Sci. Aging Knowl. Environ., 6 October 2004
Vol. 2004, Issue 40, p. pe37
[DOI: 10.1126/sageke.2004.40.pe37]

PERSPECTIVES

Genes, Longevity, and Technology: Meeting Report from the 2nd Conference on Functional Genomics of Aging in Crete

Ralf Baumeister, and Maren Hertweck

The authors are at the Laboratory of Bioinformatics and Molecular Genetics, Institute of Biology 3, Albert-Ludwig University of Freiburg, Schänzlestrasse 1, D-79104 Freiburg, Germany. E-mail: baumeister{at}celegans.de

http://sageke.sciencemag.org/cgi/content/full/2004/40/pe37

Key Words: DAF-2 • insulin/IGF-1 signaling • SGK-1 • SIR2 • systems biology

The remarkable increase in human life expectancy in the western world is accompanied by an exponential growth in the incidence of age-related pathologies, Alzheimer's disease being one prominent example. The success of whole-genome sequencing, as well as the implementation of tools for genome-wide monitoring and analysis, now offers us for the first time the opportunity to understand, and maybe to slow down or even halt, the inexorable genetic mechanisms that underlie aging.

Against a background of the wealth of scientific information collected by the various techniques tagged with "-omics," the 2nd International Conference on Functional Genomics of Aging took place this summer in Hersonissos, Crete, close to the island's capital Heraklion. The organizers, Jan Vijg and Yousin Suh, again succeeded in gathering some two hundred experts in the field from around the world. Whereas the major topic of the first conference 2 years ago, held at Seville in Spain, had been to demonstrate some powerful new efforts to determine the genetic origin of slowed aging, this year's meeting aimed at focusing on the complexity of the biochemical and physiological systems revealed by study of the aging process (or aging phenomenon, as the organizers put it) and on the challenge of computationally integrating the experimental and molecular data on this process. This is, of course, an enormous task, and therefore the presentation of candidate technologies for systems biology approaches played a major role during the meeting.

In the opening address, Paola Timiras from the University of California at Berkeley defined the central questions of aging research, suggesting that the aging phenomenon (the observable properties of tissues and organs under the continued influence of genes and the environment) would be the most important focus for age-related studies. Timiras discussed three strategies that have been used in the past decade to study aging: (i) the inactivation of certain hormonal pathways; (ii) caloric restriction by limiting food intake (see Masoro Review); and (iii) hormonal intervention affecting regeneration of the nervous system and its synaptic plasticity.

The importance of phenotypic aspects as the main target for researchers on aging was also emphasized in the keynote lecture by Roger Brent, director of the Molecular Sciences Institute (MSI) in Berkeley, California. The phenotype, in his opinion, is really the critical issue for scaling up analyses in a systematic way; because only when investigators are armed with an overt phenotype will they be able to develop quantitative understanding of a complex system over time, eventually allowing its behavior to be predicted. Brent presented recent data from the Alpha Project, which is targeted at the extra- and intracellular information flow in a system. For this purpose, investigators at the MSI started with an (at first glance) "simple" system, the baker's yeast Saccharomyces cerevisiae. Brent discussed the analytical framework needed to model aspects of signal transduction in this system in a quantitative fashion. A study of yeast mating behavior was initiated by measuring the reaction times and rates of the individual signaling events, in order to construct a mathematical description of the process. Although expression levels of the reporter genes tested were usually well behaved (that is, stable within a single cell), the variation between individual cells, even when clonal in origin, was enormous. Brent's outlook was not overly optimistic, and he called for an entirely new applied mathematics to understand the rates of some of the reactions in the pathway, which the MSI plans to gather by examination of their time-variant outputs.

Three sessions had been organized to illustrate in turn the comparative biology of aging phenotypes, functional pathways controlling aging and longevity, and pathological processes in aging. As a valuable additional information resource, cutting-edge technologies now available to address the aging phenomenon were discussed in interspersed sessions, accompanying the talks focusing on results from more established genetic approaches.

