55 Theses

on the

Power and Efficacy

Of Natural Selection for Sustaining Health

Dr. Michael R. Rose, Professor of Ecology and Evolutionary Biology, University of California, Irvine, CA 92697-2525

Out of respect for both science and medicine, the following propositions are open for discussion throughout the World-Wide Web.

1. The biological fitness of a population is the average net reproduction of its members, which in turn is determined by their capacity to survive and reproduce; biological fitness is at the core of health.
2. Natural selection reliably produces high levels of biological fitness, and thus good health, only under the environmental conditions in which it has been acting for many generations.
3. Health and adaptation thus reflect the action of natural selection on a population in its previous environments, not its present environment, when these differ.
4. Natural selection results in the evolution of good health only when there is sufficient heritable variation affecting survival and reproduction.
5. Natural selection produces good health only when population size is large enough to overcome genetic drift; inbreeding reliably impairs health in outbreeding species.
6. Natural selection produces good health only when new deleterious mutations are rare or small in magnitude; very few novel mutations will have large and generally beneficial effects, in an environment to which a population is well-adapted.
7. Natural selection will sustain nucleotide sequences that foster biological fitness however numerous and however indirect their benefits, making the genetic foundations for the evolution of health genome-wide and complex.
8. This complex genomic foundation for adaptation in turn produces a still more complex network of interacting molecules that sustain survival, health, fertility, and function.
9. The forces of natural selection weaken with adult age in species that have distinguishable adults and no fissile reproduction.
10. When the forces of natural selection weaken with adult age, declining survival and fertility evolve in adulthood, and thus produce the decline in health which is commonly called ‘aging.’
11. If the forces of natural selection are strengthened during later adulthood, improved later health will evolve if natural selection is not impeded by very small population sizes, environmental change, or an absence of heritable variation.
12. Aging is a pattern of declining or de-tuned adaptation that is correlated with adult age only because adult age is at first strongly correlated with declining forces of natural selection.
13. The declining forces of natural selection lead to an evolutionary failure to establish the genomic information required for tuning the complex networks of life well enough to provide a high level of health indefinitely; there is no mechanistic necessity at the level of physiology to this failure.
14. Aging hypotheses based solely on supposed universal imperfections of molecular, cell, or organismal physiology are wholly falsified by the existence of biological species that do not exhibit falling average rates of survival and reproduction among large cohorts maintained under good conditions, a pattern exhibited by some fissile coelenterates, for example.
15. Aging evolves because of the previously adduced evolutionary genetic limitations to the forces of natural selection, which are affected by physiology, but aging is nonetheless not a merely physiological process.
16. Among the most important physiological constraints on the action of natural selection are trade-offs between the biological functions underlying age-specific rates of survival and reproduction.
17. When such trade-offs arise from antagonistic pleiotropic effects of genetic variants, they sometimes maintain genetic variation for functional characters, and thus selectable genetic variation for patterns of aging.
18. When such trade-offs can be physiologically tuned within the lives of individual organisms, natural selection may act to produce physiological machinery that provides life-history plasticity which enhances average fitness.
19. Such adaptive life-history plasticity will sometimes produce detectable trade-offs between survival and reproduction in the range of environmental conditions that prevailed when natural selection established such life-history plasticity.
20. A single pharmaceutical or nutritional substance will never cure aging, for aging is not a simple physiological disease or dysfunction, but the de-tuning of adaptation with adult age.
21. Multiple pharmaceutical substances or nutritional supplements will only ameliorate aging to the extent that they achieve genome-wide tuning similar to that which natural selection achieves when its forces are strengthened at later ages.
22. Repairing molecular or cellular damage will provide at most partial amelioration for the problem of de-tuned adaptation with adult age, because cumulative damage will also occur at organ and systemic levels at every physiological level as a result of the de-tuning of adaptation with age.
23. Repairing all types of cumulative damage during the aging phase will provide at most partial amelioration for the problem of declining adaptation with age, because some of this decline will be due to failures of signaling and other features of gene regulation as a result of the de-tuning of adaptation with age.
24. Altering all cell-molecular regulatory signaling during the aging phase will provide at most partial amelioration for the problem of declining adaptation, because dysfunctional signaling will also arise at organ and systemic levels as a result of the de-tuning of adaptation with age.
25. Repairing all forms of cumulative damage and altering all types of regulatory signaling during the aging phase will also fail to fully alleviate aging, because some features of aging will arise from the absence of structural gene-products required to sustain health indefinitely during adulthood as a result of the de-tuning of adaptation with age.
26. The forces of natural selection can be strengthened during adulthood by postponing the first age at which they begin to decline, which can be achieved for the force of natural selection acting on age-specific mortality by postponing the first age of reproduction.
27. Among populations which have had their forces of natural selection strengthened experimentally, detectable improvements in adult survival and reproduction have been observably achieved within dozens of generations.
28. Among such experimental populations evolving greater levels of adaptation at later adult ages, evolutionary changes in (a) structural gene frequency, (b) gene regulation, (c) patterns of cumulative damage, and (d) still other features of physiological function will reveal the mechanistic changes required to enhance adaptation at later ages in that species, and thereby ameliorate its aging.
