AAN has some 17,500 neurology professionals in its membership" [10].

In my previous letter to BMJ [8] I alarmed the public about Dr. Selkoe conflict and expressed the necessity for the attention to D.Selkoe case and disciplinary actions by the societies' ethics committees and editorial boards of journals where he published or served as board member without acknowledging his competing financial interest.

The letter by Public Citizen (signed by Elizabeth Barbehenn, PhD, Peter Lurie, MD, MPH, and Sidney M. Wolfe, MD) states that the authors "have done a search of the medical literature on AD and NSAID use and have discovered that the drugs being used in this study are not only unlikely to be effective but have the potential to inflict harm on these otherwise healthy individuals with little if any possibility of benefit." The letter claims that this is due to "no lowering of amyloid levels" [1]. I have two concerns in this regard.

First, I am puzzled why the group did not discover several contributions that question amyloid hypothesis [see Ref. 11 for bibliography details, also see Ref. 12].

Second, although I do not agree with the focus of the letter discussion, I believe that the group statement is not fully supported by the currently available literature. To support the claim Public Citizen cites journal article by Koo, Golde and colleagues [the group letter citation #1], and two meeting reports by the research teams of Paul Aisen and Monique Breteler presented as Alzheimer Forum (AlzForum) news reports, not the primary literature [Public Citizen letter citations #21 and #22, respectively]. AlzForum is an important subject information source [13] that, however, commits no public responsibility to disclose competing financial interests of its' commentators and authors [14].

The reaction of Dr. Aisen on the Public Citizen letter is the following: "I would describe the letter as an inflammatory tirade rather than a scientific argument. While it does review some relevant scientific observations, the discussion is one-sided. I do not agree with the conclusions and recommendations of the letter" [15]. Monique Breteler adds: "I profoundly disagree with the interpretation of the existing evidence and the scientific argument in mentioned letter" [15].

The data of the other citation for a journal article [Public Citizen citation #1] were corrected in Science magazine two weeks after the publication of the letter [16], thus further invalidating the group argument. The later Science correction note stated that "the results of research by Edward Koo, Todd Golde, and colleagues were misrepresented... As the article noted, all experiments showing an effect of nonsteroid anti-inflammatory drugs on beta amyloid production used very high doses" [16]. The above is also present in Dr. Koo testimony to AlzForum [15]. Dr. Koo states that "many of Sidney Wolfe's accusations of ADAPT are unfounded". Dr. Golde further charges Public Citizen of being "irresponsible". He adds: "I am disturbed by the actions of Public Citizen in that they use our data to support their argument, but never once spoke to either Eddie [Koo] or myself for our take on it" [15].

Three weeks after the publication of the group letter [1] the story was communicated to Alzheimer's research community and openly commented on by twelve scientists at the AlzForum web site [17]. Public Citizen's Health Research Group letter also raised significant media interest [18] but did not become the voice of "many researchers in the field of AD research", as no one shared the letter enthusiasm [17].

Oppositely, many scientists now disagree with the group favorite amyloid hypothesis [11, 12], the fact that is erased in their letter to HHS Secretary Tommy Thompson. Below is the citation of a director of a respected institute [19]:

"...I agree whole heartily with your letter to Science concerning Alzheimer's disease and the amyloid beta protein. It is amazing how this field has been led down the "amyloid hypothesis" trail to the exclusion of other viable hypotheses. If you don't go along with the amyloid dogma, you have difficulty publishing and extreme difficulty being funded. The anti-intellectual, anti-science mentality displayed by many in this field has slowed progress to a crawl. This is a shame."

Another world class neuroscientist added with regard to amyloid-based Alzheimer's immuno-therapeutics [20]:

"...the disaster that many of us predicted would result came to pass. I thought common sense would then prevail and this whole idea would be abandoned. But as you have pointed out, the dogma is too strong to be dropped, and now it is the application, and not a faulty theory that is being blamed. More AD cases are in danger..."

The above statements call for a task force of safeguarding equal opportunities for different hypotheses of Alzheimer's research [21] and investigating the factual view that amyloid hypothesis is about business [7, 8, also see Ref. 22].

In light of the above I would like to know who stands behind ill-advised confidence in amyloid hypothesis of Sidney M. Wolfe and the Public Citizen's Health Research Group.

Alzheimer's research field reserves to know this. I and my colleagues look forward hearing from Dr. Wolfe.

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience Guidelines for Responsible Conduct Regarding Scientific Communication.

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:

1. Barbehenn E, Lurie P, Wolfe SM. Letter to HHS Secretary Tommy Thompson that raises ethical concerns about the �Alzheimer�s Disease Anti-Inflammatory Prevention Trial� (ADAPT) (HRG Publication #1637) Public Citizen publications. Public Citizen web site. (4 Sept 2002) [ FullText ].

2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297, 353-6 (19 July 2002) [ PubMed ] Erratum in: Science. 297, 2209 (27 Sep 2002) [ FullText ].

3. Corrections and clarifications. Science. 297, 2209 (27 Sept 2002) [ FullText ].

4. Attachment A: Membership Roster. National Advisory Council on Aging. National Institute on Aging. National Institute of Health web site. Summary Minutes for [ The Eighty-Sixth Meeting May 21-22, 2002 ] [ The Eighty-Fifth Meeting Jan 29-30, 2002 ] [ The Eighty-Fourth Meeting Sept 24-25, 2001 ]. Make a note of Dr. Selkoe citation at the Comments from Retiring Members.

5. Cromie WJ. Alzheimer's vaccine looks promising. Harvard Gazette. (18 Jan 2001) [ FullText ]; Weiner HL, Selkoe DJ. Inflammation and therapeutic vaccination in CNS diseases. Nature. 420, 879-84 (19-26 Dec 2002) [ PubMed ].

6. Members: Howard L. Weiner, M.D. FDA Roster of the Peripheral and Central Nervous System Drugs Advisory Committee. FDA web site. (last viewed 16 Feb 2003) [ FullText ].

7. Crowley D. Elan Alzheimer's expert in pre-slump share sale. The Sunday Business Post. (18 Aug 2002) [ FullText ]; Crowley D. Elan directors sold $43.5 million of shares before disastrous downturn. The Sunday Business Post. (11 Aug 2002) [ FullText ]; Elan Corporation PLC. Schedule 11. Notification of interests of directors and related persons. Dennis Selkoe [ 13 Feb 2001 ][ 18 Dec 2001 ].

8. Ready T. Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health. The Boston Phoenix (29 April 1999) [ FullText ]; Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal (30 Nov 1998) [ FullText ]. Also see: Koudinov AR. Ethical conundrums: an Alzheimer's case. British Medical Journal (12 Sept 2002) [ FullText ].

9. Rosenberg RN. The Potamkin Prize for Pick's, Alzheimer's Disease and Related Disorders. AAN web site. (last viewed 16 Feb 2003) [ Original .DOC file ] [ HTML cached version ].

10. Dale Schenk: Alzheimer's researcher. 'The synthesis of a hundred little ideas'. CNN web site. (23 July 2001) [ FullText ].

11. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ online. (1 Dec 2002) [ FullText ]; Koudinov AR, Smith MA, Perry G, Koudinova NV. Alzheimer's disease and amyloid beta protein. Science online. (14 June 2002) [ FullText ].

12. McGeer and McGeer. Is there a future for vaccination as a treatment for Alzheimer's disease? Neurobiol Aging. In Press article, available online 3 December 2002 [ Abstract ]; Obrenovich ME, et al. Amyloid-beta: a (life) preserver for the brain. Neurobiol Aging. 23, 1097-9 (Nov-Dec 2002) [ PubMed ]; Smith MA, et al. Ill-fated amyloid-beta vaccine. J Neurosci Res. 69, 285 (1 Aug 2002) [ PubMed ]; Atwood CS, et al. Cerebral Hemorrhage and Amyloid-beta. Science. 299, 1014 (14 Feb 2003) [ FullText ]; Koudinov AR, Koudinova NV. Alzheimer�s anti-amyloid vaccination and statins: two approaches, one dogma. The time for change. British Med J. (20 March 2002) [ FullText ][ Related Correspondence ]; Koudinov AR, et al. Alzheimer's disease and amyloid beta protein: dogma is bad for science. 32nd Soc Neurosci Meeting, Program #21.11 (2002) [ Abstract and further reading ].

13. Site visit: Alzheimer's Roundtable. Science. 286, 1643 (1999) [ FullText ].

14. E.mail response by June Kinoshita, AlzForum Executive Editor, (23 Sept 2002) on A. Koudinov e.mail letter of 20 Sept 2002. Also see: Guidelines: Responsible Conduct Regarding Scientific Communication. Society for Neuroscience web site. (2002) [ Preface ] [ Acrobat .PDF FullText ]; Smith R. Beyond conflict of interest. British Medical Journal. 317, 291-2 (1998) [ FullText ].

15. Comments by Scientists. Trials and Tribulations: Does ADAPT Have to Adapt? AlzForum web site. (4 Oct 2002) [ Comment by Paul Aisen ] [ Letter by Monique Breteler ] [ Comment by Eddie Koo ] [ Q&A with Todd Golde ].

16. Corrections and clarifications. Science. 297, 1996 (20 Sept 2002) [ FullText ].

17. Trials and Tribulations: Does ADAPT Have to Adapt? AlzForum web site. (Updated 4 Oct 2002) [ FullText ].

18. Mitchell S. Govt urged to halt Alzheimer's study. The Washington Times. (4 Sept 2002) [ FullText ].

19. E.mail response to A.Koudinov by a senior scientist (1 Jul 2002) regarding Koudinov et al. Science dEbate letter of 14 June 2002.

20. E.mail response to A.Koudinov by a senior scientist (19 Aug 2002) regarding Sunday Business Post article of 18 Aug 2002.

21. Current hypotheses. AlzForum web site. (last updated 5 Dec 2002) [ FullText ].

22. Major Commitment to Develop Immunological Approaches for Alzheimer's Disease. Senior Journal (3 July 2001) [ FullText ]; Mindset and NYU collaborate on Alzheimer's vaccine. Pharmalicensing (26 Jul 2002) [ FullText ].

SAGE Reviews
Innate Immunity, Local Inflammation, and Degenerative Disease
McGeer and McGeer (24 July 2002) [Abstract] [Full text]
Innate Immunity, Local Inflammation, and Degenerative Disease
Untitled
2 August 2002
Vijendra K Singh,
Associate Professor
Utah State University

Dear Sir, This is a very good review article, covering mainly the potential role of complement system in AD. Quite candidly, however, the authors did not discuss anything about other important immune factors that may also be involved in the immunopathogenesis of this disease. Specifically, I am referring to the autoimmune hypothesis that involves brain-specific autoantibodies, circulating cytokines, and activated T cells. Abnormalities of all of these autoimmune factors in AD has been very well documented in the literature (see not eblow) but the authors of this review article did not describe and/or discuss their involvement in AD.

Note: Reports by Singh, VK and co-workers will give ample literature pertinent to this topic.

Once again, its a very good review article but deficient in some important aspects of AD immunopathology.

Thank you very much,

SAGE Viewpoint
No Truth to the Fountain of Youth
Olshansky et al. (15 December 2004) [Abstract] [Full text]
No Truth to the Fountain of Youth
Down With Dogma
13 April 2004
Richard L. Bowen,
Research Scientist
Voyager Pharmaceutical Corp.

First let me state that I have an inherent conflict of interest by the fact that the company that I am employed by is focused on developing treatments targeting a bio-molecular pathway we believe is responsible for aging. I also want to state that I fully support and agree with the author�s effort to discourage the use of ineffective and potentially dangerous anti-aging therapies. However, I disagree with several assertions made in the paper. Foremost is your definition of aging as being impaired cellular function which is attributed to the accumulation of random damage�. If the damage is random then why do certain tissues exhibit senescence while other tissues are yet to complete development? Hearing acuity begins to deteriorate at about age 10 in the human. In addition, the free radical theory of aging is far from universally accepted and fails to explain numerous observations such as the extremely rapid aging seen in many semelparous species.

I would also suggest statements such as, �it impossible for us to possess genes that are specifically designed to cause physiological decline with age or to control how long we live� are not prudent. This is especially true since the authors go on to state, �Genes or genetic variants that prove detrimental in the postreproductive part of the life span can become commonplace, but only if they participate in important processes early on.� Indeed, this represents a separate theory of aging known as the antagonistic pleiotrophic theory.

If it turns out that the antagonistic pleiotrophic theory is correct then the author�s statement that, �The lack of a specific genetic program for aging and death means that there are no quick fixes that will permit us to treat aging as if it were a disease,� may be false. Just because there is no consensus as to which specific genetic program might be responsible for aging does not mean that such a program does not exist. This is similar to statements such as �we now know that cancer is a multifactorial disease and there will never be a single cure for cancer.� While it may be true, it could also be true that there is a single cure for cancer which is yet to be identified. Current research in C. elegans and drosophila appear to be close to identifying such a genetic program for aging.

It is true that there is no therapy proven to halt or slow the aging process in humans to date and that current anti-aging therapies are likely ineffective and possibly harmful. However, dogmatic thinking only serves to insure that a truly effective anti-aging therapy will never be found.

SAGE News Focus
Give Me Liberty or Give Me an Early Death
Leslie (3 July 2002) [Abstract] [Full text]
Give Me Liberty or Give Me an Early Death
Free mice! Free!
10 July 2002
Richard A. Miller,
researcher
University of Michigan

Two comments and a minor correction to offer:

1. I think my friend Dave Harrison may have his causal arrow on backwards. Just because the wild mice are light does not mean that they have low appetite and are for that reason similar to food restricted rodents. Short people, Shetland ponies, and miniature dogs, for example, aren't small because they hate to eat; on the contrary, they don't eat much because their small size means they don't need lots of calories to maintain body temperature. Wild-trapped mice placed into laboratory housing do indeed gain weight, though they do not reach the same weight as lab-derived stocks. They are shorter than lab-type mice, too, and do not show the exceptional leanness characteristic of food-restricted mice.

2. The article suggests that these mice are too tough to handle, but I think the author is being too pessimistic about this. It does take an experienced animal technician a week or so to learn to out-wit these mice, and an ability to tape over escape routes and use live traps to recapture the occasional escapee are requirements, but the mice are less scary than Stitch. We are hoping that other labs will want to use these mice for aging research, and would be glad to provide breeding stock to anyone who wants to use them for his/her research work. Free to good homes!

3. Minor point: the wild-derived mice are, at 4 months of age, about 55% of the weight of lab-type mice; the statement in the article that they are 75% smaller than ordinary mice isn't quite accurate.

Rich Miller

SAGE Viewpoint
Insulin-Like Growth Factor 1 and Mammalian Aging
Bartke (24 April 2002) [Full text]
Insulin-Like Growth Factor 1 and Mammalian Aging
Reply to the comments of Dr. Sonntag
27 May 2002
Andrzej Bartke

Studies performed by our group and by Flurkey and his colleagues resulted in demonstration that two spontaneous mutations in the mouse increase average and maximal life expectancy by 40 - 60 %. These mutations cause multiple endocrine defects including growth hormone/insulin-like growth factor 1 (GH/IGF-1) deficiency. Targeted disruption of GH receptor gene that causes GH resistance and consequently IGF-1 deficiency was shown by Coschigano and her colleagues to cause comparable extension of life span. These findings, their implications, and the putative mechanisms involved in life extension in these animals were briefly discussed in my recent opinion article prepared for SAGE KE. Dr. Sonntag raises an issue of the utility of these animals (referred to as �dwarf models� in his commentary) to study mechanism of aging and concludes that �transgenic animal models that disregard the developmental effects of GH and IGF-1 and the interactions of these hormones with other hormonal systems will not answer the critical questions in this field�. This conclusion is based on a number of specific arguments which, I believe, require some comments.

Secondary effects of deficiency of GH signaling on insulin levels, on the control of carbohydrate metabolism etc. as well as effects of IGF-1 deficiency on development are viewed by Dr. Sonntag as major limitations of these mouse models. We believe that all of these effects are expected from the actions of GH and IGF-1 that have been known for decades and represent potential and, in some cases, very likely MECHANISMS of actions of these mutations on aging and longevity. IGF-1 exerts a multitude of effects and the impact of mutations that alter circulating IGF-1 levels on longevity should probably not be expected to somehow �bypass� these effects. Also, a correction is needed: these long lived mouse mutants do not maintain normal body temperature and we suspect that reduction in body core temperature may represent one mechanism of delayed aging in these animals.

The suggestion of defects in cognitive development of Ames and Snell dwarf mice is consistent with known actions of thyroid hormones but surprisingly to us is not supported by data available to date from behavioral studies. Instead, old Ames dwarf mice outperformed their normal siblings in tests designed to measure learning and memory (Kinney et al, Hormones and Behavior 39: 277, 2001 and unpublished observations). An interesting footnote is offered by a report that in a human pedigree with mutation of the same gene which is mutated in the Ames dwarf mouse, the educational performance and employment history of the affected individuals argued against mental deficiency (Krzisnik et al. J. Endocr. Genet. 1: 9, 1999).

My statement that �there is no evidence that GH therapy ... has any effect on aging per se or life expectancy� is taken from a paragraph referring to GH therapy in the human. It was meant to refer specifically to these studies and I am sorry if this was not made clear in my article. I am not aware of any published studies which were designed to answer the question whether treatment with GH affects human aging or provided unequivocal evidence on this point. This issue and the controversy surrounding promotion of GH as an �anti-aging agent� was discussed previously by us and by others (Olshansky et al. Scientific American, June 2002, p 92) and key arguments in favor of this potential action of GH are clearly spelled out in my SAGE KE article.

I certainly agree that our interpretation of evidence available to date is speculative and that a direct proof of the importance of IGF-1 in the control of aging and longevity is yet to be obtained and this is stated clearly in the opening sentence of the last section of the SAGE KE article. However, I beg to differ from the conclusion that �hormone deficiency (in Ames dwarf, Snell dwarf and GHR-KO mice) MAY impact biological aging�. It seems to me that the magnitude of the extension of the average and the maximal life span, reduced collagen aging, preserved immune function, and results of behavioral testing leave little doubt that these mutations profoundly affect aging.

