6 CM2 BISCHOF Biology of aging_EN.pdf

Evolutionary Biology of Aging -- Why and how do we age? --  Dr. Oliver BISCHOF DR-CNRS / Institut Mondor for Biomedical Research (IMRB); UPEC [email protected] www.u-pec.fr/EUR-live Objective: To...

Evolutionary Biology of Aging -- Why and how do we age? --  Dr. Oliver BISCHOF DR-CNRS / Institut Mondor for Biomedical Research (IMRB); UPEC [email protected] www.u-pec.fr/EUR-live Objective: To Provide…. “…an integrative and contemporary discussion about why we get old and a firm basis for a reflection on some critical questions in our understanding of organismal senescence & human longevity.” Aging is a Global Socio-Economic Problem Jarzebski et al., npj Urban Sustain 1, 2021 Age-Related Manifestations a) Portrait of Joan Riudavets Moll (15 December 1889 – 5 March 2004)=114y b) Human cataract c) Atherosclerosis, a thickening of the artery wall. Shown here is a case of severe atherosclerosis of the aorta. Image a) courtesy of Wikipedia. Image b) courtesy of Rakesh Ahuja, M.D. Image c) courtesy of Dr. Edwin P. Ewing, Jr./CDC.  Aging = Susceptibility to (Chronic) Disease 110,000 People Die Daily of an Age-related Disease ”Intervening” in a Basic Aging Process = A Medical Revolution The Fountain of Youth: Lucas Cranach (1546) A Short History on the “Why of Aging” The Roman poet and philosopher Lucretius argued in his ”De Rerum Natura” (On the Nature of Things) that aging and death are beneficial because they make room for the next generation. Ctd… Theory of Programmed Death The 19th-century German biologist August Weissmann proposed that “selection favors the evolution of a death mechanism that ensures species survival by making space for more youthful, reproductively prolific individuals (Weissmann 1891).” …..turns out that Programmed Aging Theories are improbable!  The Force of Selection as a Function of Age: Darwin Looms The force of natural selection, a measure of how effectively selection acts on survival rate or reproduction as a function of age, declines with advancing age. Pioneers of the Evolutionary Theories of Aging Haldane J.B.S. Medwar P.B. Williams G.C. Mathematically formalized Hamilton, W. D. (1966). Examples of Age-specific Rates of Survival And Reproduction  Evolution of Ageing Natural Selection as a Driving Force Huntington's chorea: a genetic, neurodegenerative disease caused by a highly penetrant dominant mutation. Why has natural selection not acted to remove Huntington's mutation from populations? The average age of onset of Huntington's is 35.5 years. For much of the evolutionary history of mankind, most people did not live to be that old. The selective pressure to remove the Haldane J.B.S Huntington’s mutation is therefore weak (1941)  The Evolution of Aging: Mutation Accumulation Theory Detriment Medawar, P. (1952) 1) In natural populations most individuals die or get killed before they can grow old and suffer the symptoms of aging. 2) The strength of natural selection declines with increasing age, such that selection ignores the performance of individuals late in life.  The Evolution of Aging: Antagonistic Pleiotropy (AP) Benefit Detriment Williams, G.C. (1957) Aging occurs because of the pleiotropic effects of genes. Selection for alleles that enhance survivorship and/or the reproductive rate at early reproductive ages may also lower survivorship and reproductive rates at later ages. There is a tradeoff (antagonism) between fitness components early in life and later in life Aging evolves as an “accident” of natural selection in favor of survival and reproduction  Disposable Soma Theory A General Mechanism for Antagonistic Pleiotropy Organisms face tradeoffs between reproduction and maintenance/repair (soma) Alleles and physiological mechanisms increasing allocation to reproduction compromise somatic maintenance and repair (e.g., testosterone & immunity; e.g., castration can extend life) Genetic tradeoffs: physiologies that are genetically different (e.g., the genetic change increases fertility but shortens life) Kirkwood, T. Physiological tradeoffs: tradeoffs within an (1977) individual depending on conditions (e.g., have more kids, have shorter life) Predictions of Evolutionary Models of Aging (1) Aging patterns have a genetic basis at least partially: -> artificial selection for late-life reproduction leads to delayed senescence in Drosophila (Rose 1984) -> life span is heritable in humans (though only Natural habitat tests with opossums and guppies (3) Mutations with age-specific effects are common -some evidence, but need more (4) Many genes of small effect are expected to underlie antagonistic pleiotropy effects Examples Supporting Evolutionary Models of Aging Fruit fly Rose, M.R. Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution 1984, 38, 1004–1010.  Evolution of Aging in the Virginia Opossum Sources of mortality: Austad Extrinsic (1993) Intrinsic In populations with low extrinsic mortality, selection may favor delayed aging (and eliminate deleterious late-acting alleles) Study compared island population (low extrinsic mortality) to mainland population (high extrinsic mortality) https://doi.org/10.1111/j.1469-7998.1993.tb02665.x  Island Individuals Show Evidence of Delayed Aging Differences in mortality rates Differences in parental investment Differences in rates of physiological aging If extrinsic mortality is high, the best strategy may be early reproduction https://doi.org/10.1111/j.1469-7998.1993.tb02665.x The Evolution of Aging: A Summary From Ageing Research Reviews 55 (2019) Multi-Level Contexts for the Evolution of Aging 2.0 From Ageing Research Reviews 55 (2019) How Do We Age: The 12 “Synthetic” Aging Hallmarks López- Otín et al., Cell 2022  The Goal(s) of Biogerontology/Geroscience The ultimate goal is to improve the quality of life in humans. The extension of lifespan by extending healthspan. Chronic diseases and conditions of the elderly represent the main hurdle toward reaching that goal. Because aging is malleable (at least in many animal models) and aging is also the leading risk factor for those diseases and conditions, then addressing the basic biology of aging is likely to provide a better pay-off than addressing diseases one at a time. Felipe Sierra: Cold Spring Harb Perspect Med 2016; 6: a025163  Aging = Susceptibility to (Chronic) Disease 110,000 People Die Daily of an Age-related Disease ”Intervening” in a Basic Aging Process = A Medical Revolution  Example: Exploiting Senescence Targeting to Improve Health Span Senescence Elimination In Mouse Senescent Senescent Cells Cells Accumulate Eliminated  A word of caution The Greek God Zeus granted Tithonus the gift of immortality, but not of perpetual youth, as requested by his wife, Eos. Tithonus grew older and older, and begged for death. Tennyson’s poem “Tithonus”: “Man comes and tills the field and lies beneath, And after many a summer dies, the swan. Me only cruel immortality Consumes: I wither slowly in thine arms.” Living longer without youthful vitality is questionable.  Further Readings Haldane, J. B. S. New Paths in Genetics. London, UK: Allen & Unwin, 1941. Medawar, P. B. 1952. An Unsolved Problem of Biology. London: Lewis. Williams, G. C. 1957. Evolution 11(4): 398-411. Hamilton, W. D. Journal of Theoretical Biology 12, 12–45 (1966) Kirkwood, T. B., and R. Holliday. 1979. Proceedings of the Royal Society of London. Series B. Biological Sciences 205(1161): 531- 546. Charlesworth, B. Fisher, Medawar, Hamilton and the evolution of aging. Genetics 156, 927–931 (2000). Hughes, K. A. & Reynolds, R. M. Annual Review of Entomology 50, 421–445 (2005). Hughes, K. A. et al. Proceedings of the National Academy of Sciences of the United States of America 99, 14286–14291 (2002). Lopez-Otin et al. 2022. Cell 186 and 2013 Cell 153(6): 1194-1217. Steven N. Austad and Jessica M. Hoffman Evolution, Medicine, and Public Health pp. 287–294.  Graduate school of research (EUR)  Series 2 Evolutionary Biology of Aging -- Why and how do we age? -- Presenter Dr. Oliver BISCHOF, DR-CNRS Institut Mondor for Biomedical Research (IMRB) [email protected]  Programmed vs. Non-Programmed Aging Evolutionary cost/benefit of additional life span vs. age Selection Theories of Aging, Physiopedia  Example: Exploiting Senescence Targeting to Improve Health Span Senescence Elimination In Mouse Senescent Senescent Cells Cells Accumulate Eliminated