In this presentation, I will survey the historical development of evolutionary theories of aging. (For brief biographical sketches of the authors mentioned in the presentation, please see Appendix below.)
How have aging and natural death emerged in the course of evolution? According to the very definition of fitness, i.e. survival and reproductive ability, aging and natural death (that is death inherent in a living organism and not brought about by external factors) are obviously detrimental, while an increased healthy life span would seem an obvious evolutionary advantage. Why then haven’t the organisms evolved into immortal, super-longevous or non-aging life-forms? On the contrary, the phenomena of biological immortality and absence of aging are present only among unicellular organisms and somewhat higher forms like the hydra, but not in more complex evolved forms, such as mammals. These are not just theoretically intriguing questions. Many gerontologists (such as Alex Comfort, Richard Cutler and Leonid Gavrilov) have believed that the understanding of the evolutionary mechanisms of aging and natural death may help pinpoint specific ways of intervention into human life span to achieve life extension.
The idea that death is an integral part of life, moreover that it is a necessary condition for life, has long been present. According to Xavier Bichat (1771-1802), life has developed in response to the threat of death from the environment: “life is the totality of functions which resist death.” According to Carl Linnaeus (1707-1778) and Georges-Louis Buffon (1707-1788), death plays a crucial role in the “balance of nature” by regulating the population size of each species and thus maintaining harmony. According to Georges Cuvier (1769-1832), the threat of death defines not only population numbers, but the very structure and function of every given organism. In Darwin’s On the Origin of Species by Means of Natural Selection (1859), this idea is further reinforced. Without death, the mechanism of natural selection would be inoperative.
At the end of the 19th century, the famous German biologist August Weismann posited the first evolutionary theory specifically regarding aging and natural death. According to Weismann, death is not an integral part of all life, as he affirmed that unicellular organisms are immortal. However, in higher organisms, there exists a distinction between immortal germ cells and mortal body cells (the “soma”). According to Weismann, the increasing complexity of the soma and tissue differentiation in higher organisms brought about the phenomena of aging and natural death. Highly differentiated tissues have a diminished ability to replicate and restore themselves, thus aging and death are the price paid for the complexity. Another crucial aspect of Weismann’s theory is that aging and natural death are necessary conditions for evolution. Without them, aged organisms would fill the earth, exhausting all the resources, and stifling the emergence of new generations and new life forms.
Weismann’s ideas seem very cogent, even intuitive. However this is largely teleological thinking: ‘death is needed for something’ (generations shift, innovation, diversity, availability of resources, etc.). But what can be the actual causal mechanisms of such a selection for aging deterioration (remembering that prolonged life and vigor are clear advantages for an individual organism)? Already in the beginning of the 20th century, the Russian immunologist Elie Metchnikoff raised several important arguments against Weismann’s theory. Metchnikoff agreed with Weismann in that death is not a necessary prerequisite of all life: unicellular organisms are immortal, and even if they show signs of degeneration, they can be completely rejuvenated by conjugation. However, Metchnikoff did not believe that natural death can be an evolutionary advantage. According to him, “normal aging” and “natural death” almost never occur in nature. According to Metchnikoff, a relative weakening of an organism is enough to remove it from competition. There is just no chance (and no need) for it to ‘age gracefully’ or ‘die a natural death’ to assist evolution. Weakened organisms are eliminated by external causes – predation, disease, accidents, scramble or contest competition. And if aging and natural death almost never occur in nature, then natural selection cannot operate on them, let alone select for them. Regarding humans, Metchnikoff strongly asserted that we all die a “violent” and not a “natural death”, and that if we are ever able to combat the pathogens that cause our premature death, human life can be greatly prolonged.
During the twentieth century, the possible evolutionary mechanisms of aging have continued to be hotly debated. The majority of researches reached the conclusion that aging (which is mainly observed in humans and animals held in captivity) is by no means an evolutionary advantage but a result of evolutionary neglect. In the 1940s John Haldane suggested a possible evolutionary mechanism for Huntington’s progeria. The victims of this disease lead a relatively normal life and are capable of reproduction until about the age of 40. After that, they begin to show signs of rapidly accelerated aging and die within a short period. Why isn’t this genetic defect eliminated from the population? According to Haldane, it is because of the fact that the victims are completely normal during their reproductive period and able to pass on the gene to the progeny. Thus, the genetic defect operating late in life is preserved. In 1952, Peter Medawar developed this idea into a general theory of “Mutation Accumulation”. According to this theory, only the genes expressed earlier in life, during the reproductive period, are selected for and important from the evolutionary perspective. What happens after the reproductive period is largely irrelevant for the evolutionary success. The late-acting mutations accumulate and cause the damage of aging. An important implication of this theory is that under conditions favorable for survival, the late acting genes have a better chance to be expressed and hence selected for or against. Much evidence confirms this prediction. For example, bats and mice are mammals of approximately the same size, yet bats can have a maximum life span of up to 30 years, while mice live only 2 or 3 years. The explanation for this is that bats are better protected and have fewer predators. The favorable conditions for survival allowed their late-acting genes to get expressed and selected. Under such favorable conditions, long-lived animals had an advantage over short-lived ones (bats generally were able to develop an effective anti-oxidant defense system and the ability to hibernate). In contrast, in mice, it did not matter whether they had a large or small longevity potential – they just needed enough time to reproduce before getting eaten by predators. This theory, however, has its drawbacks. It seems that evolution is not completely indifferent to events happening late in life after the reproductive period is over: even a small degree of senescence damage affects survival rates and reproductive success. For example, a prolonged post-reproductive period can improve the success in raising the young. The Mutation Accumulation theory, thus, neglects intergenerational transfers and the “Grandmother effect.” Another problem is that genes that have been so far found to effect aging do not appear to be random mutations, but rather have orderly patterns. This issue will be discussed later on.