Before closing, I would like to point out that association of a constellation of phenotypic changes including reduced levels of insulin, glucose and IGF-1 as well as reduced body temperature, growth, and adult body size with delayed aging and prolonged longevity in mammals is not a new, strange or suspect concept. This association is long and firmly established by results of studies of caloric restriction (CR), including important studies in this area by Dr. Sonntag and his colleagues. Indeed, there are many reasons to believe that CR, hypopituitarism, and GH resistance delay aging and prolong life by similar (although not identical) mechanisms. The pathways involved probably converge on reduced generation of free oxygen radicals and reduced oxydative damage of macromolecules. Moreover, there is considerable evidence from studies in experimental animals and in the human that GH influences pancreatic islets, insulin release and sensitivity of target tissues to insulin action and therefore it may not be possible to dissociate effects of alterations in GH/IGF-1 axis from effects of altered insulin signaling. Possible importance of developmental effects in the determination (�programming�) of aging in mutant and KO mice is consistent not only with the effects of the somatotropic axis on growth and development but also with the observations in animals subjected to CR in which this intervention is more effective in prolonging life when started at an early age. Finally, involvement of alterations in IGF-1/insulin signaling in mediating the effect of longevity genes is already firmly established in invertebrates. We wholeheartedly agree that development of transgenic and knock out animals with alterations in hormonal signaling limited to a particular cell type or a particular stage of development will further clarify these fascinating physiological phenomena and the mechanisms involved.

Insulin-Like Growth Factor 1 and Mammalian Aging
WHAT DO DWARF MODELS REVEAL ABOUT MECHANISMS OF AGING
16 May 2002
William E. Sonntag,
Professor of Physiology
Wake Forest University School of Medicine,
Christy Carter and Melinda Ramsey

Introduction

The recent review on the role of growth hormone and IGF-1 on mammalian aging provides interesting insights into potential genetic manipulations that impact mammalian aging. Nevertheless, the review raises issues related to the interpretation of results using dwarf animal models, the relationship of results using dwarf models to studies of growth hormone and IGF-1 replacement and the future direction of studies related to aging research. Each of these issues merit additional comments.

There is general agreement that there has been remarkable progress in understanding the genetic basis of aging. Studies in C. Elegans and Drosophila provide compelling evidence that in invertebrate models deficiencies in insulin/IGF-1 signaling pathways are closely associated with increased lifespan. The logical question then is whether perturbation of the growth hormone/IGF-1 axis regulates mechanisms of aging and lifespan in mammals. The critical issue raised by the aforementioned review is whether studies using Ames or Snell dwarf animals (as well as other dwarf animal models) provide appropriate and sufficient data to warrant the conclusion that growth hormone and IGF-1 deficiency delays aging or results in increased lifespan in mammals.

Do current dwarf models reveal specific information on the effects of growth hormone/IGF-1 deficiency?

As noted in the review, Ames and Snell dwarfs are deficient in growth hormone, TSH and prolactin and, due to complex interactions between endocrine systems, animals exhibit secondary endocrine deficiencies including alterations in glucose, insulin, IGF-1, and glucocorticoids. In addition, the presence of hormonal alterations during development results in tissue anomalies that further complicate the models. For example, the effects of thyroid hormone deficiency on brain maturation (which effects cognitive development) and IGF-1 deficiency in development of a GI tract (which impairs transport capacity) are well-known examples of the consequences of such interactions. Furthermore, the ability of dwarf animals to maintain a normal body temperature and demonstrate increased lifespan is, in some cases, dependent on housing with wild type controls. Thus, perturbations in the endocrine axis that appear straightforward have complex interactions that complicate subsequent interpretation of results.

The developmental and synergistic effects of these hormones are also evident in mutations that are more specific to the growth hormone/ IGF-1 axis. The GHRHR deficient (lit/lit) mice and growth hormone receptor knockout mice indeed result in more specific or targeted mutations compared to earlier models. Nevertheless, these animals exhibit similar alterations in glucose, insulin and glucocorticoid levels and undoubtedly exhibit developmental anomalies compared to the Ames and Snell dwarf. It is entirely possible that these secondary endocrine, developmental and physiological changes mask the effects of growth hormone and IGF-1 deficiency and, therefore, the consequences of these mutations may, or may not, reveal information relevant to the effects of growth hormone and IGF- 1 deficiency on biological aging. Reconciling the results of dwarf studies with studies of growth hormone replacement to old animals

The comment by the author that 'there is no evidence that growth hormone therapy � has any effect on aging per se or life expectancy' is in error. Without appropriate assessment of the consequences of specific deficiencies in growth hormone and/or IGF-1on lifespan, it is inappropriate to speculate whether the data from these models can, or need to, be reconciled with the numerous studies demonstrating that a specific replacement regimen, e.g. growth hormone and/or IGF-1 replacement, improves cognitive function (Markowska et al., 1998; Thornton et al., 2000; Sonntag et al., 2000), immune function (French et al., 2002), cellular protein synthesis (Sonntag et al., 1985), muscle and bone mass (Rudman et al., 1990) and other endpoints typically associated with the aging phenotype. It is not surprising that long-term consequences of pathological increases in growth hormone decreases lifespan but, unfortunately, these results have little applicability to normal physiology - and probably less applicability to mechanisms of aging. Several years ago, it was reported that modest growth hormone replacement either increases lifespan (Khansari and Gustad, 1991) or has no effect on lifespan when administered to mid-aged animals (Kalu et al., 1998). The results of these studies using specific interventions should not be summarily dismissed in favor of manipulations that are either non-specific or use pathological levels of hormones.

Finally, the author appears to make distinctions between lifespan and other endpoints of aging including frailty, functionality and risk factors for disease. In fact, lifespan is only one marker of biological aging - one that is relatively easy to quantify. Functional endpoints are more difficult to measure. However, most individuals would agree that even functional outcomes are the result of an aging process and contribute to the aging phenotype. The authors' conclusion that 'reduced IGF-1 signaling mediates the action of several aging-related genes while the age-related decrease in growth hormone and IGF-1 contribute to destructive changes in body composition' again is speculation, with little definitive data to support the conclusion.

Conclusions and Future Directions

The current dwarf models that have been used to demonstrate increased lifespan support two conclusions: 1) that genetic manipulation has the potential to influence lifespan in mammals, and 2) that direct or indirect consequences of hormone deficiency has profound effects on a number of biological systems that may impact biological aging. Unfortunately, any additional conclusions related to the effects of these manipulations on the growth hormone/IGF-1 axis are purely speculative. For example, the decrease in IGF-1 in caloric restricted rodents and humans has been known for over a decade, yet it has not been suggested that the effects of moderate caloric restriction are mediated solely through the IGF-1 axis. Similarly, the Ames or Snell dwarf or models that purport to offer 'more specificity' in targeting these endocrine pathways have sufficient endocrine, developmental and physiological pertubations that one cannot make conclusions on the effects of growth hormone/IGF-1 on either mechanisms of aging or lifespan.

Transgenic animal models that disregard the developmental effects of growth hormone and IGF-1 and the interactions of these hormones with other hormonal systems will not answer the critical questions in this field. The questions related to the effects of growth hormone/IGF-1 deficiency on mammalian aging can only be addressed with the development of appropriate models to closely regulate expression of these hormones. Conditional expression of these hormones resulting in physiological changes in hormone levels that do not interfere with normal development are necessary as well as appropriate pharmacological tools to stimulate or antagonize hormone action.

References

French RA, Broussard SR, Meier WA, Minshall C, Arkins S, Zachary JF, Dantzer R, Kelley KW. Age-associated loss of bone marrow hematopoietic cells is reversed by GH and accompanies thymic reconstitution. Endocrinology. 2002;143:690-699.

Khansari DN, Gustad T. Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice. Mechanisms Ageing Development 1991;57:87-100.

Kalu DN, Orhii PB, Chen C, Lee DY, Hubbard GB, Lee S, Olatunji-Bello Y. Aged-rodent models of long-term growth hormone therapy: lack of deleterious effect on longevity. Journals of Gerontology A Biol Sci Med Sci. 1998;53:B452-463.

Markowska AL, Mooney M, Sonntag WE. Insulin-like growth factor-1 (IGF -1) ameliorates age-related behavioral deficits. Neuroscience 1998; 87:559 -569.

Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. Effects of human growth hormone in men over 60 years old. N Engl J Med. 1990;323:1-6.

Sonntag WE, Hylka VW, Meites J. Growth hormone restores protein synthesis in skeletal muscle of old male rats. Journals of Gerontology (Biological Sciences) 1985;40:689-694.

Sonntag WE, Lynch CD, Thornton PL, Khan A, Bennett SA, Ingram RL. The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain aging. Journal of Anatomy 2000;197:575-586.

Thornton PL, Ingram RL, Sonntag WE. Chronic [D-Ala2]- growth hormone- releasing hormone (GHRH) administration attenuates age-related deficits in spatial memory. Journals of Gerontology (Biological Sciences) 2000; 55a:106-112.

SAGE Perspectives
Deciphering the Gene Expression Profile of Long-Lived Snell Mice
Becker (20 March 2002) [Abstract] [Full text]
Deciphering the Gene Expression Profile of Long-Lived Snell Mice
Comment on inferences from gene arrays
22 March 2002
Rich Miller
University of Michigan

Reply to Kevin Becker:

I agree with Kevin's main theme: evidence, from array data, that expression level of a specific gene is altered by aging, diet, or (as in our paper) mutation, is not the definitive proof that the mRNA level for that gene really does differ between groups, let alone that the protein levels differ between the groups. Our paper presents a listing of 60 genes for which p < 0.001 for a difference, in liver, between dwarf and normal mice, but anyone who wanted to pursue some of the biochemical leads would do well to start by checking mRNA and protein levels for the gene product in their own set of samples. At this stage of the game, no one really knows how often genes found to be altered in an array screening study will be replicable in the next set of samples, in terms of mRNA or protein. Kevin gives a fine summary of the ways in which array data can mislead: cross-hybridization, mis-identification of the cDNAs used to construct the array of probes, and other biochemical mis-adventures.

There are some points, particularly in regard to the discussion of statistical inference, where I think Dr. Becker’s comments may be off point. The key problem is the notion of a false positive result. The term false positive is used in two distinct ways in discussing array data, and it's important to see and honor the difference. An array experiment that shows a large and consistent difference in expression of the mRNA for catalase when in fact catalase mRNAs do not differ between group has produced a misleading conclusion, a false conclusion. Such a result might come about, for example, because the arrayed cDNA probe for catalase was of the wrong sequence, or because the lysates contained mRNAs that do not code for catalase but which cross-hybridize with it. No statistical approach can estimate or reduce the number of such false conclusions. (And, alas, no statistical approach can reduce the proportion of scientists who accept mRNA data of this kind as evidence for altered protein levels.)

The second use of the term false positive is in connection with Type I error rate, the kind of error that arises when an apparent difference between groups arises by chance, that is by sampling variation, alone. If one measures the height of two Democrats (say Bill Clinton and Janet Reno) and the height of two Republicans (say Frank Sinatra and Antonin Scalia), one might conclude that on average Democrats are taller. This is a Type I error, because we have not measured enough of each group to exclude chance variation as the explanation for our observation of a difference between the groups. Statistical theorists have worked out methods familiar to all of us for reducing this kind of error. When a single hypothesis is being examined, the scientific community often accepts the conclusion offered when there is only a 5% chance (p = 0.05) that the observed difference would arise by sampling error. If a given data set yields p = 0.20 for a comparison, this does not disprove the hypothesis of interest; but as a community we’ve decided not to put much faith in the conclusion when there's a 20% chance that it's due to sampling error.

When 1000 genes are being tested at the same time, reliance on a p = 0.05 criterion greatly increases the likelihood that some of the genes will show inter-group differences by chance, that is by sampling error alone. If the tests are done with high statistical power (lots and lots of samples), then using a criterion of p = 0.05 will produce a list of about 50 apparently acceptable conclusions even if none of the genes differ between groups. These 50 conclusions can be considered false positives in the sense that they represent conclusions at odds with the underlying biological situation.

In a real experiment, we don't know how many genes really are altered by the diet or age or mutation under study. If we use a criterion of p = 0.05, and look at 1000 genes, and get a list of 50 winners, we should not put too much faith in any one of the genes on the winner list, because we'd expect to get a list of about 50 even if there were no real effects. Some of the 50 genes are likely to be true positives, i.e. likely actually to differ in the full populations from which we've taken a sample, though there's no way to know which ones are real without looking at a fresh set of samples. If instead we use a criterion of p = 0.001 on the same data set, and still find 40 genes on our list, we can be a good deal more confident that most of these do not represent sampling error alone, because sampling error would produce only one false positive in a test of 1000 genes that did not really respond to the mutation under study.

Dr. Becker is correct when he states that an increase in the number of genes examined will not alter the false positive rate in the first of these two senses, unsuspected cross- hybridization, or sequence misidentification or other misadventures that produce erroneous inferences. But increasing the number of genes examined really will increase the likelihood of Type I errors, i.e. impressive inter-group differences that arise by sampling error alone. Reducing the chance of accepting an effect that is due to sampling errors can be accomplished by appropriate experimental design (using more samples) and by selecting a significance criterion that produces an acceptably low Type I error rate.

What error rate is acceptable in this case, and how can we calculate the error rate? The community accepts p = 0.05 as an appropriate significance criterion for experiments that test a single hypothesis. For gene mapping experiments, the most conservative criterion is to use an experiment-wise error rate, set so that the entire set of gene mapping conclusions has only a 5% chance of containing one or more errors due to sampling variation. Such an experiment-wise error rate, similar to that of the Bonferroni method, is surely too stringent for gene expression profiling, because there is real merit in a list of a few dozen or hundred genes allegedly altered by diet or aging, even if the list contains a smattering of false positives due to sampling. In our paper we used p = 0.001 as our main criterion, because for our 2352 genes it did a good job of ruling out most, though not quite all, chance effects. In current and future work we're using, in addition, a false discovery rate criterion developed by Tusher et al. (PNAS 98:5116 - 5121, 2001) that takes a more sophisticated, but still user-friendly, approach to adjusting acceptance criteria based on the number of genes examined.

There are a few aspects of Becker's presentation that I'd like to comment on for the record. (1) Our comparison of dwarf to normal mice used data on 8 mice per group, not 4. An unpublished simulation, resampling from our real data set, showed that if we had used only 4 mice per group we would have found compelling evidence for only about half of the 60 genes we reported using 8/group. (2) We do present the results of using a Bonferroni-adjusted significance level, but point out that it excludes too many genes and then employ a less restrictive criterion instead. (3) Becker says that the RT-PCR method confirmed 7 of 11 of the array findings, but in fact only 8 genes gave detectable and consistent RT-PCR results, and in 7 of these 8 cases the RT -PCR findings were consistent with the array findings. It is not surprising that the dwarf/normal ratios differ between array and RT-PCR findings: the array data come from tests of 8 mice/group, and the RT-PCR data from tests of only 3 mice in each group. In addition, each test will have slightly different sources of error, including cross-hybridization for the arrays. (4) More importantly, the RT-PCR data were not presented as evidence that increasingly rigorous statistical selection alone leads to real or reliable microarray results, they are taken as evidence that we had not committed a gross blunder such as using the wrong array or an array with mis-identified sequences.

I would strongly endorse Dr. Becker's suggestion that complete sets of raw array data should be made available to anyone who wishes to re-analyze them by alternate methods. We would be glad to supply our complete raw data set to anyone who requests it (to millerr@umich.edu), in exchange for a promise to inform us of the results of the subsequent analysis. A list of the processed data (i.e. after normalization and with gene-specific average values) will also be supplied to anyone who prefers the results in this form.

Lastly, I want to second Dr. Becker's concluding recommendation that analysis should not rely simply on statistical assessment but also on other equally important experimental practices, such as replicating individual RNA samples; increasing the number of individual biological samples; and, in particular, emphasizing systematic validation of individual results. Acceptance of these principles by a critical mass of array-meisters, and by those who review array-based papers and grant applications, will be an important step towards improving the signal/noise ratio in the published literature on gene expression profiles.

Rich Miller, University of Michigan millerr@umich.edu

SAGE Noteworthy This Week
Youth Beats Experience: Older parents hatch weaker offspring (Reproduction)
Leslie (20 March 2002) [Abstract]
Youth Beats Experience: Older parents hatch weaker offspring (Reproduction)
Maternal age effects in fruit fly aging
22 April 2002
Nicholas K. Priest,
graduate student
University of Virginia,
D. Promislow

These kinds of maternal age effects on offspring aging may play a critical role in the evolution of aging. I conducted a study with Daniel Promislow to look at the effect of maternal age on offspring longevity, mortality intercept and mortaility rate in several strains of D. melanogaster. We found that older flies typically produce shorter-lived offspring, with remarkable effects on the shape of the age-specific mortality curve. We found that maternal age effects can influence the adult life history of flies and probably play an important role in the evolution of aging (the study will be published in the May issue of the journal "Evolution").

Youth Beats Experience: Older parents hatch weaker offspring (Reproduction)
Parental Age and Human Longevity
1 April 2002
Leonid Gavrilov,
scientist
Center on Aging, NORC/University of Chicago

Parental age at conception may also have an influence on human longevity:

Gavrilov, L.A., Gavrilova, N.S. Biodemographic study of familial determinants of human longevity. Population: An English Selection, 2001, 13(1): 197-222.

Gavrilov, L.A., Gavrilova, N.S. Human longevity and parental age at conception. In: J.-M.Robine et al. (eds.) Sex and Longevity: Sexuality, Gender, Reproduction, Parenthood, Berlin, Heidelberg: Springer-Verlag, 2000, 7-31.

Gavrilov, L.A., Gavrilova, N.S. Parental age at conception and offspring longevity. Reviews in Clinical Gerontology, 1997, 7: 5-12.

Gavrilov L.A., Gavrilova, N.S., Kroutko, V.N., Evdokushkina, G.N., Semyonova, V.G., Gavrilova, A.L., Lapshin, E.V., Evdokushkina N.N., Kushnareva, Yu.E. Mutation load and human longevity. Mutation Research, 1997, 377(1): 61-62.

Gavrilov L.A., Gavrilova, N.S. When Fatherhood Should Stop? Letter. Science, 1997, 277(5322): 17-18.