29. Species with fully symmetrical fission as the sole means of reproduction do not have a declining force of natural selection acting on survival, and they do not evolve aging phases in which all individuals show declining survival.
30. The forces of natural selection plateau at zero values at very late adult ages, and do not decline further for all subsequent ages.
31. After the forces of natural selection plateau, it is possible for survival and reproduction to plateau at positive values due to age-independent beneficial effects of some genetic variants.
32. Before the forces of natural selection plateau, it is possible for genetic drift, due to small population sizes among other possibilities, to weaken the ability of natural selection to distinguish among genetic variants affecting later adult life, leading to the evolution of even earlier plateaus in survival and reproduction.
33. When late-adult plateaus in survival and reproduction occur, members of biological cohorts that reach such plateaus will show stabilization of some but not necessarily all functional characters.
34. Severe antagonistic pleiotropy can cause the evolution of zero late-adult survival probability even under ideal conditions, when genetic trade-offs between early reproduction and subsequent adult survival are sufficiently strong.
35. The ages at which the forces of natural selection plateau depend on the last ages of reproduction and survival in the evolutionary history of a population, allowing experimental evolution of the cessation of aging by deliberately changing those last ages in laboratory populations.
36. Experimental populations which have evolved different time-points for the cessation of aging can be used to uncover the biological foundations that determine the timing of the cessation of aging.
37. Patterns of aging, including the rates of decline of functional characters and the timing of any cessation in such decline, depend on the environments in which cohorts are raised and live as adults.
38. Some environmentally-induced variation in patterns of aging reflects the impact of selectively-favored patterns of life-history plasticity, but some environmental variation in aging does not reflect adaptive plasticity, such as that due to novel environments.
39. Patterns of adaptation are jointly determined by long-antecedent evolutionary patterns of natural selection, mutation, and inbreeding, as well as the immediate impact of environmental manipulation.
40. Experimental strategies for the study of aging that involve the introduction of novel mutations or increased levels of inbreeding will systematically impair the scientific study of aging, as they degrade and disrupt adaptation generally.
41. Experimental strategies for the study of aging that involve the use of environments that are evolutionarily novel will systematically impair the scientific study of aging, as natural selection will not have previously fostered adaptation to such novel environments.
42. As a pattern of age-dependent adaptation, aging and the post-aging period are best studied using the range of methods used to study adaptation by evolutionary biologists, such as the comparative method, experimental evolution, and genomics.
43. Experimental manipulation of the forces of natural selection is one of the most powerful methods of studying the biological foundations of aging, because it can direct experimental evolution to produce extensive genetic differentiation with respect to both the rates of aging and the cessation of aging.
44. Most of our ancestral hominin populations of the last million years benefited from increased forces of natural selection at early adult ages under conditions of relatively abundant nutrition derived from hunting, gathering, and cooking and an increased ability to defend themselves against predators, which led to the evolution of relatively slow rates of aging among humans.
45. Our ancestral hunter-gatherer populations had generally low population densities, and thus low effective population sizes, which produced relatively early cessation of aging at relatively high function due to genetic drift.
46. In the last ten to twenty thousand years, some human populations adopted extensive agricultural cultivation of grass species and the use of milk from other mammals for nutrition, a novel environment which changed the action of natural selection among populations in Eurasia and elsewhere.
47. This novel agricultural lifestyle initially depressed adaptation and health, leading to intense natural selection for adaptations to the digestion of foods derived from grasses and milk, which has since produced adaptation to agricultural conditions at early ages.
48. Agricultural populations have also undergone substantial increases in population size compared to those of their ancestral hunter-gatherer populations, which increased the effectiveness of natural selection at later adult ages, resulting in the evolution of a delay in the cessation of aging under agricultural conditions.
49. In agricultural populations over the last ten thousand years, the longer-sustained effectiveness of natural selection has resulted in an age-dependent pattern of falling adaptation to agricultural conditions in which functional decline is sustained over a longer period than was the case under hunter-gatherer conditions.
50. Children and young adults with predominantly agricultural ancestry are well adapted to agricultural conditions of nutrition and activity, but children and young adults without agricultural  ancestry are not adapted to such conditions.
51. Older adults from all human populations are not adequately adapted to agricultural patterns of nutrition and activity, resulting in an amplification of aging under such conditions.
52. All people without significant agricultural ancestry should revert to patterns of nutrition and activity which have physiological effects like those of hunter-gatherer lifestyles, in order to slow their aging and hasten its cessation.
53. Young people with significant agricultural ancestry can sustain their health with agricultural patterns of nutrition and activity, but not with an evolutionarily novel industrial lifestyle.
54. Older adults with significant agricultural ancestry cannot sustain their health with either agricultural or industrial patterns of nutrition and activity, and should instead switch to hunter-gatherer patterns of nutrition and activity in order to slow their later aging and possibly hasten its cessation.
55. Once this switch to a hunter-gatherer lifestyle among older adults has become widespread, further changes that would enhance human health at later ages can be discovered using evolutionary research tools, such as experimental evolution with model organisms and the molecular genetic analysis of human evolutionary history.