In 1957, George Williams added an important specification. (According to Alex Comfort, writing in 1956, very similar principles were posited by George Bidder in 1932). According to Williams, it is not just the mere accumulation of late-acting mutations that causes senescence. According to him, the very same genes that aid survival and reproduction in an early period of life history, can be damaging and cause senescence in a later period. This concept came to be known as the “Antagonistic Pleiotropy” theory. A large number of observations seem to support it. In Williams’s reasoning, the rapid accumulation of calcium early in life can be beneficial for bone and muscle development, hence increased stamina. However, later in life, enhanced calcium deposition can contribute to atherosclerosis. Similarly, high levels of testosterone give a good edge in sexual competition, yet later in life may contribute to prostate growth. Even at a more fundamental level, oxidative phosphorylation in the respiratory chain is what sustains life, yet the free radicals formed in the process cause aging damage. In another instance, the shortening of telomeres plays a part in cell differentiation and prevents cancer, but it also leads to cell replication limit and thus aging and death. This is indeed a very cogent theory, but also not unproblematic. The concept of temporal antagonism is still largely hypothetical and its epigenetic timing mechanism remains unclear: Why would a gene that helps survival until, say age 40, would be suddenly becoming detrimental at the age of 41? Not all discovered genes that affect aging rate, also affect fertility early in life. In fact almost no such genes were found8 (except perhaps DAF2, I might add). In Michael Rose’s experiments, some strains of extremely long-lived fruit flies were bred without any decrease in early fertility. Perhaps even more persuasive, I would suggest, are the observations showing that people who have good athletic abilities early in life also live longer and are more active later in life.
The propositions of the above two theories were formalized in 1966 by William Hamilton. Using Fisher’s reproductive value or the “Malthusian parameter”, he showed that there is always a greater selective premium on early rather than late reproduction, since a probability to survive to a certain age, declines with age. The problem is that these equations apply both to the Mutation accumulation and Antagonistic pleiotropy theories. According to Brian Charlesworth, “it is at present hard to be sure which of the two most likely important mechanisms by which this property of selection influences senescence (accumulation of late-acting deleterious mutations or fixation of mutations with favorable early effects and deleterious late effects) plays the more important role.”
Later on, in 1977, Thomas Kirkwood suggested the “Disposable Soma” theory. This is in fact an extension of the Antagonistic Pleiotropy theory, but instead of genetic and phenotypic terms, Kirkwood mainly uses terminology of energy expenditure. According to this theory, the expenditure of energy on reproduction (early in life) is more important for evolutionary success than the energy expended on a prolonged body/soma maintenance (throughout the life history). In this view, the body is “disposable”: most energy resources are spent on reproduction at the expense of individual longevity. The life histories of semelparous organisms offer perhaps the best demonstration of this principle. Organisms like may-flies or the marsupial antechinus, copulate so vigorously that after several hours of it they burn out and die of exhaustion. This trade-off mechanism seems to operate also in non-semelparous animals. Thus, Jens Rolff and Michael Siva-Jothy demonstrated that frequent mating of beetles shortens their life (“Copulation corrupts immunity” 2002). Also, Michael Rose showed that delayed reproduction in drosophila flies drastically increases their life-span. Several studies of monks and nuns showed that monks have a greater than average longevity (according to a recent German study about 5 years above average men, however in earlier Polish and Dutch studies only 1 or 2 years higher). Still, there exists a wide array of data contradicting this theory. This concept has been challenged by studies professing that sexual activity may actually strengthen the immune system and prolong life, and that survival is not necessarily antagonistic to reproduction. This was suggested for ants by Schrempf et al (“Sexual cooperation: mating increases longevity in ant queens” 2005) and for humans by Davey Smith et al (“Sex and Death: Are They Related?” 1997). This was also the conclusion of the Duke Longitudinal Study which showed that more sexually active people live longer. According to Leonid Gavrilov, childless women do not live longer. On the contrary, greater longevity seems to correlate with greater fecundity. Gavrilov’s findings agree with those made by Karl Pearson and George Yule over a hundred years ago, but seem to completely contradict both the Disposable Soma theory and Kirkwood’s own demographic observations.