Gavrilov L.A., Gavrilova N.S., Semyonova V.G., Evdokushkina G.N., Kroutko V.N., Gavrilova A.L., Evdokushkina N.N., Lapshin E.V. Maternal age and offspring longevity, Proc. Russian Acad. Sci. [Doklady Akademii Nauk], 1997, 354(4): 569-572. English translation published in Doklady Biological Sciences, 1997, 354(4): 287-289.

Hope it helps.

Best wishes,

______________________________________ Dr. Leonid A. Gavrilov, Center on Aging NORC/University of Chicago 1155 East 60th Street Chicago, IL 60637-2745 USA Fax: (773) 256-6313, Phone: (773) 256-6359 FOR MORE INFO PLEASE VISIT OUR SCIENTIFIC WEBSITE : http://www.src.uchicago.edu/~gavr1/

Youth Beats Experience: Older parents hatch weaker offspring (Reproduction)
Re: What age constitutes
27 March 2002
Phyllis Wise,
Researcher

The reproductive hormones that are secreted during pregnancy have half lives of minutes. Therefore, when a pregnancy is terminated, they return to normal within hours or days at the most. Evolutionarily it makes sense that a female should return to reproductive competence quickly so that she can be fertile and bear young rapidly. Studies have been done in primates to show that the ovary begins to grow new follicles immediately upon termination of pregnancy. There is no data that I am aware of that shows any repercussions of an unsuccessful pregnancy on future pregnancies. It is true that some women are less fertile because they have repeated miscarriages, but it is thought that this is due to genetic, hormonal or physical abnormalities, not due to previous pregnancy experience.

Youth Beats Experience: Older parents hatch weaker offspring (Reproduction)
What age constitutes "older/younger" and which lifestyles constitute aging?
22 March 2002
Maryse,
chem

What I'd like to know is do smoking, noticeable metabolistic decreases, onset of "greying" denote being in the "older" category? I would also like to be referenced to information about the effects of abrubtly stopping pregnancy (termination) and the human body's "acceptance" of the loss, for example, do not the hormones stay inside the body indefinitely, along with the other changes in pregnancy (increased memory). Could an older previously abortive parent have a "carry over effect" to producing healthy offspring?

SAGE News Synthesis
More Than a Hot Flash
Davenport (13 March 2002) [Abstract] [Full text]
More Than a Hot Flash
Male testosterone need not decline with age
20 March 2002
Allan Mazur,
professor
syracuse university

The usually observed decline in testosterone as U.S. males age is accompanied by a tendency toward increased body fat. In male Air Force veterans followed for several years, testosterone did not decline if their weight stayed constant. Testosterone decline, with age, is a function of increasing body fat. Possibly, by maintaining constant body weight, the age-related decline in testosterone can be considerably postpone or eliminated.

SAGE Perspectives
Cancer and Aging: Yin, Yang, and p53
Campisi (9 January 2002) [Abstract] [Full text]
Cancer and Aging: Yin, Yang, and p53
Cancer curable, aging probably not
22 February 2002
Charles R Fred

Recent research promises easy cancer cures within a few years.

But the destructive processes of aging, especially apoptosis, may prove more refractory.

This shifts the risk/reward ratio inherent in raising Sir2 activity.

Cancer and Aging: Yin, Yang, and p53
p53: The yin, the yang, and the universal
23 January 2002
Charles Mobbs,
Associate Professor
Mt. Sinai School of Medicine

The recent report on the relationship between p53 alleles, cancer, and lifespan is indeed of great interest. However, much of the attendant publicity has been in want of sufficient skepticism regarding the applicability of this result to fundamental processes of senescence. For example, caloric restriction increases lifespan while decreasing the incidence of most cancers. Furthermore, post-mitotic organisms (e.g., that are not at risk for cancer) still exhibit typical patterns of senescence (e.g., longevity curves obey the Gompertz curve and caloric restriction increases lifespan). Finally, many alleles reduce lifespan, but almost without exception these are not considered by gerontologists to reflect accelerated aging (see very useful discussions by Rich Miller and George Martin elsewhere on this site). Thus while the concept of a trade-off between cancer and longevity is highly appealing, the general applicability of this concept to more general processes of senescence (of the sort, presumably, activated by caloric restriction) remains in doubt.

SAGE Noteworthy This Week
Reviving Biomedicine: New Basel institute tackles aging and aims to bolster Swiss research (Research funding)
Weiss (9 January 2002) [Abstract]
Reviving Biomedicine: New Basel institute tackles aging and aims to bolster Swiss...
A Welcome move worth emulating by other countries
12 January 2002
Kalluri S Rao,
Emeritus Professor
University of Hyderabad, Hyderabad.India

I was extremely happy to note the conception of the Basel Institute for Diseases of Aging( BIDA ) . There is a global need to augment research and health care of the elderly throughout the world . The aging population, treated properly would be a valuable human resource to that country and to the rest of the world at large. The purpose of the research is not to obviate the inevitable but to reach the inevitable in a fitting and prepared manner.Until that point the wisdom and experience of these " old " people should be turned into a national and global asset.

I would like to venture to recommend that the BIDA may also have a component division to augment the Institute's efforts in the areas of psychological and sociological aspects of getting old. I wish the BIDA all the success and congratulate the people behind this nobel thought.

SAGE Viewpoint
A Position Paper on Longevity Genes
Miller (28 November 2001) [Full text]
A Position Paper on Longevity Genes
We can add new genes as well as change existing ones
2 December 2001
Aubrey de Grey


Rich Miller's classification of "longevity genes" ends with a strange implicit assertion: that we have not yet found any genes responsible for the differences in longevity between different mammals. In fact, inter- and intraspecies comparisons are the strongest evidence we have that mitochondrial free radical production rates are a major player in the rate of aging, and hence that the relatively few (a few dozen at most, probably only half a dozen) genes encoding proteins responsible for that process are members of category 6. Stronger proof will come not from genetic triangulation but from technical advances (such as the manipulation of mouse mitochondrial DNA) and from crystallography (identifying the detailed structure and mechanism of Complex I).

This way of looking at genes whose discovery might worry life insurance agents makes it clear that a seventh category must be added to Rich's classification. We should not restrict ourselves to trying to improve genes that we already possess; rather, we should look at the *process* we're trying to improve and consider whether genes that mammals lack might be effective. Long-standing [1] candidates are nuclear-coded versions of our 13 mitochondrial protein-coding genes, which would completely eliminate the deleterious effects of mitochondrial mutations (such as they may be). This may sound incredibly ambitious at first hearing, but the past few years have seen key breakthroughs [2-4]. The alternative of replacing some or all of our Complex I subunit genes with ones from parrots, for example, seems altogether too timid.

Refs: [1] Lander and Lodish, Cell 61:925; [2] Seo et al, JBC 275:37774; [3] Perez-Mart�nez et al, JBC 275:30144; [4] Zullo, Semin Neurol 21:327.

A Position Paper on Longevity Genes
Using the term gerontogenes
30 November 2001
Suresh Rattan,
Professor
Univesity of Aarhus

Richard Miller has written a very useful and logically constructed position paper on genes that may influence aging and longevity. He has avoided the use of the term "gerontogenes" in his paper because of, perhaps, the evolutionary reasons against the existence of such real genes for aging. However, I think that using the term gerontogenes (which was first coined by me in 1985, and has been used by several authors over the last 15 years) can have several advantages, including drawing attention to the subject of biogerontology and underlining the focus of discussion.

The nature of gerontogenes as either being "virtual", that is having only a functional reality by affecting aging and longevity, or being physically real as the so-called longevity assurance genes, is a matter of further detail. In my opinion, biogerontologists could definitely use the term gerontogenes, and assert the independence of the field of biogerontology by developing appropriate terminology within the subject.

SAGE News Focus
Drugs Protect Mice From Pernicious Forms of Oxygen
Tuma (7 November 2001) [Abstract] [Full text]
Drugs Protect Mice From Pernicious Forms of Oxygen
Meal frequency
11 November 2001
Michael Gates,
Physician

Perhaps a study comparing a dietary regimen of small, frequent meals vs large, infrequent meals of equal total calories would demonstrate a threshold effect for anti-oxidant systems. If so, populations eating small, frequent meals should outlive the large, infrequent meal cohort.

SAGE News Focus
Death and Aging, Together at Last
Hopkin (24 October 2001) [Abstract] [Full text]
Death and Aging, Together at Last
Cancer curable, aging probably not.
22 February 2002
Charles R Fred

Recent research promises easy cancer cures within a few years.

But the destructive processes of aging, especially apoptosis, may prove more refractory.

This shifts the risk/reward ratio inherent in raising Sir2 activity.

Death and Aging, Together at Last
Cancer curable, aging probably not.
22 February 2002
Charles R Fred

Recent research promises easy cancer cures within a few years.

But the destructive processes of aging, especially apoptosis, may prove more refractory.

This shifts the risk/reward ratio inherent in raising Sir2 activity.

Death and Aging, Together at Last
Cancer curable, aging probably not.
22 February 2002
Charles R Fred

Recent research promises easy cancer cures within a few years.

But the destructive processes of aging, especially apoptosis, may prove more refractory.

This shifts the risk/reward ratio inherent in raising Sir2 activity.

SAGE Noteworthy This Week
Faustian Bargain: Cellular senescence at first prevents, later promotes, cancer
Davenport (17 October 2001) [Abstract]
Faustian Bargain: Cellular senescence at first prevents, later promotes, cancer
A question about stoichiometry
18 October 2001
Rich Miller,
Gerontologist
University of Michigan

This paper from the Campisi group follows up with hard evidence Dr. Campisi's hypothesis that senescent cells, of the kind that occur in late passage cultures of human fibroblasts, might contribute to oncogenesis by producing an oncogenic local environment. This is a lovely idea, but I'd want to take it very cautiously until someone comes up with evidence that there are enough senescent cells in real live old humans to do the trick. The only evidence I know of that actual old humans have any senescent fibroblasts in them comes from the famous Dimri/Campisi paper using beta- galactosidase to identify such cells in skin of old people. This observation has proven difficult to replicate (at least two groups have looked hard for such cells in skin biopsies without success), and even in the Dimri/Campisi paper the incidence of such cells, while not stated explicitly, seems to be pretty low (1/1000? less?) in the photomicrographs presented. In the new PNAS paper, senescent cells are mixed at a 1:1 ratio with preneoplastic cells to achieve the stimulation of tumorigenesis in nude mice. It would be nice to know if the authors had tried experiments that used lower ratios of fibroblasts to preneoplastic cells, and if so if they saw any stimulus at ratios similar to those that actually occur in old human skin. Evidence that senescent cells were detectable in other cancer-prone organs in old people, though clearly beyond the scope of this current paper, would also help to put this interesting idea to a key critical test.

SAGE Viewpoint
Realizing Wisdom
Olshansky (10 October 2001) [Full text]
Realizing Wisdom
More kudos for our social science colleagues
11 October 2001
George M Martin,
Pathologist
University of Washington

I want to thank Jay Olshansky for this lovely memoir, especially for his moving tribute to Bernice Neugarten. Back in the early days of NIH- supported research on aging, basic biologists, clinicians and social scientists often sat together on the same panel. I thus came to know and admire Bernice and other social scientists sharing her passionate, scholarly and visionary approach to the problems of older people. A particularly fine example is Matilda White Riley. She is still going strong! Matilda, Bernice and their friends taught me to embrace the life course view of aging. Social gerontologists thus have a lot in common with evolutionary biologists concerned with gerontology.

Jay has inspired me to write my own little piece on "how I got into research on aging". Stay tuned! Meanwhile, how about hearing from others on that subject?

SAGE Viewpoint
Can Current Evolutionary Theory Explain Experimental Data on Aging?
Mitteldorf (19 December 2001) [Full text]
Can Current Evolutionary Theory Explain Experimental Data on Aging?
Evolutionary theory is nicely compatible with experimental research on aging
12 November 2001
Steve Austad,
Professor
University of Idaho

The three so-called empirical �challenges� that Mitteldorf imagines experimental aging research has raised for evolutionary senescence theory are actually nothing of the sort. He misinterprets each finding to suggest that natural selection has somehow favored �aging genes,� that is genes that were favored by evolution because they accelerate aging. Since accelerated aging per se could be of no conceivable benefit to an individual, he posits that group selection may explain how �aging� genes came to be. Let�s look at each of his �challenges.�

1. Aging genes and fertility. Because a number of mutations disabling the activity of individual wild-type alleles have been shown to extend life, Mitteldorf posits that the unmutated, wild-type, alleles must be �aging genes,� that is genes which have evolved to cause aging by group selection. He also assumes that the only way these observations might be compatible with traditional evolutionary aging theory is if these mutations depress fertility. His errors are two-fold. First, he assumes that alleles associated with extended life in the laboratory are associated with higher darwinian fitness of those individuals. The fact that such alleles have never been isolated in nature is prima facie evidence against such an interpretation. Second, he assumes that fertility (which indeed is often suppressed in these mutant phenotypes) is the only component of fitness. Of course, there are many fitness components in addition to fertility per se, for instance juvenile viability, competitive ability, resistance to environmental stresses, adult competitive ability for resources or for mates, that might be negatively affected by such mutations. In fact, each of these long-lived mutants, when studied in detail, has been found to have pleiotropic negative effects on growth rate, fertility, or competitive ability � traits in other words that have a more direct relation to darwinian fitness than does longevity (Kirkwood, T.B.L & Austad, S.N. 2000. Nature 408: 233-238). If one wished to characterize the unmutated �wild-type� genes by their adaptive value, they would more properly be called �growth,� or �fertility� or �competitive ability� genes rather than �aging� genes as he calls them and their adaptive value is obvious. Therefore neither the existence of these wild-type alleles, nor extended longevity accompanying their disablement, poses any problem for evolutionary theory. In contrast, the fact that disabling these genes leads to longer life nicely supports Williams� theory of the evolution of aging by �antagonistic pleiotropy.� The mouse p66shc mutant mentioned by Mitteldorf is notable mainly in that it has been scarcely characterized at all with respect to other life history traits than laboratory longevity. Significantly the increased resistance to chemical stressors exhibited by the p66shc mutant is reminiscent of that reported in calorically-restricted mice, which leads to his second point.

2. Caloric restriction and aging. The crux of the �challenge� of calorically-restricted rodent paradigm is �experiments suggest that the life extension brought about by CR is independent of their effect on fertility.� The implication, it seems, is that the retarded aging rate of calorically-restricted animals could not be part of an adaptive tradeoff among life history traits under conditions of food shortage. First, none of the evidence cited by Mitteldorf supports this assertion. Fertility is reduced or completely suppressed in both male and female calorically-restricted rodents in all studies in which it has been examined. Mitteldorf�s point seems to be that further restriction, even after reproduction has been completely suppressed, leads to an even further increase in longevity when there are no remaining tradeoffs available. As in the previous �challenge,� the interpretive problem is that he assumes that ever increasing laboratory longevity must be associated with higher fitness, and that fertility is the only fitness component other than survival. As previously mentioned, other fitness components such as foraging efficiency, competitive ability, and resistance to environmental stresses might be impacted in addition to reproduction. The reason that fully-fed animals do enter the slower aging rate characteristic of caloric restriction is that their extra energy is better used for other things such as warding off cold, escaping predators, or defending territories. For instance, my laboratory has observed that calorically-restricted mice have a lower sprint speed than fully-fed mice when each is forced to run on a treadmill. Again, as with long-lived laboratory mutants, the extended longevity of caloric restriction should not be interpreted as having relevance for animals in nature. It is painfully obvious, that calorically-restricted rodents would likely have substantially lower survival in nature than better-fed animals. Specifically, calorically-restricted mice are more susceptible to cold stress than ad lib fed mice (Campbell & Richardson, 1988, Exp. Gerontol. 23:417-427) and we know that cold stress is a major cause of mouse mortality in nature (Berry, 1981, Mammalian Rev. 11:91-136). Also, we know that calorically-restricted rodents would be more susceptible to death from short-term food shortage. Like the single gene mutants, calorically-restricted rodents are a useful tool for exploring mechanisms of aging, but they represent a low-fitness alternative states, except in the especially favorable conditions of the laboratory.

3. Conserved mechanisms of aging. All researchers in the field ardently hope that at least some fundamental mechanisms of aging are highly conserved, otherwise research with model organisms is a waste of time. To Mitteldorf, the challenge to evolutionary theory of these mechanisms is that he imagines that general cellular phenomena such as apoptosis have the appearance of deliberate adaptations, hence their adaptive value must be in accelerating aging. Researchers who study these phenomena would likely differ. Apoptosis plays an invaluable adaptive role in development and morphogenesis, as well as in protecting us from genetically-damaged cells in danger of neoplastic transformation. As for replicative senescence, it has been cogently interpreted by Campisi as an instructive example of antagonistic pleiotropy � a process which evolved to limit uncontrolled cell proliferation during early life, but which might have deleterious side-effects later in life.

In conclusion, existing evolutionary theory, emphasizing selection at the level of individuals rather than groups, is perfectly compatible with the modern experimental findings of aging research.

Can Current Evolutionary Theory Explain Experimental Data on Aging?
Discussion 3 Introduction
7 November 2001
By Joshua Mitteldorf

As Mitch Leslie has so lightly reminded us in "Aging Research Grows Up" (1), study of the evolution of aging is not without its controversy, but those who disagree with the orthodoxy are all wrong. These dissidents tend to be experimental geneticists, developmental biologists, complexity theorists, and others who are ignorant of the basic principles of evolutionary biology established thirty years ago (2).

Since that time, mainstream evolutionary theory has been committed to a paradigm of selection exclusively at the individual level. Aging entails a fitness cost to the individual, who has nevertheless acquired a network of genes that determines and regulates the rate of aging. So the prevailing theories of aging have been built on a presumption that aging has evolved as a side-effect of genes that carry a fitness benefit for the individual. This benefit must be strong and universal to account for the universality of aging; hence there is wide agreement that genes that cause aging must enhance fertility.

But in the two generations since foundations were laid for the current evolutionary theories of senescence, new data have come to light that challenge the theories at their core. Today, the theories survive as a framework in which to interpret data, but their persistence might result from an absence of viable alternatives rather than because there is an excellent fit with experimental results. It might be appropriate to consider whether the data demand of us a new paradigm; recent developments in evolutionary theory point toward origins for this new paradigm.

