Sci. Aging Knowl. Environ., 6 March 2002
Vol. 2002, Issue 9, p. vp2
[DOI: 10.1126/sageke.2002.9.vp2]


Help Wanted: Physiologists for Research on Aging

George M. Martin

The author is the Editor-in-Chief of SAGE KE and is in the Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA. E-mail: gmmartin{at};2002/9/vp2

Key Words: physiology • physiologist • statistics • integrative

It is an open secret that faculty members in departments of physiology have become just like the rest of us engaged in basic science research and teaching in medical schools; virtually all of them seem to have morphed into cellular and molecular biologists. We've seen this happen before in departments of anatomy; traditional teaching of gross anatomy often had to be picked up by surgeons, and research in gross anatomy was more often found in clinical departments of radiology. Although these changes have produced some great science--witness, for example, the spectacular advances in deciphering biological structure at the molecular level--as a gerontologist, I see some dangers in the failure to nourish certain of the older, more traditional, organ-based and integrative aspects of physiology.

There are, thankfully, a few clinical geriatricians with special interests in aspects of integrative physiology; Lew Lipsitz (Harvard) is one of them. But when I go to meetings that deal with the biology of aging, I find in attendance only a single professional integrative physiologist. It is always the same one: Professor Eugene Yates of the University of California, Los Angeles (UCLA). Because Gene is a member of an endangered species, it is important to document his phenotype for future historians of science (Fig. 1).

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Fig. 1. Professor F. Eugene Yates of UCLA. The pin he is wearing is from the American Physiological Society. On the subject of recruiting physiologists to the study of aging, Yates remarked, "The plea for engaging integrative physiologists in the program of understanding human senesence is exactly right for today. Even physicists [including some with Nobel Prizes (for example, Philip Anderson and R. B. Laughlin)], whose achievements have been in the scales of the very large (the Cosmos itself) and the very small (virtual particles in an energetic vacuum), are crying out for a 'middle way'--the search for laws and principles intermediate between the microscopic state of fundamental particles and the macroscopic state of higher levels of organization." [See (10).]

Why is integrative physiology so important to those of us concerned with research on the biology of aging? The answer is obvious. Aging involves each and every organ system. Organ systems communicate with each other in order to maintain homeostasis. We need to understand how these diverse systems integrate their several languages (endocrine, paracrine, autocrine, and central and peripheral neural), which include distinct accents found in individual subjects. In addition, we need to decipher how these communications change over the life course. Solving such enigmas requires complex systems research into such issues as nonlinear dynamic networks, information theory, chaos, and fractals. These are related approaches to a new way of thinking about the core problem of biological aging: the loss of homeostasis. Yates has coined the term "homeodynamics" (1), to encapsulate the importance of understanding complex functional organizations that consist of multiple interacting, but often loosely coupled, subsystems; many of these subsystems can be envisioned as nonlinear oscillators, and essentially all can change over time, with attendant decreases in free energy and increases in entropy. Glossaries and extended discussions of these and related terminologies can be found in papers by Yates (1), Bassingthwaighte (2), Lipsitz and Goldberger (3), Faure and Korn (4), and Vaillancourt and Newell (5), among others.

As a geneticist, I have a specific agenda for wanting more physiologists to join those of us interested in the biology of aging. At the National Institute on Aging (NIA)-sponsored workshops on genetic epidemiology, I have argued vigorously for the funding of physiological assays of aging beginning at middle age (6). And I have published briefs (7, 8) on the considerable potential of longitudinal studies of middle-aged sibling pairs for revealing the genetic basis of specific components of unusually successful or "elite" aging. Here is a summary of the proposed research plan.

1) On your next trip to Bethesda, drop in to chat with NIA program managers concerned with genetic epidemiology. If their bank accounts are depleted, go home to work with yeast, fruit flies, or nematodes. If they are encouraging, go to step 2.

2) Choose a phenotype--the more specific the better, as the approach I am suggesting will not work if there are large numbers of genes, each with very small effects. For inspiration, have a look at Nathan Shock's classic cross-sectional studies of declines in various physiological parameters (Fig. 2). Note, for example, that the rate of decline in pulmonary function is particularly steep. That might influence a decision to focus on the pulmonary system. But given the hard work ahead in assembling large populations of human subjects, you would be well advised to investigate more than one system. The taxpayers who support our research seem to be particularly interested in preserving cognitive function as they age, so do not ignore the central nervous system. And especially do not ignore hippocampal functions.