I am grateful to P. Shahrestani, M.K. Burke, and L.D. Mueller for their many useful suggestions concerning improvements to the 55 theses, not all of which I could adopt.

RECENT BOOKS AND ARTICLES THAT ILLUMINATE OR SUPPORT SOME OF THE 55 THESES FROM THE ROSE LABORATORY AND THE LABORATORIES OF OUR COLLEAGUES:

M.K. Burke, J.P. Dunham, P. Shahrestani, K.R. Thornton, M.R. Rose, and A.D. Long. 2010. Genome-wide analysis of a long-term evolution experiment with Drosophila. Nature 467: 587-590.

A.K. Chippindale, A.M. Leroi, S.B. Kim, & M.R. Rose.  1993.  Phenotypic plasticity and selection in Drosophila life-history evolution.  I. Nutrition and the cost of reproduction. J. Evol. Biology  6:171-193.

M. Matos, M.R. Rose, M.T. Rocha Pite, C. Rego, & T. Avelar. 2000. Adaptation to the laboratory environment in Drosophila subobscura. Journal of Evolutionary Biology 13: 9-19.

L.D. Mueller & M.R. Rose.  1996.  Evolutionary theory predicts late-life mortality plateaus. Proc. Natl. Acad. Sci. USA 93: 15249-15253.

L.D. Mueller, C.L. Rauser, and M.R. Rose. 2011. Does Aging Stop? Oxford University Press, New York.

C.L. Rauser, L.D. Mueller, & M.R. Rose.  2006.  The evolution of late life.  Aging Research Reviews 5: 14-32.

C.L. Rauser, J.J. Tierney, S. M. Gunion, G. M. Covarrubias, L. D. Mueller, and M. R. Rose.  2006. Evolution of late-life fecundity in Drosophila melanogaster. Journal of Evolutionary Biology 19:  289-301.

M.R. Rose.  1991.  Evolutionary Biology of Aging.  Oxford University Press, New York.

M.R. Rose.  2004.  The metabiology of life extension.  Pp. 160-176 in The Fountain of Youth; Cultural, Scientific, and Ethical Perspectives on a Biomedical Goal (S.G. Post & R.H, Binstock, Eds.) Oxford University Press, New York.

M.R. Rose.  2008.  Making SENSE:  Strategies for Engineering Negligible Senescence Evolutionarily.  Rejuvenation Research 11: 527-534.

M.R. Rose. 2009. Adaptation, Aging, and Genomic Information. Aging 1:  444-50.

M.R. Rose, M.D. Drapeau, P.G. Yazdi, K.H. Shah, D.B. Moise, R.R. Thakar, C. L. Rauser, & L. D. Mueller.  2002. Evolution of late-life mortality in Drosophila melanogaster.  Evolution 56: 1982-1991.

M.R. Rose and G.V. Lauder, Editors.  1996. Adaptation. Academic Press, New York.

M.R. Rose & L.D. Mueller.  1998. Evolution of human lifespan: past, future, and present. American Journal of Human Biology 10: 409-420.

M.R. Rose, H.B. Passananti, and M. Matos, Editors. 2004. Methuselah Flies: A Case Study in the Evolution of Aging. World Scientific Publishing, Singapore.

M.R. Rose, C.L. Rauser, G. Benford, M. Matos, & L.D. Mueller.  2007.  Hamilton’s Forces of Natural Selection after forty years.  Evolution 61: 1265-1276.

M. R. Rose, C.L. Rauser & L.D. Mueller.  2005.  Late life:  A new frontier for physiology. Physiological and Biochemical Zoology 78(6):869-878.

M. R. Rose, C.L. Rauser, L.D. Mueller, & G. Benford.  2006.  A revolution for aging research. Biogerontology 7: 269-277.

P. Shahrestani, L.D. Mueller, & M.R. Rose. 2009. Does aging stop? Current Aging Science 2: 3-11.