What are the theoretical reasons for thinking that selection operates exclusively at the individual level? The reasons are cogent, and are well-argued in George Williams's classic, Adaptation and Natural Selection (2). The essence of the argument is that a prerequisite for group selection is the persistence and fixation of a mutation, arising originally in a single individual. But evolution at the individual level is rapid and direct, scaled by the lifetimes of individuals; evolution at the group level proceeds at a slower pace, scaled by the extinction time of populations. Hence it seems unlikely that any trait entailing even a small cost to the individual can persist long enough to test its effect on fitness of the population as a whole.

What are some experimental challenges to the prevailing theories?

1. Aging genes and fertility. Over the last decade, single gene mutations have been discovered that extend life-span in nematodes(3), fruit flies (4), and mice (5). Because deletion of these genes causes the animal to live longer, it seems inescapable to characterize them as "aging genes." It is far from clear, however, that they offer any benefit to fertility. For example, the mouse gene p66shc affects apoptosis in damaged cells, which appears to be upregulated to the point where healthy cells are routinely being killed in older individuals. Experiments show that this substantially shortens the mouse life-span, but it is hard to imagine what benefit it might carry for fertility.

2. Caloric restriction and aging. In calorically restricted (CR) rodents, the aging rate is slowed substantially, while the immune system is more effective and activity levels are enhanced (6). Where does the capacity come from to sustain this effort, and why does the body choose not to extend its life when fully fed? This phenomenon is a particular embarrassment to the reigning "Disposable Soma" theory of senescence, which holds that a tight caloric budget is the root cause of aging. Theorists have responded by emphasizing the large fertility cost entailed in the CR response (7), but experiments suggest that the life extension brought about by CR is independent of the effect on fertility (8): In male rodents, life-span is substantially extended with only modest curtailment of fertility; in females, life-span continues to lengthen as the severity of caloric restriction is increased (9). For example, with caloric restriction at >30%, a regime in which the females are already completely infertile, life-span continues to grow with severity of caloric restriction all the way down to the threshold of starvation, around 60%.

3. Conserved mechanisms of aging. Some mechanisms of aging appear to have been conserved over vast evolutionary time scales (10, 11). For example, evidence is emerging that implicates apoptosis as a senescence mechanism (12-16). Apoptosis has all the appearance of a deliberate adaptation, and hints that it plays a role in aging are problematic for the standard theories. Likewise, replicative senescence through telomere attrition is an independent, purposeful adaptation, and its implication in cellular senescence in the aging of higher organisms belies all theories of pleiotropy. If processes such as telomeric senescence and apoptosis, which we think of as purposeful adaptations, do turn out to play a central role in the aging of higher organisms, conventional theories of aging will face trouble: It would then be difficult to support the notion of aging as a side-effect of processes that primarily enhance fertility, and impossible to maintain the idea that aging derives from a failure to allocate adequate resources to repair and maintenance functions.

What new theoretical developments might hint at an alternative framework?

1. Almost as old as the proscription on arguments from group selection is David Sloan Wilson's work on multi-level selection (MLS) theory (17, 18). In recent years, the body of literature on MLS has swelled, as has the number of recognized mechanisms by which group-level adaptations might emerge (19, 20).

2. Complexity theorists revel in the distinction between smooth, analytical processes that closely track our intuitions and the surprising, chaotic realms of complex systems. There is now a community of Artificial Life specialists, who study evolution with computer models rather than differential equations. They shun the equations and theorems of population genetics, because these have been derived on the assumptions of infinite populations and negligible epistasis, conditions that are rarely achieved in nature. Most of the people in this community hail from backgrounds in physics or computer science rather than evolution and have little reverence for the distinction between individual and group selection. It is arguable that a complex systems approach makes group selection far more plausible than does an analytical approach (21).

3. The evolution of evolvability has been an intriguing field of study since the ground-breaking paper of Wagner and Altenberg (22). Evolvability advocates argue that the structure of chromosomes and the organization of the genome appear to be optimized in ways that promote the efficiency of evolutionary processes. But evolvability is a property of populations, not individuals. Evolvability itself can only evolve via a process of long-term selection on populations, which is exactly the kind of selection that traditional evolutionary theory warns us does not exist. And if evolvability has somehow evaded the theoretical ban on group selection, can senescence be viewed as a population trait that contributes to evolvability? Senescence contributes to the adaptability of a population by reducing the effective generation length and enhancing genetic diversity, as Weismann (23) pointed out over a century ago.

What's next? It's one thing to take pot shots at established evolutionary theory, and quite another to put forward a viable alternative. It remains to be seen whether a plausible model of the evolution of senescence can be constructed on the basis of long-term and widely dispersed benefits of higher population turnover and increased genetic diversity.

References

1. M. Leslie, Aging Research Grows Up. Science's SAGE-KE (2001) http://sage ke.sciencemag.org/cgi/content/full/sageke;2001/1/oa1.

2. G. C. Williams, Adaptation and Natural Selection (Princeton Univ. Press, Princeton, NJ, 1966).

3. C. Kenyon, J. Chang, E. Gensch, A. Rudner, R. Tabtiang, A C. elegans mutant that lives twice as long as wild type. Nature 366, 461-464 (1993).

4. M. Tatar, A. Kopelman, D. Epstein, M.-P. Tu, C.-M. Yin, R. S. Garofolo, A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107-110 (2001).

5. E. Migliaccio, M. Giorgio, S. Mole, G. Pelicci, P. Reboldi, P. P. Pandolfi, L. Lanfrancone, P. G. Pelicci, The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313 (1999).

6. R. Weindruch, R. Walford, The Retardation of Aging and Disease by Dietary Restriction. (Thomas, Springfield, IL, 1986).

7. D. Shanley, T. B. L. Kirkwood, Calorie restriction and aging: a life history analysis. Evolution 54,740-750 (2000).

8. J. Mitteldorf, Can experiments on caloric restriction be reconciled with the disposable soma theory for the evolution of senescence. Evolution 55,1902-1905 (2001).

9. L. V. De Paolo, Dietary modulation of reproductive function. In: Modulation of aging processes by dietary restriction, Yu, ed. (CRC Press, Cleveland, OH, 1993), pp 221-246.

10. W. Clark, A means to an end: the biological basis of aging and death. (Oxford University Press, NY, 1999).

11. C. Kenyon, A conserved regulatory system for aging, Cell 105, 165-168 (2001).

12. W. Clark, Reflections on an unsolved problem of biology: the evolution of senescence and death. Unpublished manuscript.

13. S. Cornillon et al., Programmed cell death in Dictyostelium. J. Cell Sci. 107, 2691-2704 (1994).

14. K. Hopkin, Death and aging, together at last. Science's SAGE-KE (2001) http://sageke.sciencemag.org/cgi/content/ full/sageke;2001/4/nf2.

15. J. Luo, A. Y. Nikolaev, S. Imai, D. Chen, F. Su, A. Shiloh, L. Guarente, and W. Gu, Negative control of p53 by sir2 promotes cell survival under stress. Cell 107,137-148 (2001).

16. H. Vaziri, S. K. Dessain, E. N. Eaton, S. Imai, R. A. Frye, T. K. Pandita, L. Guarente, R. A. Weinberg, hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell 107, 149-159 (2001).

17. D. S. Wilson, The Natural Selection of Populations and Communities. (Benjamin Cummings, Menlo Park, CA, 1980).

18. E. Sober, D. S. Wilson, Unto Others. (Harvard University Press, Cambridge, MA, 1998).

19. D. S. Wilson, Ed. Multilevel Selection. The American Naturalist (1997 suppl.).

20. L. Keller, Ed. Levels of Selection. (Princeton University Press, Princeton, NY, 1999).

21. J. Mitteldorf, D. S. Wilson, Population viscosity and the evolution of altruism. J. Theor. Biol. 204, 481-496 (2000).

22. G. P.Wagner, L. Altenberg, Complex adaptations and the evolution of evolvability. Evolution 50, 967-976 (1996).

23. A. Weismann, Essays Upon Heredity and Kindred Biological Problems. (Clarendon Press, Oxford, U.K. 1889).

SAGE Viewpoint
Identifying Differentially Expressed Genes in cDNA Microarray Experiments Authors
Bengtsson et al. (19 December 2001) [Full text]
Identifying Differentially Expressed Genes in cDNA Microarray Experiments Authors
Re: lowess normalization
12 October 2001
Henrik Bengtsson

Dear Kristen Carlberg, I am sorry but I know too little about Excel or SPSS to help you out here. I searched Google Groups for "Excel lowess" and "Excel loess" and found a few requests but no answers. Try to post your question there

http://groups.google.com/groups?hl=en&group=microsoft.public.excel

or at

http://groups.google.com/groups?hl=en&group=comp.soft-sys.stat.spss

Regards

Henrik Bengtsson, Lund University
Identifying Differentially Expressed Genes in cDNA Microarray Experiments Authors
lowess normalization
10 October 2001
Kristen Carlberg

Can anyone tell me how to do a global lowess normalization using either Excel, or SPSS? With SPSS at least, I can generate a lowess line on a scatter graph, but I don't know how to get the lowess equation c(A) to use for normalization. I'd like to be able to do this using Excel, but I don't even know whether Excel is capable of this.

Identifying Differentially Expressed Genes in cDNA Microarray Experiments Authors
Re: False discovery rates and ease of use
9 October 2001
Henrik Bengtsson
Mathematical Statistics, Lund University

Dear Richard Miller, I will try to answer your questions to the best of my knowledge. (The references are the same as in the introductory paper Bengtsson et al.)

1. Using an ordinary t-test we found 61 genes where p < 0.001. Because we had looked at 2352 genes, we expected to see only 2 or 3 "false positives" at p = 0.001, and so we concluded that most of the genes on our list were probably ok.

A1. Assuming the validity of the t-tests for each individual gene that you perform, it reasonable to conclude that most of the genes that you have found are "probably ok".

2. The statistical program SAS has a test (MULTTEST) that automatically calculates a "false discovery rate" statistic that adjusts for the number of genes being tested at the same time. We found that 72 of the genes had an FDR p-value < 0.05. But to do this test requires you to know someone who can write SAS programs.

A2. As you say, the PROC MULTTEST function in SAS i a p-value adjustment method and it is doing the same as the procedures described in Dudoit et al. ([14]). If you do not want to use SAS the methods described by [14] are all implemented in the sma package [5] and will later be "lifted up" into the sma add-on package com.braju.sma [4]. All methods in the sma package are accessible from the com.braju.sma package. These package requires the free software R [6,7].

3. VG Tusher and colleagues have written a nice paper on significance analysis of microarray data (it's PNAS 98:5116 - 5121, 2001) that you refer to in your own paper as Citation 17. The approach they suggest makes it very easy to "tune" the calculation to adjust the false discovery rate to one the investigator is comfortable with. (For some purposes you might be happy with a list of 100 genes of which 20 are false; for other purposes you might want to examine the same data set to find the 20 best genes for which only 2 are false positives.) The Tusher group have produced an Excell add-in program (free!) that makes this calculation a snap even for the statistically impaired.

A3. There is an important technical difference between Tusher et al's test procedures [16] and those in [14] and PROC MULTTEST. The method by Tusher et al. only provides what is known as "weak control" of the type I error (a true null hypothesis is rejected). In other words, it controls the error rate under the complete null hypothesis that no genes are differentially expressed and this is unsatisfactory.

4. I've glanced at (but not yet had time to read carefully) your own posted paper linked to the SAGE web site. You say that your favorite statistic (B-statistic) is a bit better than the statistic used by Tusher and company - but is the difference substantial enough to justify the pain needed for us users to master the intricacies of the approach you are recommending for picking the best winner genes from the list ranked by the S-, B-, or t-statistic?

Can you provide some advice on which of these approaches has the best balance between statistical rigor and ease-of-use?

A4. Yes, the B-statistics method by L�nnstedt et al. [17] is somewhat tricky to understand, but the implementation of it in [4,5] is pretty straightforward. However, as everything else in data analysis it is important to understand the methods you apply. In [17] it is shown that the S-statistics does almost perform as good as the B-statistics. The t-stastics is worse and using plain M-values (log ratios) should be avoided.

There are important differences between the approaches which relate to the structure of your experiment. For example, the step-down maxT used in PROC MULTTEST and [14] is available for use when the experiment has replicated treated and control slides, and a common reference, but not when there is (only) a treatment and control target cDNA on the same slides (as in the poster paper). Replicated trt/ctl slides cannot be permuted, and so any formal testing with them must be based on parametric statistical modelling assumptions. As [17] suggests, it is better to avoid making such assumptions, and simply rank one's genes using some sensible criterion. As argued in [17] (downloadable), and in section 5.1 in the posted one, the t-statistics should not be trusted.

I hope this answered your questions.

Henrik Bengtsson, Lund University

Identifying Differentially Expressed Genes in cDNA Microarray Experiments Authors
False discovery rates and ease of use
2 October 2001
Richard Miller,
Biogerontologist
University of Michigan

In our own data set (based on gene expression levels from liver of 8 young Snell dwarf mice and 8 young control mice for 2352 genes), we compared a number of methods to estimate the "false discovery rate," ("FDR") i.e. the probability that a gene we decided did differ in its expression in the dwarf samples was merely a chance effect. Some of these approaches are easy for anyone who can handle Excell; others required more sophistication and the services of expensive statisticians. I'd like your advice on which of these seem sensible:

1. Using an ordinary t-test we found 61 genes where p < 0.001. Because we had looked at 2352 genes, we expected to see only 2 or 3 "false positives" at p = 0.001, and so we concluded that most of the genes on our list were probably ok.

2. The statistical program SAS has a test (MULTTEST) that automatically calculates a "false discovery rate" statistic that adjusts for the number of genes being tested at the same time. We found that 72 of the genes had an FDR p-value < 0.05. But to do this test requires you to know someone who can write SAS programs.

3. VG Tusher and colleagues have written a nice paper on significance analysis of microarray data (it's PNAS 98:5116 - 5121, 2001) that you refer to in your own paper as Citation 17. The approach they suggest makes it very easy to "tune" the calculation to adjust the false discovery rate to one the investigator is comfortable with. (For some purposes you might be happy with a list of 100 genes of which 20 are false; for other purposes you might want to examine the same data set to find the 20 best genes for which only 2 are false positives.) The Tusher group have produced an Excell add-in program (free!) that makes this calculation a snap even for the statistically impaired.

4. I've glanced at (but not yet had time to read carefully) your own posted paper linked to the SAGE web site. You say that your favorite statistic (B-statistic) is a bit better than the statistic used by Tusher and company - but is the difference substantial enough to justify the pain needed for us users to master the intricacies of the approach you are recommending for picking the best winner genes from the list ranked by the S-, B-, or t-statistic?

Can you provide some advice on which of these approaches has the best balance between statistical rigor and ease-of-use?

It's kind of you to offer tutorials in this format, and I'll look forward to hearing your advice.

Rich Miller, University of Michigan

SAGE Viewpoint
Is Life-Span the Best Measure of Aging?
Crawford (19 December 2001) [Full text]
Is Life-Span the Best Measure of Aging?
Segmental aging
2 October 2001
George Martin

2 October 2001

Back in the 1960�s, when Charlie Epstein, Arno Motulsky and I first became interested in the Werner syndrome and its possible relationship to the biology of aging, George W. Casarett, a radiation biologist, suggested a set of rather rigid criteria for determining if one could conclude that a given intervention was responsible for altering the rate of aging (Adv Gerontol Res 1:109, 1964). While he was mainly concerned about the degree to which the life-shortening effects of ionizing radiation can be considered to induce premature aging, one could also apply his criteria for the evaluation of agents that can in fact retard the rate of aging. In brief, he argued that a given agent had to alter life span without changing the basic pattern of the mortality curve. It also had to change each and every morphological and physiological manifestation of aging in a synchronous manner and had to alter all diseases of aging and all causes of death in a proportionate manner.

While some degree of synchronization of the wide array of phenotypes associated with aging is clearly to be expected, evolutionary theory does not demand perfect synchronization. Given the substantial genetic heterogeneity and diverse environmental impacts that wild type creatures like us experience, there is ample opportunity for various degrees of asynchrony. Thus, is would be helpful for us to consider the idea that rates of aging may proceed segmentally, at least to some extent. Geriatricians will certainly not be surprised by this proposition. They see this expressed in their patients every day.

Incidentally, Table 5.1 (page 233) of Rick Weindruch�s and Roy Walford�s wonderful monograph on �The Retardation of Aging and Disease by Dietary Restriction� (Charles C. Thomas, Springfield, Illinois, 1988) lists nine age-sensitive phenotypes that do not respond to dietary restriction. I imagine that more parameters can be added to that list by now. Could you respond to that, Rick or Roy? Are you out there in cyberspace?

George M. Martin, University of Washington

Is Life-Span the Best Measure of Aging?
Life span as gerontometric - an asymmetric problem
2 October 2001
Rich Miller,
Bioigerontologist
University of Michigan

The question as posed in the title (�Is life span the best measure of aging?�) is too easy, but is closely related to a much tougher question: �can an intervention that does not affect aging lead to impressive increases in life span?�

To deal first with the initial question: there are lots and lots of things that shorten life span by ways that do not involve alterations in aging. These include genes that cause lethal perinatal conditions, deciding to join a brigade of firefighters, or not wearing seat belts. Each of these (and many more from the same shelf) shorten life span, but do not do so by a change in aging using any plausible definition of that many-splendored term.

To my mind, it�s more interesting to talk about whether you can extend life span (a lot) by interventions that do not work by alterations of aging rate. To discuss this carefully requires consideration of some specific examples:

1. Lots of things can improve mean life span by effects on diseases that kill juveniles and young adults; most of the increase in life expectancy at birth in the past century has come from lowering mortality risks in the first 40 years of life (see Olshansky et al., Science 291: 1491, 2001, for real numbers.) This kind of change does not involve changes in aging rate, and that�s why most claims that a gene or drug slows aging usually start with documentation of an increase in the longevity of those adults who reach the last 10% or so of the life span. (This number used to be called the �maximum longevity� before demographers started to raise a fuss about it.)