In the first session, Caleb Finch (University of Southern California) and Linda Partridge (University College London) both presented demographic studies, of human and Drosophila populations, respectively, intended to characterize the influences of genes and environment on aging in various organisms. Quite remarkably, studying fruit flies offers the opportunity to dissect individual signaling pathways and their temporal role in preventing or accelerating mortality. Most notably, there is no obvious memory for the influences of "bad" diet; according to Partridge, dietary restriction has no effect on the accumulation of irreversible age-related damage, and instead acutely reduces the risk of death. Good news for junk food addicts: All that matters is one's current diet, so it is not too late to change.

Partridge also introduced the major role of the insulin/insulin-like growth factor-1 (IGF-1) pathway in controlling longevity, not only in Drosophila but also in Caenorhabditis elegans, the mouse, and most likely also in the human population (see "One for All"). This pathway, also serving to control stress responses in essentially all organisms studied so far, was further addressed by several other speakers during the conference. Nir Barzilai (Institute for Aging Research, Albert Einstein College of Medicine) discussed his remarkable study on Jewish centenarians, offering insights into the metabolic syndrome and the significant contribution of longevity-assurance genes that, among many other functions, seem to control (that is, reduce) plasma concentrations of IGF-1 in long-lived families. In this study of more than 300 families with centenarian members, no environmental coordinate could be linked to longevity. Instead, age-related diseases have been delayed by 30% in these families, and they are more frequently protected from metabolic syndrome. Furthermore, they have normal IGF-1 levels and normal maximal heights, suggesting that reduced insulin/IGF-1 signaling is not necessary to obtain exceptional longevity in humans. Families of centenarians also have a dramatic increase in their levels of adiponectin, an insulin sensitizer and anti-inflammatory peptide.

Tom Johnson (University of Colorado at Boulder) and Cynthia Kenyon (University of California, San Francisco), together with many others from around the world, exploit the superb genetic toolbox available to study age-related issues in the nematode C. elegans. This tiny worm has helped us to identify more than 70 genes that are involved in controlling longevity (see Johnson Subfield History), the latest being that encoding the serum- and glucocorticoid-responsive kinase SGK-1. SGK-1 functions at a crucial position in the insulin/IGF-1 signaling pathway in C. elegans and most likely in other organisms too. Genome-wide studies using RNA interference and microarray analyses have helped to begin the task of identifying downstream genes that are regulated by reduced insulin/IGF-1 signaling, caused by inactivating the key cell surface receptor DAF-2, as Kenyon originally demonstrated. Interestingly, many of the genes that extend life span when down-regulated also increase stress resistance in the nematode. This dual role is also evident for SGK-1, a kinase that is itself controlled through phosphorylation by the kinase PDK-1 and plays a major role in regulating stress response and life span in C. elegans by phosphorylating the forkhead transcription factor DAF-16. SGK-1 works together with two other kinases, AKT-1 and AKT-2, that are more important for dauer larva formation by C. elegans, as shown on one of the two award-winning posters at the meeting, by Maren Hertweck from Freiburg (1). Notably, down-regulating DAF-2 signaling in adult animals is sufficient to extend life span (see Sonntag Perspective), avoiding the obvious side effects of this manipulation that could occur during development.

Insulin/IGF-1 signaling is only one of the important players in the life-span game, however; SIR2 being another. This NAD-dependent histone deacetylase, discovered first in yeast, is studied by Lenny Guarente (Massachusetts Institute of Technology, Cambridge, Massachusetts), who uses both yeast and mouse model systems to address the consequences of SIR2 function and dysfunction. SIRT1 (a mammalian version of SIR2) may couple insulin signaling and caloric restriction, the two best-studied inputs into the genetic control of longevity, because it regulates one of the primary responses to caloric restriction, the mobilization of fat (2) (discussed in "Counterattack"; but see "Calorie Restriction Un-SIR-tainty" for a discussion of recent indications that extension of yeast life span by caloric restriction may not involve SIR2).

Although the invertebrate model systems greatly facilitate analysis of the detailed genetic interplay between molecular pathways involved in aging, the complexity of insulin/IGF-1 regulation in mammalian systems is evident, as pointed out in the special lecture by Nadia Rosenthal (EMBL, Monterotondo, Italy). This has so far prevented a quantitative characterization of IGF-1 signaling in the mouse. Nevertheless, transgenic expression of IGF-1 in skeletal muscle, for example, induces hypertrophy during aging and enhances healing of injuries. It even allows complete repair of the injured heart after myocardial infarction, suggesting that therapeutic strategies to counter the aging process and enhance tissue regeneration are feasible.