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Fig. 2. Linear declines of functional assays for several different human physiological parameters as studied cross-sectionally by the late Nathan W. Shock and colleagues. The values are expressed as percentages of the average performances of healthy 20- to 35-year-old male subjects. (A) Fasting blood glucose. (B) Nerve conduction velocity. (C) Cardiac index (resting). (D) Vital capacity and renal blood flow. (E) Maximum breathing capacity. (F) Maximum work rate and maximum oxygen uptake. [Adapted from (12), with permission.]

3) Find a group of friendly, imaginative, hard-working physiologists with special experience with functional assays relevant to your chosen systems of interest. Their charge will be to develop highly sensitive assays, so that aging individuals with unusually robust retention of structure and function can be easily teased out of large populations. Given the need to screen large populations, their assays should be relatively noninvasive, quick, and cheap. Your physiologists should be willing to wait 5 or 10 years for coauthorship on papers that will be too long for publication in high-impact journals. You, therefore, will have to make some special pitch to keep them on board. Emphasize, for example, that they could publish on their novel assays while waiting for the bigger picture to emerge. And tell them that their work will be covered in SAGE KE.

4) Find at least one equally friendly and patient human statistical geneticist who can join the team on day one. (These folks are in such great demand, they will have to be hired right out of graduate school.)

5) Recruit a molecular genetics lab with facilities for exceptionally efficient high-throughput genotyping.

6) Get some local institutional pilot funding and, eventually, write an application to the NIA for Program-Project (multidisciplinary, long-term research program) or Consortium (multiple institutional) grant support.

7) Recruit a population of several thousand healthy middle-aged males and females, preferably from a cohort that is relatively homogeneous in its ethnic composition. Choose only subjects who have at least one close-aged sib (within 2 or 3 years). I would be inclined to exclude smokers, although I appreciate the interest in discovering genetic polymorphisms that may provide partial protection to smokers from the hundreds of carcinogens, mutagens, and gerontogens they inhale for most of their adult lives. Why middle-aged? Part of the answer is in Fig. 3, a summary of marathon records as functions of age. The folks who made those records are indeed members of the elite aging population. All of their body systems had to be functioning superbly well. But note that we can begin to see declines after age 30. Thus, aging begins in middle age. A particular merit of studying middle-aged subjects is that, unlike centenarians, middle-aged people do not often suffer from multiple morbid conditions. Also unlike centenarians, they are highly likely to be around for a 5- or 10-year longitudinal study of rates of decline of specific physiological functions. Finally, they are likely to have siblings in a similar age group, living parents, and living progeny. This is a scenario that sweetens the lives of geneticists. DNA from three generations can establish phase relationships of markers (that is, the determination of which allelic variations are linked to the maternal versus the paternal chromosomal lineage). Sibs allow sib-pair studies, including statistically robust approaches that emphasize extreme concordances and, especially, extreme discordances, assuming a sufficiently large sample size (9).

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Fig. 3. Records for marathon runners as a function of age. [Adapted from (11), with permission.]

8) Determine the statistical distributions of the results of annual assays to determine the rates of decline over the initial period of 5 years. Choose, as index cases for further study, subjects whose rates of decline fall into the upper one and lower one percentiles of that distribution. You are now ready to carry out sib-pair studies to seek pairs that show either extreme discordances or extreme concordances in their rates of decline. Or your statistician may encourage you to use all sib pairs who fall within those extreme ends of the distributions.

9) Collect DNA from the sib pairs for whole-genome screens and subsequent higher resolution screens. Establish the map locations of these candidate polymorphic alleles (or, conceivably, mutant alleles) that influence specific parameters of aging.

10) After having spent 5 or more years of research time and millions of dollars of grant money, you are now ready for the hard part: cloning the loci of interest and establishing haplotypes. The highest priorities, of course, are linkages that appear to influence rates of change for all or almost all of the phenotypes of interest. If we do find such global modulators, we will then have to turn to our integrative physiologists to take us to the next level.