2. Ok, so you�ve got a chemical that doubles mean life span and also doubles the life span of the longest-lived 10% of the crowd�now can you conclude that the agent is slowing down aging based on the mortality data alone? I suspect that this is usually a safe conclusion, but it�s not too hard to come up with hypothetical (and even a few real) counter-examples. For example, imagine a population of inbred mice in which everybody dies, age 5 months, from hemophilia. A gene (or Medi-mouse HMO plan) that provided the missing clotting factor would lead to major improvements in mean and maximal longevity, not because clotting factors prevent aging, but because this particular mouse stock has its life span limited by one specific syndrome. This scenario is not so far-fetched as it may seem: a famous paper showing the effects of different alleles of the mouse histocompatibility locus H-2 on life span now seems to reflect, at least partly, the effects of some of these alleles on a specific, early-life form of thymic lymphoma.

3. One way to dodge the �one-disease� bullet is to do careful necropsies on every mouse in the treated and control group. If the mice are dying of a range of diseases, and the increase in life span seen in the treated group affects with roughly equal force those mice dying of each of the major causes of death, then I think it�s safe to conclude that the treatment really does slow down aging. But this standard of proof is a lot to ask � necropsies are expensive, and you have to wait a long time to get the mice to die. The whole literature contains only a handful of papers that include terminal necropsies (as opposed to cross sectional data, which tells you little about cause of death) on more than a few dozen animals.

4. So this puts the onus on finding a reasonably wide range of age- sensitive traits that can be used in middle-aged adults to test the idea that the gene or treatment affects not merely life expectancy but also multiple signs of advancing age. If, for example, we found that a specific diet not only extends maximal longevity but also produces 22-month old mice or rats that have the immune responsiveness, clear lenses, impressive biceps, endocrine profiles, and gene expression patterns of a healthy 12 month old, we�d be able to claim that the stuff slowed down aging. It took the calorie restriction folks a generation to accumulate this kind of a dossier on CR rodents, and parallel work on mutations that extend mouse life span is only slowly getting under way (advertisement: see Flurkey et al., PNAS 98: 6736 � 6741, 2001). This is a tough (but not hopeless) problem for worm and fly mavens, whose favorite organisms are short on biceps and T cells.

In practice, I try to take a compromise position: if the treatment extends maximum longevity, I promise to take it very seriously indeed, and vote a good priority score even if the grant application has a few problems here and there. If the longevity data is accompanied by evidence that the treatment or gene alters a handful of age-sensitive traits in a consistent direction, then I add the treatment to the short list of age-retarding regimens. This list is, however, a very short one so far: calorie restriction and dwarf mice.

Rich Miller, University of Michigan

SAGE Viewpoint
SAGE KE: An Intellectual Home for Scientists Who Seek to Understand Why and How Organisms Age
Martin (3 October 2001) [Full text]
SAGE KE: An Intellectual Home for Scientists Who Seek to Understand Why and How...
Plaudits and comments on SAGE KE
4 October 2001
Dave Teplow,
Protein chemist/neurologist/logophile
Brigham and Women's Hospital and Harvard Medical School

First, let me applaud your efforts and offer my opinion that the SAGE KE site will be of immense value as a central repository and provider of information to those doing research in aging. A similar type of site devoted to Alzheimer's disease, the Alzheimer's Forum (www.alzforum.org), has already demonstrated the utility of this type of information resource.

Second, it's nice to know that as we researchers age, there will be a home for us. As you stated, "Our goal is to serve as an intellectual home base for the aging research community."

Third, as an alumnus of the U Dub, "Go Dogs!"

SAGE KE: An Intellectual Home for Scientists Who Seek to Understand Why and How...
Re: basic science or clinical science?
3 October 2001
George M Martin,
Pathologist
University of Washington

It is very nice indeed to hear from a colleague in Allergy and Immunology who has a focus on pulmonary obstructive disease. In answer to his question, the focus of SAGE KE during this early phase of its existence is very much on basic science, but this would include basic science that may inform us as to how underlying processes of the biology of aging that may impact upon clinically significant phenotypes, including pulmonary obstructive disorders. (Are there pulmonologists out there who can weigh in on that subject?)As I indicated in my Viewpoint article, we look forward to a second phase in the development of SAGE KE with a strong focus on the clinical sciences as they relate to problems of aging. Needless to say, all of us want to see translational research that benefits patients.

SAGE KE: An Intellectual Home for Scientists Who Seek to Understand Why and How...
basic science or clinical science?
3 October 2001
Monroe King,
Allergist immunologist
U of South Florida

Is the focus of the site basic, molecular science or applied clinical science? We are trying to bridge this gap in our division of Allergy and Immunology at the University of South Florida. We are particularly intested in the effects of aging on the diseases of asthma and related obstructive pulmonary disease. I welcome input and dialogue on this subject.

Monroe King

SAGE Viewpoint
A SAGE KE Primer
Davenport et al. (3 October 2001) [Full text]
A SAGE KE Primer
Re: More historic archived info on Human genome?
18 October 2001
Paul Anthony Mazzuca,
researcher/ caretaker
Mom and Dad

Dear Editors: I imagine it would be useful to see some articles from around the end of last year when the Human Genome Project was mainly finished. Speeches were given about the importance of knowing the sequential nature of human genes and that the next challenge was the relationships between genes and how their messangers/proteins communicated their directions. Thanks and good work! Paul Mazzuca 703 751-0005

A SAGE KE Primer
More historic archived info on Human genome?
18 October 2001
Paul Anthony Mazzuca,
researcher/caretaker
Mom and Dad

While I love brownies and seek their points, I imagine it would be useful to see some articles from around the end of last year when the Human Genome Project was mainly finished. Speeches were given about the importance of knowing the sequential nature of human genes and that the next challenge was the relationships between genes and how their messangers/proteins communicated their directions. Thanks and good work! Paul

SAGE Perspectives
Biomarkers of Aging
Miller (3 October 2001) [Abstract] [Full text]
Biomarkers of Aging
near term solutions consistently ignored: alt-711
11 November 2001
Michael L Murray,
geneticist
Reliagene Technologies

I have read several articles on this site and I have also done several literature searches. The site consistently ignores the development of near-term solutions to some of the problems of aging in favor of long- winded theoretical discussions. This article is a case in point: it mentions high levels of collagen cross-linking but fails to mention that a drug exists that is currently in 2 phase 2 and one phase 1 trial, and that has already produced promising results in animal studies and in phase 1 and 2 clinical trials. The drug is alt-711. See www.alteonpharma.com for info. Also, see these references: : Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG. Related Articles

Improved arterial compliance by a novel advanced glycation end- product crosslink breaker. Circulation. 2001 Sep 25;104(13):1464-70. PMID: 11571237 [PubMed - indexed for MEDLINE]

2: Doggrell SA. Related Articles

ALT-711 decreases cardiovascular stiffness and has potential in diabetes, hypertension and heart failure. Expert Opin Investig Drugs. 2001 May;10(5):981-3. Review. PMID: 11424901 [PubMed - indexed for MEDLINE]

3: Ulrich P, Cerami A. Related Articles

Protein glycation, diabetes, and aging. Recent Prog Horm Res. 2001;56:1-21. Review. PMID: 11237208 [PubMed - indexed for MEDLINE]

4: Vaitkevicius PV, Lane M, Spurgeon H, Ingram DK, Roth GS, Egan JJ, Vasan S, Wagle DR, Ulrich P, Brines M, Wuerth JP, Cerami A, Lakatta EG. Free in PMC , Related Articles

A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1171-5. PMID: 11158613 [PubMed - indexed for MEDLINE]

5: Melton L. Related Articles

Age breakers. Rupturing the body's sugar-protein bonds might turn back the clock. Sci Am. 2000 Jul;283(1):16. No abstract available. PMID: 10881297 [PubMed - indexed for MEDLINE]

6: Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. Free in PMC , Related Articles

An advanced glycation endproduct cross-link breaker can reverse age- related increases in myocardial stiffness. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2809-13. PMID: 10706607 [PubMed - indexed for MEDLINE]

7: Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, Poitevin P, Swennen GN, Vasan S, Egan JJ, Ulrich P, Cerami A, Levy BI. Free in PMC , Related Articles

Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4630-4. PMID: 9539789 [PubMed - indexed for MEDLINE]

SAGE Perspectives
Using Yeast to Discover the Fountain of Youth
Kaeberlein et al. (3 October 2001) [Abstract] [Full text]
Using Yeast to Discover the Fountain of Youth
Re: Re: Re: The sir2 overexpression and knockout
19 November 2001
Charles R Fred,
E.E.
none

&#65279;Re: Re: Re: The sir2 overexpression and knockout

Increasing Sir-2 expression via transgenic overrepresentation of Sir- 2 genes is only one of the paths suggested by this work.

The other path is to simulate the way caloric restriction increases Sir-2 expression - via an increased pool of NAD/NADH. Let me suggest a quick, easy experiment - with immediate and intimidating implications.

Divide a group of genetically normal mice into three groups, each fed differently. 1) A controlled diet simulating ad libitum eating; 2) a restricted calorie diet known to extend lifespan; 3) a controlled diet simulating ad libitum eating, but supplemented with additional NADH (either IV or orally with enteric coating).

Charles R. Fred cfredc1@yahoo.com

Using Yeast to Discover the Fountain of Youth
Re: The sir2 overexpression and knockout
29 October 2001
Matt Kaeberlein,
Grad Student
Guarente Lab - MIT

In response to the message from Florian Muller, a Sir-2.1 transgenic worm is in fact shown to have an extended life span. This experiment can be found in Tissenbaum and Guarente, Nature 410:227 (2001). In figure 2C, life span is shown for three different lines carrying multiple copies of Sir-2.1 integrated into the genome. In each case, both mean and maximum life span is longer than the wild type control.

The transgenic lines were constructed by PCR amplifying the Sir-2.1 gene and injecting the PCR product into wild type animals. This experiment is identical to the SIR2-overexpression experiment in yeast described in Kaeberlein et al., Genes Dev 13:2570 (1999), except for the following: (1) In yeast there were only two copies of SIR2, in worms there were multiple copies of Sir-2.1, and (2) the location of the chromosomal integration in worm

Using Yeast to Discover the Fountain of Youth
The sir2 overexpression and knockout
28 October 2001
Florian Muller

Dear Sir,

It is really great to see that a vigorous debate is starting on this web page. It is with great interest that I read your article summarizing yeast research. It seems to me that the strongest piece of evidence arguing that the clonal aging system in yeast has anything to do with aging in multicellular organisms is the "overexpression" of sir2 in C. elegans leading to increased longevity. The article cited, however, doesn't talk about overexpression but about a naturally occurring duplication in the sir2 gene of C. elegans. The obvious experiment to confirm whether higher levels of sir2 are really the causative agent in that strain is to make a transgenic worm.....is such an experiment planned or perhaps already published?

Most sincerely yours,

Florian

Using Yeast to Discover the Fountain of Youth
Re: comments on Yeast and the Fountain of Youth
25 October 2001
Matt Kaeberlein,
Grad Student
Guarente Lab - MIT

In his response to our Perspective, Dr. Gershon states that �yeast do not make a proper paradigm for aging research�. Clearly, we are not arguing that yeast are a perfect model for human aging. No model organism perfectly replicates the aging process in humans � that�s why they are models. Similar criticisms have been raised about the use of worms, flies, and mice to study aging. Some scientists would argue that human aging should only be studied in humans. We disagree.

As pointed out in our review, there are several specific features of human aging that have been, and continue to be, usefully modeled using yeast. These include oxidative stress, mitochondrial dysfunction, metabolic changes under caloric restriction, genomic integrity during aging, and the biology of Werner Syndrome/Bloom Syndrome/Rothmund-Thompson Syndrome. Furthermore, we believe that we have already gained valuable information from studying aging in yeast that suggests avenues of pursuit with respect to human aging. Specifically, the discovery that the SIR2 gene affects aging in both yeast and C. elegans begs the question of whether it also affects human longevity.

We would also like to respond specifically to Dr. Gershon�s criticisms. He claims that yeast lacks a �differentiation system which leads to the development of very specialized cell types with unique and limited repertoire of functions.� In fact, under non-standard growth conditions, yeast can form specialized cell types that are capable of pseudohyphal and/or invasive growth. This developmental switch is accompanied by a dramatic change in gene expression patterns. This example, though not directly related to yeast aging, exemplifies the principle that yeast possess the ability to respond to environmental changes with significant metabolic and morphological change. Multicellular organisms certainly have similar mechanisms for coping with environmental changes and stressful situations; it is likely that some of these can affect longevity. Therefore, the identification of the genetic pathways that modulate these responses in yeast should serve as a starting point for studies in higher eukaryotes.

Dr. Gershon also states that �A review of work from various laboratories that investigate aging in yeast shows many discrepancies and contradictions that are quite hard to reconcile.� This is a misleading argument. Some of these so-called �discrepancies� are due to strain specific differences in genetic background. In other words, genetic predispositions affect life span. The same thing is true in other model systems as well as humans, and should not be used to invalidate yeast aging. Other �discrepancies� have been caused by misinterpretation of results. For example, we and others have failed to detect more ERCs in sgs1 mutants relative to wild type (discussed in our perspective). This has been misinterpreted to suggest that ERCs do not cause aging in wild type cells � which would be a discrepancy. However, the correct interpretation is that sgs1 cells are not dying for the same reason as wild type cells, a hypothesis that has been subsequently verified.

Dr. Gershon�s final criticism, that replicative senescence plays no role in the aging of multicellular organisms, is also misleading. The study he cites does indeed suggest that cells from older individuals fail to show reduced replicative capacity. However, many other studies have found an inverse correlation between replicative capacity in tissue culture and donor age (for a recent example see Yan et al., Mech Age Dev. 122:695). The importance of replicative senescence in the human aging process is still an open issue, and is likely to be cell type specific. Clearly then, it is not appropriate to dismiss yeast as a model system based on this argument.

Matt Kaeberlein Department of Biology Massachusetts Institute of Technology

Mitch McVey Department of Biology University of North Carolina at Chapel Hill

Using Yeast to Discover the Fountain of Youth
comments on Yeast and the Fountain of Youth
11 October 2001
David Gershon,
Professor
Technion

This is a response to the article by Kaeberlein et al in the October 3 issue of SAGEKE. Although the authors alluded to our review on yeast as model for aging research (1), they neglected to mention our main arguments in that review which cast great doubt on the validity of yeast as a proper paradigm for aging research. 1)Unlike multi-cellular organisms yeast has no differentiation system which leads to the development of very specialized cell types with unique and limited reperoire of functions. Thus in order to maintain the integrity of the multi-cellular organism there has evolved an intricate communication system among the various cell types which constitutes the control over cell replication, physiological functions and indeed programmed cell death. Another tightly related system that has evolved is a the formation of a precise and strict internal homeostatic environmet that allows secialized cell systems to function and maintain viability under varying environmental challeges. The time-dependent impairment in inter-cellular communication and homeostasis are, therefore, major elements of aging. These are completely missing in yeast. 2) What the authors call "replicative senescence" in yeast has no analogous phenomenon in multi-cellular organisms. An appropriate example is the work of Cristofalo et al(2) which demnstrates that cells derived from healthy individuals of varying ages have the same replicative capacity in tissue culture. Also there are several studies that demonstrate no limitations on cell proliferation that lead to cell depletion in old organisms (reviewed in 3). 3) A review of work from various laboratories that investigate "aging" in yeast shows many discrepancies and contradictions that are quite hard to reconcile. This and other important points are discussed in detail in our review (1). The conclusions we made were that despite the outstanding characteristics and contributions of the yeast system to molecular genetics and cell biology it is a poor paradigm for aging of multi-cellular organisms. References: 1)H. Gershon, D. Gershon, The budding yeast, Saccharomyces cerevisiae, as a model for aging research: a critical review. Mech. Ageing Dev. 120,1-22 (2000). 2) V.J. Cristofalo et al., Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc. Natl,Acad. Sci. USA 95,10614-10619 (1998). 3)H. Gershon, D. Gershon, Critical assessment of paradigms in aging research. Exp. Geront. 36,1035-1047 (2001).

SAGE Noteworthy This Week
Aiming for Ames: Test promises to ease breeding task
Strauss (3 October 2001) [Abstract]
Aiming for Ames: Test promises to ease breeding task
Untitled
2 October 2001
Jim Harper,
Postdoc
University

Admittedly, the work described in this paper is simple and straightforward, but I think it is important because of what it has to offer to gerontologists interested in using Ames dwarves as a model of delayed aging.

SAGE Noteworthy This Week
Protecting the Heart: Will studying the young save the old?
Strauss (3 October 2001) [Abstract]
Protecting the Heart: Will studying the young save the old?
Untitled
2 October 2001
Kathy Rosewell

I suggested this paper because of the profound difference of the pharmacological manipulations between the young and the old. So many times studies are only performed in young subjects and then the results are extrapolated to the older population.

SAGE News Synthesis
Life Extension--Our Salvation or Our Ruin?
Barinaga (3 October 2001) [Abstract] [Full text]
Life Extension--Our Salvation or Our Ruin?
The unpleasant necessity to discuss timescales
10 October 2001
Aubrey de Grey


Many biogerontologists are happy to state publicly that dramatic increases in human healthy lifespan potential will eventually be achieved. Few, however, are willing to predict how soon this will probably (or possibly) occur, in humans or even in mice. This is generally agreed to be the right and proper position for scientists to take regarding the relatively distant future (say, anything that's certainly several years away). Is biogerontology an exception? I believe it is. If a biogerontologist feels that we are still many decades away from really controlling aging even in mice, he or she can persuasively argue that public discussion of life extension as a realistic prospect is counterproductive to the field, since it will be interpreted as tacit approval of bogus claims that outrageously simple interventions will be effective. But conversely, a biogerontologist who considers that profound interventions in mouse aging (especially ones that can be classified as reversal of aging, as opposed to just retardation) could well be only a decade away is morally obliged to state the case for that view, lest those advances catch civilisation unawares. (Interventions in mouse aging may very well not be readily translatable to humans, particularly not already-alive humans, but to rely on that -- and on the public accepting it and continuing to view extension of their own lives as science fiction -- seems like tempting providence.) Moreover, society has a right to hear the true opinions of experts on such matters now, if only to allow informed decisions on how well to fund biogerontology research. Hence, the optimist has a duty to state a timeframe within which such advances might plausibly occur and how, and the pessimist has an equal duty to specify which of those advances are in fact implausible in that timeframe and why. For an example of the former, see an article in press in Annals NY Acad Sci (linked from SAGE-KE under Resources > Web Links > Miscellaneous).