The discussion of aging in the context of physiology and pathophysiology was the focus of a whole day of the meeting, including discussions of the relation between aging and neurodegeneration (Dale Bredesen, Buck Institute, Novato, California), the circadian clock (Gijsbertus van der Horst, Erasmus Medical Center, Netherlands), and cancer (Judith Campisi, Lawrence Berkeley National Laboratory, California). The study of additional pathways contributing to our understanding of aging and decay, such as defective DNA repair resulting in Werner's syndrome (presented by Vilhelm Bohr, NIA/GRC; see also Monnat Review), also offers new perspectives on mechanistic aspects of cellular maturation and decay. A striking presentation by Nektarios Tavernarakis (Institute of Molecular Biology and Biotechnology, Crete) again made use of C. elegans as a powerful system to study the genetics of lysosomal disintegration during cellular necrosis. Examination of the crucial role of lysosomes during neurodegeneration, in particular in Parkinson's disease (see "Stuck in the Craw"), is currently experiencing a rebirth.

In addition to the genetic pathway-oriented talks, a major incentive of the meeting was the presentation of new technologies to study aging on a genome-wide or systems biology level (see Pletcher Perspective). The organizers had collected a remarkably diverse and fascinating set of experts in fields ranging from biocomputing (Jan Vijg himself contributed to this topic) and single-cell transcriptome analyses (Christoph Klein, Ludwig-Maximilians-University, Munich, Germany) to the production of biochips (Jing Cheng, Tsinghua University, China). High-throughput analyses were discussed at both the transcriptional (Edison Liu, Genome Institute of Singapore) and proteomic levels (Sam Hanas, University of Michigan Health System, and Markus Stoeckli, Novartis Institute for BioMedical Research, Basel, Switzerland). Parallel approaches to speed up drug discovery were the topics of Ralf Baumeister (University of Freiburg, Germany), whose lab uses C. elegans as a whole-animal model for target validation in high-throughput procedures, and Oliver Ploetz (Natural and Medical Sciences Institute at the University of Tübingen, Germany), who discussed the use of peptide chips for parallel analysis of ligand binding. In both talks, it became obvious that in many instances it is advisable to focus on the quality of the analyses rather than merely on the sample size, the latter now often being the criterion most in demand in industry. The wealth of data produced by integrated methods requires new concepts for data retrieval, as exemplified by the text-based analyses presented by Saira Mian (Lawrence Berkeley National Laboratory), and data storage (IUPS Physiome Project represented by Peter Hunter, University of Auckland, New Zealand). The IUPS Physiome Project tries to provide, among many other tools, a modeling framework to follow the consequences of a mutation from gene to disease. One aspect of this collaborative effort is the standardization of data input that can now be offered via the Internet; for example, to collect data from experiments on mouse mutants carried out worldwide.

This perfectly organized meeting, in a splendid environment close to the Aegean Sea, also offered culinary attractions that made one temporarily forget about the alleged longer-term benefits of caloric restriction (it is, however, the quality not the quantity of life that counts, as an obviously Epicurean attendee pointed out). The high spirits of all participants resulted in lively discussions at the posters, in the hotel lounges, and even on the beaches of the resort. Efcharisto to Yousin Suh, Jan Vijg, the omnipresent Sarah Phillips from Elsevier Science, and the local organizer, Nektarios Tavernarakis, for this splendid get-together on an island with an ancient (yet not aging) history--see you again in 2 years!


October 6, 2004
  1. M. Hertweck, C. Gobel, R. Baumeister, C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev. Cell 6, 577-588 (2004).[CrossRef][Medline]
  2. F. Picard, M. Kurtev, N. Chung, A. Topark-Ngarm, T. Senawong, R. Machado De Oliveira, M. Leid, M. W. McBurney, L. Guarente, Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771-776 (2004).[CrossRef][Medline]
Citation: R. Baumeister, M. Hertweck, Genes, Longevity, and Technology: Meeting Report from the 2nd Conference on Functional Genomics of Aging in Crete. Sci. Aging Knowl. Environ. 2004 (40), pe37 (2004).








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