How can we act now to get more physiologists involved in gerontological research? The availability of dedicated NIA funds for training and research grants is likely to make the greatest immediate impact. But this should be preceded by informal discussions between NIA Health Science administrators and various physiologists, gerontologists, and geneticists (such as Gene Yates, Ed Masoro, Tom Kirkwood, Mike Jazwinski, Marilyn Albert, Ellen Wijsman, Neil Risch, and Rudy Tanzi, to name but a few). This could be followed by at least two workshops: one on integrative physiology in aging research and one on physiological assays of aging in middle-aged cohorts of human subjects. The NIA might then make a decision as to the most appropriate set of requests for proposals for research and training grants.

March 6, 2002

  1. F. E. Yates, Fractal applications in biology: Scaling time in biochemical networks. Methods Enzymol. 210, 636-675 (1992).[Medline]
  2. J. B. Bassingthwaighte, Physiological heterogeneity: Fractals link determinism and randomness in structures and functions. N. I. P. S. 3, 5-9 (1988).
  3. L. A. Lipsitz, A. L. Goldberger, Loss of "complexity" and aging. J. Am. Med. Assoc. 267, 1806-1809 (1992).[CrossRef][Medline]
  4. P. Faure, H. Korn, Is there chaos in the brain? I. Concepts of nonlinear dynamics and methods of investigation. C.R. Acad. Sci. Paris Life Sci. 324, 773-793 (2001).
  5. D. E. Vaillancourt, K. M. Newell, Changing complexity in human behavior and physiology through aging and disease. Neurobiol. Aging 23, 1-11 (2002).[CrossRef][Medline]
  6. E. C. Hadley, W. K. Rossi, S. M. Albert, J. Bailey-Wilson, J. Baron, R. Cawthon, J. C. Christian, E. H. Corder, C. Franceschi, B. Kestenbaum, L. Kruglyak, D. S. Lauderdale, J. Lubitz, G. M. Martin, G. E. McClearn, M. McGue, T. Miles, G. Mineau, G. Ouellette, N. L. Pedersen, S. H. Preston, W. F. Page, M. Province, F. Sch�chter, N. J. Schork, J. W. Vaupel, J. Vijg, R. Wallace, E. Wang, E. M. Wijsman, Genetic epidemiologic studies on age-specified traits. Am. J. Epidemiol. 152, 1003-1008 (2000). See also E. C. Hadley, W. K. Rossi, S. M. Albert, J. Bailey-Wilson, J. Baron, R. Cawthon, J. C. Christian, E. H. Corder, C. Franceschi, B. Kestenbaum, L. Kruglyak, D. S. Lauderdale, J. Lubitz, G. M. Martin, G. E. McClearn, M. McGue, T. Miles, G. Mineau, G., Ouellette, N. L. Pedersen, S. H. Preston, W. F. Page, M. Province, F. Sch�chter, N. J. Schork, J. Vaupel, J. Vijg, R. Wallace, E. Wang, E. M. Wijsman, Genetic epidemiologic studies on age-specified traits.[Abstract/Free Full Text]
  7. G. M. Martin, in Handbook of the Aging Brain, E. Wang, D. S. Snyder, Eds. (Academic Press, San Diego, CA, 1998).
  8. G. M. Martin, Some new directions for research on the biology of aging. Ann. N.Y. Acad. Sci. 908, 1-13 (2000).[CrossRef][Medline]
  9. N. J. Camp, A. Bansal, The effect of selective sampling on mapping quantitative trait loci. Genet. Epidemiol. 14, 767-772 (1997).[CrossRef][Medline]
  10. R. B. Laughlin, The middle way. Proc. Natl. Acad. Sci. U.S.A. 97, 32-37 (2000).[Abstract/Free Full Text]
  11. J. F. Fries, L. M. Crapo, Vitality and Aging: Implications of the Rectangular Curve (Freeman, San Francisco, CA, 1981), p. 115.
  12. N. W. Shock, in C. E. Finch, L. Hayflick, Eds., Handbook of the Biology of Aging (Van Nostrand-Reinhold, New York, 1977), p. 639.

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