Life Extension--Our Salvation or Our Ruin?
A Sage Discussion
3 October 2001
Greg Fahy,
Scientist
21st Century Medicine

Compliments for writing a piece which properly ruminates on many of the standard misconceptions about interventive gerontology and on many of the rationalizations about "the joys of decrepitude" without falling prey to any of them. Your article ended on just the right note, i.e., Butler's observation that in a sense, we've been there and done that already. And, as the old saying goes, the best is yet to come.

Greg Fahy

SAGE Aging in the Arts
Reverse Living
Unknown (3 October 2001) [Full text]
Reverse Living
author
18 November 2001
walter bortz,
md
stanford

Author of reverse living piece is Bernie Siegel

Evolution
A test of evolutionary theories of aging
Hughes et al. (29 October 2002) [Abstract] [Full text]
A test of evolutionary theories of aging
Comment on Recent Hughes et al. Paper
28 October 2002
Daniel Promislow

Evolution has resulted in countless natural wonders�100-ton mushrooms, lizards that can walk upside down, and no less than thirty independent origins of the eye. Why, then, can such a force not hold back the seeming inevitability of senescence? A half-century ago, two biologists, Peter Medawar and George Williams, developed independent theories to explain why natural selection cannot eliminate, and will sometimes even favor, organisms that senesce.

Medawar pointed out that the ability of selection to eliminate germ-line deleterious mutations will depend on when in the course of life these mutations act. Mutations that act at very late ages will be effectively hidden from selection, and so will accumulate over evolutionary time. This occurs because mutations that reduce survival or fecundity late in life will only affect the relatively few individuals who survive to that age, and among those who do survive, these individuals will have already passed those deleterious genes on to future generations. This pool of late-acting mutations, Medawar argued, would lead to senescence.

As a corollary to Medawar's 'Mutation Accumulation' (MA) theory, George Williams developed his 'Antagonistic Pleiotropy' (AP) theory, whereby genes with late-acting deleterious effects might actually be favored by selection if these same genes are beneficial early in life. Experimental tests of these two theories date back nearly twenty-five years. Pioneering work by Michael Rose and others focused on tests of AP, looking for trade-offs between early-life fecundity and late-life survival. These early studies generally supported AP as a primary evolutionary cause of aging.

It was not until the early '90's that Kim Hughes, at the time a graduate student with Brian Charlesworth, developed the first explicit test of MA. Hughes and Charlesworth argued that under MA, additive genetic variance for fitness traits (that is, the total variation in a fitness trait that is due to genes with additive effects) should increase with age. Surprisingly, no previous studies had directly tested this idea. Hughes and Charlesworth measured mortality rates at different ages in the fruit fly, Drosophila melanogaster, and found that additive variance did, in fact, increase with age. Later studies by Promislow, Tatar, and others suggested that variance components very late in life might actually decline, contrary to what was predicted by either theory of aging. To further complicate matters, it turned out that the predicted increase in variance with age was not unique to Medawar's theory.

In a later study, Charlesworth and Hughes noted that additive genetic variance could also increase if senescence were due to genes with antagonistic pleiotropic effects. In this light, they developed models from which they derived novel predictions that were unique to each theory. According to their models, inbreeding load for fitness traits (i.e., the difference in fitness traits between outbred and inbred genotypes) should increase with age under MA but not AP. Furthermore, dominance variance (variation due to genes with dominant effects) should be relatively constant under AP, but should increase if aging is due to MA. (A third, widely cited evolutionary theory of aging�Kirkwood's 'Disposable Soma' theory�is not addressed by Charlesworth's and Hughes's quantitative genetic models).

In the October 29, 2002 issue of PNAS, Kim Hughes and her colleagues present results from a simultaneous test of these two mutually exclusive predictions. Hughes et al. measured genetic variance components for reproductive success in flies of different ages. Reproductive success, simply measured as the number of offspring produced in a vial by five males and five females, declines steadily with age. Hughes et al. discovered that as reproductive success declines, inbreeding load, additive variance and dominance variance all increase with age. They argue that these results provide strong support for the MA model and are counter to the AP model. An apparent strength of this recent work over previous studies by Hughes and others is that it focuses on reproductive success rather than mortality. The use of mortality rates to bridge the gap between quantitative genetics and experimental gerontology presents enormous statistical challenges. Early in life when mortality rates are low, and late in life when few individuals are still alive, the number of deaths is small and we may underestimate the actual variance for mortality in the population. By focusing on reproductive success, Hughes and her coworkers have attempted to circumvent these problems.

Reproductive success is not without its own challenges, however. As the authors note, this focus on reproduction narrows the window of time over which the aging process can be studied. Whereas many flies in Hughes et al.'s study survived for almost two months, reproduction had virtually ceased in most flies by the end of the first month. Thus, the apparent decline in variance seen in earlier studies could have still occurred among the flies studied by Hughes et al., but at an age later than was observed in the study. Of course, one might then ask whether a decline in genetic variance for reproductive success at an age later than anyone ever reproduces would really matter.

More importantly, although reproductive success has simpler statistical properties than mortality rates, there are still pitfalls for even the most wary. Hughes et al.'s result may be somewhat compromised by the transformation that the authors used. Reproductive success is likely to be Poisson distributed. For Poisson variables, the expected variance is equal to the mean. But we are interested in determining whether the variance changes with age (i.e., does the variance increase as the mean decreases). To eliminate this confounding mean-variance relationship, the authors square-root transformed the data. This equalizes the variance over a broad range of values. Unfortunately, the authors then further 'standardized' these transformed data to a mean value of 1 by dividing each value by the mean for the block and age in which it was found. This second transformation creates a very strong negative relationship between the mean and the variance. For Poisson-distributed random data, over a wide range of mean values (from 0.1 to 50), variance of standardized values increases as true mean decreases, approximately following the relationship: variance (of standardized value) is approximately equal to 1/2 µˆ(-5/4), where µ is the mean reproductive success. Thus, the increase in variance components observed by Hughes et al. may have been an artifact of their transformation process.

Fortunately, the other main comparison in support of MA is not affected by this issue. By comparing the pattern of decline in reproductive success between inbred and outbred flies, the authors demonstrated a marked increase in inbreeding load with age, consistent with MA.

In light of these results, Hughes et al. argue that their data provide strong support for the MA theory of aging, and little or no support for the AP theory, at least in this population. This is certainly supported by the inbreeding results, though we may need to await further analysis, in my opinion, before we can be certain about the variance component analysis.

So what are we to conclude from this study? Is AP an aged theory?

Given previous evidence in favor of AP, and now the accumulating data supporting MA, it is likely that both forces play an important role in the evolution of aging. Why might Hughes et al.'s study have found little evidence for AP? Hughes et al. analyzed reproductive success, whereas previous studies have focused on survival rates. It may turn out, as experiments by Rose and his colleagues have shown, that the genetic architecture of aging differs among traits. Perhaps reproductive traits are more likely to be influenced by MA, while survival is affected by AP. This question is likely to be a continuing focus of research in the coming years. In answer to the question of which theory explains the evolution of aging, if I were a betting man, I'd put money down on both.

Thanks to work by Kim Hughes and others, we now have substantial evidence for both MA and AP models for the evolution of senescence. It is likely that genes of both types influence the aging process. A continued 'MA versus AP' debate may do little to advance evolutionary studies of senescence. But evolutionary gerontologists still have much to do. Among the many avenues of study that should provide fruitful findings in the evolutionary study of aging, I suggest three here. First, we need to integrate modern molecular genetic approaches with existing evolutionary models, identifying specific genes or gene regions that show effects consistent with MA or AP. Second, we need to develop theories to determine if specific types of traits are more likely to be influenced by MA versus AP, if in fact both forces are important. And finally, we need to move from a focus on the genetic causes of senescence to a broad exploration of the evolutionary and ecological consequences of senescence.

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer...
MA Pappolla, TK Bryant-Thomas, D Herbert, J Pacheco, M Fabra Garcia, M Manjon, X Girones, TL Henry, E Matsubara, D Zambon, B Wolozin, M Sano, FF Cruz-Sanchez, LJ Thal, SS Petanceska, and LM Refolo
Neurology 2003; 61: 199-205 [Abstract]
Cholesterol and Alzheimer's: is amyloid beta a cause or consequence of the disease? 10 August 2003
Alexei R. Koudinov,
neuroscientist and editor
Russian Academy Med Sciences; Neurobiology of Lipids

Dear colleagues, @

I would like to alert you of a series of Neurology articles and communication arising on the role for cholesterol and lipids in Alzheimer's disease and other neurodegenerative diseases [ 1 ].

I particularly enjoyed July 22, 2003 article by Pappolla et al. [ 2 ] that adds important additional information to this hot subject of the biomedical research. This article concludes that "serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology."

I feel obliged to extend the discussion of the study by Pappolla et al. by highlighting the missed point. While many scientists continue to believe that amyloid beta protein is "a central pathologic feature of brains with AD" I feel convinced that it is an essential brain chemical [ 3 ].

I am glad that recent articles in two premier neuroscience journals, Journal of Neuroscience and Neuron [ 4 ], add to my confidence. The Journal of Neuroscience article reported "evidence suggesting that loss of endogenous amyloid beta by the pharmacological inhibition of amyloidogenesis results in a severe reduction in the viability of central neurons. In three different neuronal phenotypes, the pharmacological knock-down of amyloidogenic secretase activity resulted in cell death. This study further supports a key physiological role for the enigmatic amyloid beta peptide" while Neuron article reports on the function of amyloid beta at synapse, and that neuronal activity modulates the formation and secretion of amyloid beta peptides in the hippocampus.

Our own research suggests that amyloid beta protein is a functional player in an activity-dependent cholesterol neurochemical pathways and in synaptic structure-functional plasticity [ 5 ]. It also supports our proposed hypothesis that the change in amyloid beta biochemistry in Alzheimer's disease and related disorders is a functional (but NOT pathologic [ 5 ]) compensatory phenomenon aiming to counterbalance impaired cholesterol dynamics and associated break of neurotransmission and synaptic plasticity. Such cholesterol mediated failure of synaptic function and neural degeneration in our view may represent the primary cause of the major sporadic form of Alzheimer's disease [ see scheme in Ref. 5 ].
 

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org

Footnote: This letter is intended for researchers in all fields of biomedicine (including Neurosciences, lipid research, neurodegeneration and Alzheimer's disease). I will appreciate alerting your colleagues about Neurology articles [ 1, 2 ] and this letter. Inform a colleagues form is provided. This letter was originally prepared  as Neurology correspondence . The link for the Newsweek (July 14, 2003; July 28, 2003 International edition) cover story on cholesterol is provided below.

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience  Guidelines for Responsible Conduct Regarding Scientific Communication. This comment represents my personal view. The patent of one of the authors of the Neurology article under discussion [ 2 ] may indicate competing interest.
 

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:
 

Please note: Should you find a dead link below please navigate to Correspondence section of the author web site for updated links.

1. Engelhart MJ  et al. Diet and risk of dementia: Does fat matter? The Rotterdam Study. Neurology 2002 59: 1915-21 [ PubMed ] [ Letter to the editor ]; Jaworska-Wilczynska M et al. Three lipoprotein receptors and cholesterol in inclusion-body myositis muscle. Neurology 2002 58: 438-45 [ PubMed ] [ Letter to the editor ]; Launer LJ et al. Cholesterol and neuropathologic markers of Alzheimer's disease: a population-based autopsy study. Neurology 2001 57: 1447-52 [ PubMed ] [ Letter to the editor ]; Simons M, Keller P, Dichgans J, Schulz JB. Cholesterol and Alzheimer's disease: Is there a link? Neurology 2001 57: 1089-93 [ PubMed ] [ Letter to the editor ]; Fassbender K et al. Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology 2002 59: 1257-58 [ PubMed ].

2. Pappolla MA et al. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 2003 61: 199-205 [ PubMed ].

3. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ.  (Nov 30, 2002) [ FullText ] [ Author Related Articles and Scientific Correspondence ].

4. Plant LD et al. The production of amyloid-beta peptide is a critical requirement for the viability of central neurons. J Neurosci. 2 July 2003 23: 5531-5 [ PubMed ]; Kamenetz F et al. APP Processing and Synaptic Function. Neuron 27 March 2003 37: 925-37 [ PubMed ] [ Related Correspondence ].

5. Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol Lipids. 1, 6 (2003) [ FullText ].
 

Also see:

Cover package "Cholesterol - And Beyond" of the Newsweek issue of July 14, 2003.

Available at: http://www.msnbc.com/news/934526.asp


 

RecBCD enzyme is a bipolar DNA helicase.
MS Dillingham, M Spies, and SC Kowalczykowski
Nature 2003; 423: 893-7 [Abstract]
Two heads are better than one! 2 July 2003
Nancy Maizels

Companion papers from Taylor and Smith (Nature 423: 889) and Kowalczykowski's laboratory (Nature 423: 893) report very elegant biochemistry on E. coli's premier recombination complex, RecBCD, with direct implications for aging and genomic stability in mammals. These papers show that RecBCD containstwo separate helicase activities, one the fast 3' to 5' helicase that we've known about for years; and the other a 5' to 3' activity, vested in the previously mysterious D subunit. The two activities mean that RecBCD can completely search each strand of a duplex DNA substrate; and the paired motors explain processivity, since the holoenzyme will always have a strand to cling to. Most compellingly from Sage Ke's perspective, the results provide a likely analogy and model for function of TFIIH, composed of the XPB and XPD helicase, which themselves have opposite polarity and are clearly implicated in aging.

Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease.
C Hock, U Konietzko, JR Streffer, J Tracy, A Signorell, B Muller-Tillmanns, U Lemke, K Henke, E Moritz, E Garcia, MA Wollmer, D Umbricht, DJ de Quervain, M Hofmann, A Maddalena, A Papassotiropoulos, and RM Nitsch
Neuron 2003; 38: 547-54 [Abstract]
Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure? 29 May 2003
Alexei R. Koudinov,
neuroscientist and editor
Russian Academy of Medical Sciences; Neurobiology of Lipids, P.O.Box 1665, Rehovot 76100, Israel

Kenneth Blum
Neuron, Cell Press
1100 Massachusetts Avenue,
Cambridge, MA 02138

cc: Nobel Foundation, editors of 50+ neuroscience journals, Alzheimer�s neuroscientists worldwide

Editor,

I do not agree with (rather then doubt) your commentary [1] statement (associated with featured Neuron article of May 22, 2003 entitled �Antibodies against b-amyloid slow cognitive decline in Alzheimer's disease�[2]) that i) "the effects of antibody production are impressive� and that ii) �the findings presented are important in providing further evidence for the validity of the prevailing working hypothesis, the Amyloid Cascade Hypothesis�. The doubt is implied in the opinion of a top-level Alzheimer�s researcher David Holtzman [3], and editor-in-chief of the top-level American experimental biology FASEB Journal Vincent Marchesi [4].

Dr. Holtzman found that �the title and some of the conclusions of this study are not yet justified� [3]. He specifies that �the plasma and CSF Ab levels are not interpretable with the technique used here.� Dr. Marchesi is �concerned about the different results that are reported for the ELISA tests and the authors' tissue amyloid plaque assay� (TAPIR) [4]. Dr. Marchesi asks: �Can we rule out some nonspecific immunological reactions that cause improvement independent of the ability of the antibodies to bind to Ab?� No, we can not. Moreover, I did not find experimental evidence that TAPIR assay detects specifically Ab, not some other constituent of the amyloid plaque [2, 5]. Many studies showed great number of proteins in amyloid plaques (while amyloid beta deposition was reported in a number of human disorders including cardio-vascular pathology and several other neurodegenerative diseases [6]). Therefore, biological effects of Ab (that Hock et al. [2] as well as Winblad and Blum [1] are blindly ignoring [7]) may trigger some biochemical changes [8, 9] and cause �nonspecific immunological reactions� [4].
 

�The title and some of the conclusions of this [Neuron, Ref.2] study are not yet justified� 

(David Holtzman, Alzheimer's Potamkin Prize 2003 winner, see Ref. 3).

I would call Neuron article [2] and associated commentary [1] a bias in favor of the expired amyloid dogma-based Alzheimer�s therapy approach in case of a confidence of the authors' conflict of interest. Zurich group article acknowledgment claims that there is no conflict: �the authors declare that they have no competing financial interests related to Elan/Wyeth-Ayerst.� Prof. Dr. Roger Nitsch institutional web site [10], however, indicates that his research is funded by �AHP-Wyeth-Elan", a reasonable situation for a researchers performing clinical study �to the pharmaceutical companies ELAN and WEYTH multi-center vaccination trial of Alzheimer's disease� [11]. Dr. Nitsch also chaired the symposium on Alzheimer�s disease on July 15, 1999 during the IBRO Congress 1999 in Jerusalem [12]. This symposium was �kindly supported by Elan Pharmaceuticals, NeoTherapeutics, Parke Davis�, indicating a situation, fitting the conflict of interests definition by BMJ [13], a major general medicine journal.
 

�Science, and biomedical science in particular, is competitive, and for many is a pursuit that generates considerable passion and emotion. No wonder, then, that competing scientists working in the most competitive disciplines occasionally come to blows. Research into HIV and Alzheimer disease seems to suffer more than most in this respect. Judging by recent events, this reputation seems justified, at least for the Alzheimer field. 

Repeating the charges and details of these cases here would only serve to highlight a small number of individuals who are in fact only a subset of a much larger community of biomedical researchers balancing the often conflicting demands of academia and commerce.� 

(Nature Medicine July 1999 5(7):713, see Ref. 17).

The above indicates that there is a conflict by a senior author of the Neuron article by Hock et al. [2]. If so, what is the reason of the dishonesty and breaking the cardinal tenet of academic science to make such conflict public and let readers decide whether the article �speaks for the science or for the company� [14] ?

Neuron readers also must know about the conflict associated with the key reference of the article by Hock et. al. This is �The National Institute on Aging, and Reagan Institute working group on diagnostic criteria for the neuropathological assessment of Alzheimer's disease� [15], a Neurobiol Aging publication that has important follow up competing financial interest disclosure in The Wall Street Journal article �Did ties to Alzheimer's test maker sway NIH report ?� [16] and in the Boston Phoenix article �Science for sale: a Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health� [14]. It was also covered as Nature Medicine reports [17].

The above is tightly linked with my earlier correspondence with Neuron requesting editorial investigation and disciplinary action to punish Dennis J. Selkoe, (a Harvard professor, recent member of the NIH National Advisory Council on Aging, Athena founder and Elan director [14, 18, 19]), apparent non disclosure of competing financial interests in prior Neuron publication, and while serving Neuron editorial board member [20]. You should be in receipt of my letter emailed to you and Emilie Marcus [21] on August 19, 2002. Shortly thereafter I received a reply from Neuron senior scientist Stacie Weninger. Dr. Weninger wrote to me: �I wanted to thank you for bringing this matter to our attention. We take these issues seriously, and we will look into the matter further� [21]. Since then Neuron did not come to any action [that I expected to be] commensurate with the pattern of Dr. Selkoe misconducting academic nondisclosure dishonesty [22]. Moreover, February 2003 Neuron article by Sharon et al. [23] again hided D. Selkoe (a senior author) competing financial interest, disclosure that is required by the academic ethics and the uniform requirements for the manuscripts submitted to the biomedical journals [24].

For a non disclosure of a competing interest in April 18, 2003 Science report on amyloid oligomers (a brand-new Alzheimer's disease culprit substituting amyloid plaque in the pathogenesis scheme by the amyloid cascade proponents [25]) please see Ref. 26.
 
 

�Factors such as the scope of the misconduct, the length of time the misconduct went undetected, the prestige of the individuals or institutions involved, the possible impact on public health or clinical treatment, retaliation against the complainant or other mishandling of the allegation, as well as the extent of media coverage can all play a role in the impact that a particular case may have on individual researchers or their institutions.�

(Office of Research Integrity, Handling Misconduct web page, Ref. 22)

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org
 

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience  Guidelines for Responsible Conduct Regarding Scientific Communication.
 

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:

1. Winblad B, Blum KI. Preview: Hints of a Therapeutic Vaccine for Alzheimer's?  Neuron. 38, 517-8 (22 May 2003) [ PubMed ][ SAGE KE Record ].

2. Hock C, et al. Report: Antibodies against b-Amyloid Slow Cognitive Decline in Alzheimer's Disease Neuron. 38, 547-554 (22 May 2003) [ PubMed ][ SAGE KE Record ].

3. Holtzman D, ARF advisor. ARF Commentary on [2]. Alzheimer Research Forum. Published online May 21, 2003 [ FullText ][ Associated ARF news item ].

4. Marchesi V, ARF advisor. ARF Commentary on [2]. Alzheimer Research Forum. Published online May 21, 2003 [ FullText ][ Associated ARF news item ].

5. Hock C, et al. Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 8, 1270-5 (2002). [ PubMed ].

6. Koudinov AR, Berezov TT, Koudinova NV. Alzheimer's amyloid beta and lipid metabolism: a missing link? FASEB J.  12, 1097-9 (1998) [ PubMed ]; Koudinov AR, Koudinova NV, Beisiegel U. Cholesterol homeostasis failure at neuromuscular junctions and CNS synapses: a unifying cause of synaptic degeneration ? Neurology online.  (Feb 26, 2002) [ FullText ].

7. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ online (Nov 30, 2002) [ FullText ].

8. Kamenetz F,  et al. APP processing and synaptic function. Neuron. 37, 925-37 (2003) [ PubMed ] [ Abstract at Neuron ] [ Related correspondence ].

9. Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol Lipids. 1, 6 (2003) [ FullText ].

10. Prof. Dr. Roger Nitsch. Neuro Science Center Zurich - Research Groups. University of Zurich web site. Last time viewed: May 26, 2003 [ FullText ].

11. Vaccination study for Alzheimer's disease (14.10.02). Medieninformation. University of Zurich web site. Last viewed: May 26, 2003 [ Acrobat .PDF FullText ] [ HTML Cache ].

12. Symposium on Alzheimer�s disease. Scientific Programme for 15 July 1999. IBRO Congress 1999, Jerusalem, Israel [ HTML Cache FullText ].

13. Smith R. Beyond conflict of interest. BMJ. 317, 291-92 (1998) [ FullText ] [ BMJ declaration of competing interest form ].

14. Ready T. Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health. The Boston Phoenix. (29 April 1999) [ FullText ].

15. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Consensus recommendations for the post-mortem diagnosis of Alzheimer's disease. Neurobiol. Aging.18, S1-S2 (1997) [ PubMed ].

16. Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal. (30 Nov 1998) [ FullText ].

17. Editorial. Taking more interest in conflict. Nat Med. 5, 713 (1999)  [ PubMed ] [ FullText ]; Birmingham K, Ready T. Conflict-of-interest problems lead to policy changes. Nat Med. 5, 717-8 (1999) [ PubMed ] [ FullText ].

18. Crowley D. Elan Alzheimer's expert in pre-slump share sale. The Sunday Business Post. (18 Aug 2002) [ FullText ]; Koudinov AR. Ethical conundrums: an Alzheimer's case. BMJ. Published  online Sept 12, 2002 [ FullText ]; Koudinov AR correspondence with American Academy of Neurology, Nov, 2002 - March, 2003 [ FullText ].

19. Koudinov AR. Open letter to Public Citizen's Health Research Group on Alzheimer's disease research. BMJ online. (Feb. 21, 2003) [ FullText ]; SAGE KE (Feb. 21, 2003) [ FullText ].

20. Selkoe DJ. Biography. ISI HighlyCited.com. Last updated August 15, 2001 [ FullText ].

21. Stacie Weninger response on Alexei Koudinov letter of August 19, 2002 (27 August 2002) [ FullText ].

22. Introduction. Handling Misconduct. Office of research integrity web site [ FullText ].

23. Sharon U, et al. The formation of highly soluble oligomers of a-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron. 37, 583-95 (2003) [ PubMed ].

24. Uniform requirements for manuscripts submitted to biomedical journals. International Committee of Medical Journal Editors. Med Educ.  33,  66-78 (1999) [ FullText ].

25. Robinson SR, Bishop GM, Munch G. Alzheimer vaccine: amyloid-beta on trial. Bioessays. 25, 283-8 (2003) [ PubMed ].

26. Koudinov AR. Alzheimer's amyloid beta oligomers versus lipoprotein Abeta. Science SAGE KE. (May 1, 2003) [ FullText ].
 
 

Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of...
T Sunderland, G Linker, N Mirza, KT Putnam, DL Friedman, LH Kimmel, J Bergeson, GJ Manetti, M Zimmermann, B Tang, JJ Bartko, and RM Cohen
JAMA 2003; 289: 2094-103 [Abstract]
Amyloid beta and Alzheimer's disease: an endpoint relation? 13 July 2003
Alexei R. Koudinov,
neuroscientist and editor
Russian Acad Med Sci, Moscow Russia; Neurobiol Lipids

Editor $
JAMA
515 N State St,
Chicago, IL 60610
 

Editor,

Over the past decade amyloid hypothesis for Alzheimer's disease nor provided an explanation for the pathogenesis, nor yielded the disease cure [ 1 ].

Likewise, there is no understanding for the difference in the body fluid ratio for the isoforms of the normal soluble Ab peptide, in particular for the major Ab1-40 and present in a trace quantities Ab1-42 [ 1 ].

On the other hand research by many groups provided solid evidence that in the CSF as well as in plasma Ab1-40 is associated with high density lipoproteins (HDL) (reviewed in Ref. 2). This observation integrates the association "for increasing late-life HDL cholesterol (HDL-C) levels and an increasing number of neocortical NP" [ 3 ] (neuritic plaques, composed of Ab and many other constituents, including cholesterol, and present in a number of neurodegenerative diseases and in cardio-vascular pathology, not just in Alzheimer�s [ 2 ]), thus futhering a discussion of the role for cholesterol proper in Alzheimer's disease and a role for Ab in cholesterol dynamics and lipoprotein functional biochemistry [ 2 ].

Importantly, Ab association with lipoproteins has emerged as a key factor in arresting Ab toxicity, a fact missed in the recent experimental articles on oligomeric A [ 4 ], a brand-new Alzheimer�s disease culprit substituting amyloid plaque in the pathogenesis scheme by the amyloid cascade proponents [ 1 ].

The above i) explains why it would be critical for the true disease understanding not to limit the JAMA study by Sunderland et al. to CSF Ab1-42 quantification, and to extend it with the evaluation of the CSF Ab1-40 [ 5 ]; and ii) doubts the appropriateness of the selection of the essay "designed specifically to measure the human b-amyloid 1-42 peptide in CSF in a 10 x excess background of 1-40" despite of the bequest of the Consensus report of the working group on: "molecular and biochemical markers of Alzheimer's disease", a key citation of the JAMA study [ 5 ].

With regard to this consensus report there is a need to inform readers of the missed in JAMA [ 5 ] post-publication disclosure of the competing financial interests by the chairman and the members of the working group advisory committee [ 6, 7, also see Refs. 8, 9, 10 ].
 

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org

Footnote: The earlier 312 words 5 citations version of this letter was submitted to JAMA  (Letter # JLD30273, July 1, 2003; rejected July 12, 2003).

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and an unbiased development of Alzheimer's neuroscience. I observe the Society for Neuroscience  Guidelines for Responsible Conduct Regarding Scientific Communication.
 

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:

1. Robinson SR, Bishop GM, Munch G. Alzheimer vaccine: amyloid b on trial. Bioessays.25, 283-8 (2003) [ PubMed ] ; Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ.  (Nov 30, 2002) [ FullText ].

2. Koudinov AR, Berezov TT, Koudinova NV. The levels of soluble Ab in different HDL subfractions distinguish Alzheimer's and normal aging CSF: implication for brain cholesterol pathology? Neurosci Lett. 314: 115-118 (2001) [ PubMed ] [ Author Related Articles and Scientific Correspondence ]; Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol Lipids. 1, 6 (2003) [ FullText ].

3. Launer LJ, White LR, Petrovitch H, Ross GW, Curb JD. Cholesterol and neuropathologic markers of AD: a population-based autopsy study. Neurology. 57, 1447-52 (2001) [ PubMed ] [ Correspondence ].

4. Koudinov AR. Alzheimer's amyloid beta oligomers versus lipoprotein Abeta. Science SAGE KE. (May 1, 2003) [ FullText ].

5. Sunderland T, Linker G, Mirza N, et al. Decreased b-Amyloid 1-42 and Increased Tau Levels in Cerebrospinal Fluid of Patients With Alzheimer Disease. JAMA. 289, 2094-103 (2003) [ PubMed ].

6. Growdon JH, Nitsch RM, Wurtman RJ, inventors; Massachusetts Institute of Technology, assignee. Antemortem diagnostic test for Alzheimer's disease. US patent  5,631,168. 1997 May 20 [ USPTO Record ].

7. Thies B, Truschke E, Morrison-Bogorad M, Hodes RJ. Consensus report of the Working Group on: molecular and biochemical markers of Alzheimer's disease. Letter to the editor. Neurobiol Aging.20, 247 (1999) [ PubMed ] [ Article under discussion Neurobiol Aging. 19(2), 109-16 (March-April 1998) [ PubMed ]; Erratum in: Neurobiol Aging. 19(3), 285 (May-June 1998) ].

8. Koudinov AR. Open letter to Donald Kennedy: AAAS, Science, Alzheimer�s disease and academic dishonesty. Science SAGE KE. (June 16, 2003) [ FullText ] ;

9. Barinaga M. Confusion on the cutting edge. Science. 257, 616-8 (1992) [ PubMed ] ;  Koshland DE Jr. Conflict of interest policy. Science. 257, 595 [ PubMed ].
 
 

Ref 9 key citation:

"Consider two cases that epitomize the thorny problems associated with conflicts of interest in today's cutting-edge biology. Harvard neurologist Dennis Selkoe is at the top of his field- the biological mechanisms of Alzheimer's disease- and is widely sought after as an author of both scientific and semipopular reviews. Indead, within 2 recent years, reviews of Alzheimer's research by Selkoe appeared in Science, Neuron, and Scientific American. All Three reviews mention work by scientists at Athena Neurosciences, a young biotech company that is doing key research aimed at eventually developing diagnostic tests or treatments. But what readers don't learn from reading any of these reviews is that Selkoe is the scientific founder and one of the largest shareholders in Athena: According to the company's prospectus, when Athena went public last November, Selkoe owned 255,000 shares of Athena stock, worth just over $3 million. ...Editors at Science [AK: in 1992, not now, so see Ref. 8 for the story extension] weren't aware of Selkoe's role in founding Athena when he wrote a commentary on several papers, including one from Athena, in 1990..."
 

10. Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal. (30 Nov 1998) [ FullText ] ; Ready T. Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health. The Boston Phoenix. (29 April 1999) [ FullText ] ; Birmingham K, Ready T. Conflict-of-interest problems lead to policy changes. Nature  Med. 5, 717-8 (1999) [ PubMed ] [ FullText ].

JOURNAL OF GERONTOLOGY: BIOLOGICAL SCIENCES
Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period
Walford et al. (1 June 2002) [Abstract] [Full text]
Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal,...
Untitled
25 June 2002
Steven Austad
University of Idaho

In September 1991 four men and four women entered the Biosphere 2, a 3+ acre ecological chamber containing miniature biomes (rain forest, savannah, desert, ocean, marsh, agricultural station, and living quarters), with the express purpose of remaining completely self-sufficient over a two-year stay. It quickly became apparent that the "Biosphereans" were not going to be able to produce as much food as they had anticipated, and so began the only long-term experiment in human caloric restriction with a nutrient-dense diet.

Roy Walford, one of the Biosphereans, and colleagues have now published the analysis of blood and urine samples taken at intervals during the entire experiment, as well as similar measures from before and after, so that these these results could be compared to similar measures in laboratory rodents (in which caloric restriction clearly slows aging) and monkeys (in which the effects of caloric restriction on aging are not yet established).

The first thing to note is that there are substantial differences between the human and animal studies. First of all, the humans were highly variable in size hence were calorically restricted to various degrees in that they all consumed the same diet, which ranged from about 1750 to 2100 kcal/day over the course of the experiment. Thus, the subjects were calorically restricted to varying degrees. In fact, the largest person lost nearly one-third of his body mass over the first six months of the experiment while the smallest lost about 11% of hers. The body mass index of some of the individuals even reached levels that would be consistent with anorexia nervosa in a clinical setting. Second, the atmosphere in the Biosphere did not remain at equilibrium, so that at times the oxygen levels were equivalent to living at 14,000 feet elevation. And finally, unlike laboratory animals, the Biosphereans were forced to assume a brutal work (i.e. exercise) level � 70-80 hour work week, often entailing heavy manual labor.

Several aspects of the results are of note. The Biosphereans were in excellent health at the beginning of the experiment, with blood pressures averaging 108/77 mm Hg and total blood cholesterol of about 190 mg/dL. These values (as previously reported for the first six months of the experiment) dropped even further during the experiment, but notably returned to pre-experiment levels within eight months after the experiment ended. Many of the physiological changes observed were consistent with both rodent and monkey experiments, although the interpretation of these changes aren�t always obvious. For instance, total white cell count fell by nearly one-third, which is consistent with rodent and monkey experiments, but lowered white cell count is also a predictor of increased mortality probability in the elderly. So whether the Biosphereans were immunostimulated or immunosuppressed isn�t clear. Also, somewhat surprising is the fact the women did not miss menstrual cycles nor did the men exhibit declines in testosterone. A robust results of caloric restriction in rodents is a suppression of reproductive ability, which did not seem to occur in these humans. One interpretation would be that even at this level of caloric intake, the humans were not subjected to anything like the degree of restriction in most rodent studies. The last intriguing result is that neither growth hormone, nor insulin-like growth factor-1 (IGF-1) was significantly altered, which is in contrast to most rodent studies. In fact, reduced IGF-1 is now a primary candidate for a causal hormonal change associated with extended life, since it is observed universally under caloric restriction in rodents, and also in all four genetically-altered dwarf mice which live up to 50% longer than controls.

With this mixture of consistent and inconsistent changes relative to rodent experiments, my guess is that people who previously took it as an article of faith that caloric restriction would retard aging in humans will feel this even more emphatically. Also, researchers who were more skeptical will remain so. However, this is likely the best data on caloric restriction in humans that is likely to be available in the foreseeable future. We should appreciate the considerable efforts of the Biosphereans to accumulate these data.

Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal,...
Comment on Walford J. Gerontol (2002) paper
17 June 2002
Richard M. Miller

Comment on Walford J. Gerontol. (2002) paper

No one has ever faulted Roy Walford for cowardice, either personal or scientific. A career that starts in the professional theater, moves to the fore of research on immunological aging, pioneers the rediscovery of caloric restriction as an essential strategy for investigation of the aging process, and then takes a leave of absence from our home planet's biosphere can hardly be considered typical, or recommended to the faint of heart. Walford's 1967 monograph on the aging immune system was the first hardcover work I purchased on biogerontology, and his magisterial review, with Rick Weindruch, on the effects of caloric restriction is the book I take down to consult most frequently. Tired (I suppose) of the vicissitudes of academia, sated (one can assume) with documenting the palatability of low calorie, high broccoli diets and the effects of radical tonsure on body temperature, and proud (we conjecture) to see hoards of new scientists prying apart the calorie restricted rodent he helped to bring to prominence, Roy in 1991 locked himself up for two years in his own semi-private biosphere, at age 67 the one quasi-geriatric outlier in a crowd of 8 astronaut explorer types and an unexpectedly abundant menagerie of cockroaches, from which he has now emerged, much thinner, with the first comprehensive data set in which to explore the effects of long-term caloric restriction on human physiology.

His newly published paper (J. Geronotol. Biol. Sci. 57A:B211-B24, 2002) provides much to ponder and to admire. By mischance, the Biospherians found themselves with a good deal less to eat than they would have wished to eat given their druthers, and (like the average CR rodent) no way to do anything about it. They spent the next two years doing more hard physical work than your average reader of the Journal of Gerontology, and eating a nutritionally adequate, low fat, mostly vegetarian diet containing about 70% - 80% of their pre-entry caloric intake. Each of the eight volunteers lost about 15% - 21% of their starting body weight, maintained this weight, perforce, until they emerged two years later, and then promptly regained the weight they'd lost, all the while donating tubes of blood as frequently as most of us check our e-mail. Although the Biosphere experiment had not originally been planned as a model for human caloric restriction, Walford and his colleagues quickly realized, in medias res, that they had been offered a serendipitous opportunity to monitor the effects of longish-term restriction on a wide range of physiological and (particularly) blood chemical indices, and took full advantage of their good luck to collect and analyze serial blood samples taken throughout their confinement and for several years thereafter. Analysis of these materials, and the accompanying data on blood pressure, heart rate, temperature, and related clinical information, make up the bulk of this valuable compilation.

Were this paper merely a data dump of this unprecedented set of measurements, it would still be of high scientific interest; but Walford and his colleagues provide many bonuses: an innovative statistical approach that squeezes as much information as possible from the low number of independent subjects, a very valuable table comparing the results with analogous studies of monkey and rodent CR and with the few comparable human studies, and a cogent, focused discussion of the implications of the new findings with respect to postulated mediators of the CR-longevity association, such as alterations in glucose and insulin levels, alterations in hormones on the GH/IGF axis, blood lipids thought to protect against specific forms of cardiovascular illness, and effects on reproductive endocrinology. It is noteworthy that the CR regime did not interrupt the menstrual cycle of any of the four women volunteers, potentially good news for those who might wish to delay pregnancy until their sixth or seventh decade through dietary manipulation of aging rate. The before-and-after pictures of the senior author, in the style of Richard Avedon, should make reprints of this paper highly sought after as collector's items.

This is not a flawless study. If one wished to design such a study from scratch, the design would allow disentanglement of the effects of low caloric intake from the potential confounders of hard labor, low fat intake, and the psychological stresses of moving to new accommodations with new companions and new job assignments and unfamiliar food choices, heavy on the papaya and light on the Fritos. (Such a study would elicit an amused chuckle at the local IRB.) On the other hand, it is not a study likely to be repeated until NASA starts to ship tourists to Mars. I suspect that Roy Walford plans to be in the front of the line for Mars tickets, vacutainer kit in hand. In the meantime we should be grateful for this optimally informative exploitation of a lucky windfall.

- Rich Miller, University of Michigan, June 14, 2002

Articles
Increased T cell reactivity to amyloid ß protein in older humans and patients with Alzheimer disease
Monsonego et al. (1 August 2003) [Abstract] [Full text]
Increased T cell reactivity to amyloid ß protein in older humans and patients with...
Amyloid beta road show
13 August 2003
Alexei R. Koudinov,
neuroscientist and editor
Russian Academy Med Sciences, Neurobiology of Lipids

Where the mind is without fear and the head is held high; 
Where knowledge is free; 
Where the world has not been broken up into fragments by narrow domestic walls; 
Where words come out from the depth of truth; 
Where tireless striving stretches its arms towards perfection; 
Where the clear stream of reason has not lost its way into the dreary desert sand of dead habit; 
Where the mind is led forward by thee into ever-widening thought and action-- 
Into that heaven of freedom, my Father, let my country awake. 

from Rabindranath Tagore's Gitanjali 
Source: BMJ Clin Med Netprints Poem
 

Dear colleagues, @

I read with interest the articles on Alzheimer's disease and amyloid beta protein in the August 1, 2003 issue of The Journal of Clinical Investigation (JCI). These are articles by Monsonego et al. [ 1 ] and by Eriksen et al. [ 2 ]. Additional "insight into research articles" is provided in the accompanying commentary by Cirrito and Holtzman, in the issue cover image, and in two associated EurekAlert news reports [ 3 ].

The above contribution series in my view represent the road show (a term used in Nature Medicine citation, see below) built on a promise for amyloid beta pathogenic primacy in Alzheimer's disease, a well overdue amyloid hypothesis, and an expired approach to treat Alzheimer's by tackling brain b-amyloid.

What all three articles miss is a single mention that amyloid b protein is an essential brain chemical. This was covered in details in the contribution published elsewhere [ 4, 5, 6, 7 ].

The major flaw of the reported Alzheimer's research is the failure of the article by Monsonego et al. to provide a true competing financial interest declaration for senior authors, Dr. Dennis J. Selkoe and Dr. Howard L. Weiner. The Monsonego et al. article footnotes� conflict of interest disclosure says that "the authors have declared that no conflict of interest exists." This statement does not seem to be true.

An early report on D. Selkoe financial conflict of interest come from the Science magazine issue of July 31, 1992 [ 8 ]:
 

"Harvard neurologist Dennis Selkoe is at the top of his field - the biological mechanisms of Alzheimer's disease - and is widely sought after as an author of both scientific and semipopular reviews. Indead, within 2 recent years, reviews of Alzheimer's research by Selkoe appeared in Science, Neuron, and Scientific American. All Three reviews mention work by scientists at Athena Neurosciences, a young biotech company that is doing key research aimed at eventually developing diagnostic tests or treatments. But what readers don't learn from reading any of these reviews is that Selkoe is the scientific founder and one of the largest shareholders in Athena: According to the company's prospectus, when Athena went public last November, Selkoe owned 255,000 shares of Athena stock, worth just over $3 million. ...Editors at Science [AK: in 1992, see Ref. 9  for the story extension] weren't aware of Selkoe's role in founding Athena when he wrote a commentary on several papers, including one from Athena, in 1990..." (detailed in Ref. 8).

We later learn that Dr. Selkoe is "a Harvard researcher [who] stands to profit from a product he "independently" reviewed for the National Institutes of Health", and that Dr. Selkoe is an "Elan Alzheimer's expert in pre-slump share sale" [in 2002] [ 10, 11; also see Ref. 9, 12 ].

Two minute search with a web search engine for Howard Weiner uncover three reviews [ 13, 14, 15 ] (including the one in Nature Medicine [ 13 ]) for the book by Quinn entitled "Human Trials: Scientists, Investors, and Patients in the Quest for a Cure". Quoting WebMD review [ 14 ]:
 

"The book tells the story of Howard Weiner, a professor of neurology at Harvard conducting research on multiple sclerosis (MS), who develops a technique for inducing immunologic tolerance by oral administration of antigen. He forms a company, Autoimmune, Inc., which attempts 2 clinical trials -- one a trial of myelin basic protein to treat MS, and the other a trial of collagen to treat rheumatoid arthritis (RA). In neither trial does he show a significant difference between the experimental agent and placebo, due to an unusually high placebo response rate. This leads to the failure of Autoimmune, Inc." (detailed in Ref. 14).

Further search for "Selkoe+Weiner" links to a story in Harvard Gazette on how D. Selkoe and H. Weiner "decided to fight Alzheimer's with the same protein that seems to cause it", and how "they have successfully treated Alzheimer's disease in mice by putting drops of vaccine in their noses" [ 16 ].  An additional search for "Elan+Autoimmune" uncovers apparently related to JCI article agreement between Weiner's Autoimmune Inc. and Selkoe's Elan, while the latest news are briefed at Autoimmune Inc. page at Forbes magazine Markets section.

The search of USPTO web site further discloses that Dr. Weiner is an inventor of twenty nine US patents [ 17 ]. All 29 patents list "Autoimmune, Inc. (Lexington, MA)" as patents' "Assignee:" (Please note that the total number of  Autoimmune, Inc. patents is 31 according to the USPTO search performed on August 4, 2003).

The above information indicates the break of the Uniform Requirement for Manuscripts submitted to biomedical journals [ 18 ]. The Uniform Requirements state:
 

"Authors: When they submit a manuscript, whether an article or a letter, authors are responsible for recognizing and disclosing financial and other conflicts of interest that might bias their work. They should acknowledge in the manuscript all financial support for the work and other financial or personal connections to the work.  ...the information should be made available so that others can judge their effects for themselves." (detailed in Ref. 18).

Please note that JCI commentary author [ 3 ] has related patent [ 19 ] that may also indicate a conflicting interest.

As Nature Medicine reports in a book review [ 13 ], "Quinn's version of the Weiner-AutoImmune story is not fashioned to examine how corporate interests and funding influence, distort - and maybe even corrupt - the training of research fellows, the agenda of academic researchers, the integrity of research data and the dissemination of research results."

In light of the provided facts I feel that the above definition also does apply to the August 1, 2003 JCI Alzheimer's contribution [ 1 ].

I wonder what my colleagues think about the above? I welcome all to express their opinion using a SAGE KE response feature. This is because as Alzheimer's researchers we (but not JCI, Science, Nature, or Neuron editors [ 9 ]) are responsible for safeguarding honest development of Alzheimer's neuroscience for the public (not private) interest.
 
 

Nature Medicine book review (Ref. 13) key citation on 
Weiner-AutoImmune relationship.

"To be sure, there is whispered acknowledgment that the potential impact on AutoImmune's stock price might have affected the selection of the journals in which to publish, and questions are raised about the appropriateness of jumping to a Phase III randomized trial in MS when oral tolerance had been tried on only a handful of patients, without ever having determined a 'correct' dose. But much more is missing. Quinn writes, "because AutoImmune was cutting back to bare bones, the company could no longer underwrite much research in the [Weiner] lab." Nothing more is said of the ethical concerns raised by the apparent co-mingling of the company and Weiner's Harvard research group. Indeed, that this might be a serious concern does not even seem to occur to Quinn. One chapter describes the 'road show' by Weiner and AutoImmune's CEO, Bob Bishop, to raise investor interest. While Weiner's videotaping of the road show and the bonhomie between Weiner and Bishop are tenderly described, no serious treatment is attempted of the ethics or wisdom of a Harvard professor spending 18 continuous days wooing investors, and the countless other days devoted to work at the biotechnology company. Quinn's version of the Weiner-AutoImmune story is not fashioned to examine how corporate interests and funding influence, distort and maybe even corrupt the training of research fellows, the agenda of academic researchers, the integrity of research data and the dissemination of research results."

Does the above paint D. Selkoe role in Alzheimer�s field

While thinking of it please make a note of  both D. Selkoe and H. Weiner service for federal advisory boards, National Advisory Council on Aging [ 20 ] and FDA Peripheral and Central Nervous System Drugs Advisory Committee [ 21 ], respectively. 

Sincerely,

Alexei Koudinov, MD, PhD
neuroscientist and editor
http://anzwers.org/free/neurology
http://neurobiologyoflipids.org

Footnote: This letter is intended for researchers and graduate students in all fields of biomedical research (including Neurosciences and Alzheimer's disease research). The bodies that were informed about this letter are: Alzheimer's association (thanks to a caring reader); Neuroscience and Neuropsychology of Aging Program, National Institute on Aging, NIH; WAME; COPE; editors of 50+ neuroscience journals; ORI; and Nobel Foundation. I will appreciate alerting your colleagues about JCI articles and this letter. Inform a colleague form is provided.

Competing financial interests: I do not have any competing financial interest. I aim free information dissemination and a honest development of Alzheimer's neuroscience. I observe the Society for Neuroscience  Guidelines for Responsible Conduct Regarding Scientific Communication. This letter represents my personal view and  aims to contribute to SAGE KE scope "to create a setting where researchers feel encouraged to share data and engage in discussion".
 

[ Inform a colleague ] [ koudin{at}med.pfu.edu.ru ]

References:
 

Please note: Should you find a dead link below please navigate to Correspondence section of the author web site for updated links. Also watch for [ Reprint ] links next to dead links (if any) to have instant access to documents at alternative web resources.

1. Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, Budson AE, Sperling R, Selkoe DJ, Weiner HL. Increased T cell reactivity to amyloid b protein in older humans and patients with Alzheimer disease. J Clin Invest. (1 August 2003) 112: 415-22 [ PubMed ].

2. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, and Golde TE. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta42 in vivo. J Clin Invest. (1 August 2003) 112: 440-9 [ PubMed ].

3. Commentary: Cirrito JR, Holtzman DM. Amyloid b and Alzheimer disease therapeutics: the devil may be in the detail. J Clin Invest. (1 August 2003) 112: 321-3. [ PubMed ]; J Clin. Invest. issue of Agust 1, 2003 [ EurekAlert News 1 | 2 ] [ Cover image ] [ Cover image note: 'Congo Red- stained amyloid plaques in an aged Tg2576 APP mouse brain. Older Alzheimer patients have increased antibodies to amyloid b  (page 415), but long-term NSAID use may cut amyloid b  accumulation (page 440)' ].

4. Koudinov AR. Amyloid was never clearly implicated in Alzheimer's disease, so look at Abeta from a different angle. BMJ.  (Nov 30, 2002) [ FullText ] [ Author Related Articles and Scientific Correspondence ].

5. Robinson SR, Bishop GM, Munch G. Alzheimer vaccine: amyloid b on trial. Bioessays. 25, 283-8 (2003) [ PubMed ] ; Koudinov AR, Smith MA, Perry G, Koudinova NV. Alzheimer's disease and amyloid beta protein. Science online.  (14 June 2002) [ FullText].

6. Koudinov AR. Cholesterol and Alzheimer's: is amyloid beta a cause or consequence of the disease? Science's SAGE KE. (30 July 2003) [ FullText ] [ Reprint ]; Koudinov AR. Amyloid beta and Alzheimer's disease: an endpoint relation? Science's SAGE KE. (13 July 2003) [ FullText ] [ Reprint ].

7. Koudinova NV, Kontush A, Berezov TT, Koudinov AR. Amyloid beta, neural lipids, cholesterol and Alzheimer's disease. Neurobiol Lipids. 1, 6 (2003) [ FullText ] ; Koudinov AR, et al. Alzheimer's disease and amyloid beta protein: dogma is bad for science. 32nd Soc Neurosci Meeting, Program #21.11 (2002) [ Abstract and further reading ].

8. Barinaga M. Confusion on the cutting edge. Science. 257, 616-8 (1992) [ PubMed ]. Also see: Koshland DE Jr. Conflict of interest policy. Science. 257, 595 [ PubMed ].

9. Koudinov AR. Open letter to Donald Kennedy: AAAS, Science, Alzheimer�s disease and academic dishonesty. Science's  SAGE KE. (June 16, 2003) [ FullText ]  [ Reprint ]; Koudinov AR. Hasta la vista, amyloid cascade hypothesis, OR will academic dishonesty yield Alzheimer's cure? Science's SAGE KE (May 26, 2003) [ FullText ] [ Reprint ].

10. Ready T. Science for Sale: A Harvard researcher stands to profit from a product he "independently" reviewed for the National Institutes of Health. The Boston Phoenix (29 April 1999) [ FullText ]; Waldholz M, King RT, Jr. Did ties to Alzheimer's test maker sway NIH report? The Wall Street Journal (30 Nov 1998) [ FullText ]; Editorial. Taking more interest in conflict. Nat Med. 5, 713 (1999)  [ PubMed ] [ FullText ]; Birmingham K, Ready T. Conflict-of-interest problems lead to policy changes. Nat Med. 5, 717-8 (1999) [ PubMed ] [ FullText ].

11. Crowley D. Elan Alzheimer's expert in pre-slump share sale. The Sunday Business Post. (18 Aug 2002) [ FullText ]; Koudinov AR. Ethical conundrums: an Alzheimer's case. BMJ. (12 Sept 2002) [ FullText ].

12. Koudinov AR. Open letter to Public Citizen's Health Research Group on Alzheimer's disease research. BMJ online. (27 Feb 2003) [ FullText ].

13. Book review by Emanuel EJ. Nature Medicine. (Sept 2001) 7: 991, doi:10.1038/nm0901-991a [ FullText ]. Book details: Human Trials: Scientists, Investors, and Patients in the Quest for a Cure July 31, 2001 By Susan Quinn Perseus Publishing ISBN:0-7382-0182-0.

14. Book review by: David S. Shimm, MD, FACP WebMD web site. (Last viewed 3 August 2003) [ FullText ]

15. Book review by Chris Lombardi. Inside MS. Library and Literature. National Multiple Sclerosis Society Web site. (Winter 2002)  20: Issue 1 [ FullText ]. Also see: Book review by Kunii IM. Book briefs: Lab report. Business Week (30 July 2001) [ FullText ].

16. Cromie WJ. Alzheimer's vaccine looks promising. Harvard Gazette.  (14 Dec 2000) [ FullText ]. Also see: Weiner HL, Selkoe DJ. Inflammation and therapeutic vaccination in CNS diseases. Nature. 420, 879-84 (19-26 Dec 2002) [ PubMed ].

17. Howard L. Weiner, M.D. Result of the search (29 patents, performed 4 August 2003) for USPTO patents by inventor name. [ Search Result ].

18. Uniform Requirements for Manuscripts Submitted to Biomedical Journals. International Committee of Medical Journal Editors (ICMJE) web site. (Updated October 2001) [ FullText ]. Also see: Sponsorship, Authorship, and Accountability. International Committee of Medical Journal Editors (ICMJE) web site. (Last viewed 4 August 2001) [ FullText ]

19. Holtzman DM, Niven Fagan A, inventors; Washington University (St. Louis, MO), assignee. Predictive diagnostic for Alzheimer's disease. US patent  6,465,195. 2002 October 15 [ USPTO Record ].

20. Attachment A: Membership Roster. National Advisory Council on Aging. National Institute on Aging. National Institute of Health web site. Summary Minutes for [ The Eighty-Sixth Meeting May 21-22, 2002 ] [ The Eighty-Fifth Meeting Jan 29-30, 2002 ] [ The Eighty-Fourth Meeting Sept 24-25, 2001 ]. Make a note of Dr. Selkoe citation at the Comments from Retiring Members.

21. Members: Howard L. Weiner, M.D. FDA Roster of the Peripheral and Central Nervous System Drugs Advisory Committee. FDA web site. (Last viewed 4 August 2003) [ FullText ].
 

A must-read book for every student, scientist, editor, public citizen :

Science in the Private Interest: 
Has the Lure of Profits Corrupted Biomedical Research?
by Sheldon Krimsky, Ph.D.

0-7425-1479-X August 2003 240pp 

See further book details 
and read selected chapters at the publishers' book web site.


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