There seems to be a large number of methodological problems on both sides of the dispute. It is generally difficult to project animal studies (of insects or marsupials) on humans. Human studies also seem to be indeterminate. Regarding, for example, the longevity of monks, the positive effect of their supposed abstinence on longevity may be confounded by many other factors, such as absence of alcoholism or smoking. On the other hand, Davey Smith et al “Caerphilly study” (“Sex and Death: Are They Related?”) has become very famous for suggesting that high sexual activity reduces mortality rates. It appeared in 1997 and has been making the headlines since. My own criticism of the Caerphilly study is that its representation is very uncertain. Its sample size is by an order of magnitude less than that of Marc Luy’s “Cloister Monks/Nuns study”. The Caerphilly study examines 918 men aged 45-59, with a 10 year follow up. Thus, it disregards earlier sexual habits and activities that might be determinative for the life-span. This may even be a case of “delayed reproduction.” The effect on the actual life-span is also unclear. It may well be that a short-term increase in well-being is followed by rapid deterioration (as in the famous Brown-Sequard’s case). And most importantly, this may be a case of “reversed causality” – Do the more sexually active people become healthier, or are the healthier people more active? It is difficult to disentangle these issues.
The “disposable soma” theory also seems to be at odds with data on calorie restriction in animals. Since 1930s, calorie restriction has been consistently shown to increase the life span in almost all animals tried. It is perhaps the only well substantiated experimental method of life prolongation known so far. In mice, it can increase the life span by 50%. Yet, according to the disposable soma theory, well fed animals should live longer (because they will have enough energy for both reproduction and body maintenance). This, however, does not occur. Moreover, in many calorie restricted models, fertility does not diminish as predicted by the theory. Still, the “disposable soma theory” is now a most widely accepted evolutionary theory of aging.
It is interesting to observe how ideological agendas affect areas of scientific interest. The above mainstream theories (with the exception of Williams, by British evolutionists) figure prominently in almost every review of evolutionary theories of aging. However, in several books by advocates of radical life extension (mostly Americans), such as Durk Pearson and Sandy Shaw’s Life Extension. A Practical Scientific Approach (1982) or Saul Kent’s The Life Extension Revolution (1983) – Peter Medawar, George Williams and Tom Kirkwood are hardly ever mentioned. In contrast, the theories by the American gerontologists Richard Cutler and George Sacher receive there the utmost notice and cited as the primary authority. This might be an issue of possible British-American rivalry (according to George Martin, Sacher was “singularly unimpressed by Medawar’s theory, and only thanks to the British born Michael Rose, it made its entrance in the US). Another, perhaps more plausible, explanation I could offer is that the 3 mainstream theories by Medawar, Williams and Kirkwood sound somewhat pessimistic. According to them, aging has emerged as a result of evolutionary neglect, it is due to an enormous multitude of intractable random mutations, it is inevitable if species are to survive early in life and reproduce. The implied message is that there is not much we can do about it.
Theories by Sacher and Cutler, on the other hand, offer a glimpse of hope. Both authors show a consistent increase in longevity during the evolution of mammalian species, including man. Sacher posited a general formula relating the weight of an animal and the weight of its brain to its maximum life span (MLS):
MLS = (10.83)x(Brain wt., g)0.636x(Body wt., g)-0.225
This formula gives correct results with 25% accuracy for a large number of species. (Assuming 1400-1500 g weight of the human brain, the maximal life span would be somewhere around 90-100 years). Large animals have been long known to live longer (this may be due to a lower surface/volume ratio, hence slower metabolism per unit weight, hence less toxic metabolites/free radicals). A larger brain, on the other hand, allows for a better internal regulation, and intelligence and social behavior reduce extrinsic mortality. Thus, an increase in brain size correlates with an increase in longevity. Sacher’s formula weighs these two parameters (interestingly, according to it, in any given species, lower body weight is associated with greater longevity, and only the combination of the brain and body weight distinguishes between the life-spans of different species). Using the above formula, as also the formula relating sexual maturation age and life span: Sexual maturation age = (0.2) (MLS), carbon dating, and mutation rate estimates – Richard Cutler calculated a consistent increase in longevity during human evolution. During the past 100,000 years it increased by ~14 years, associated with changes in ~0.6% of the genome (~250 genes according to his calculations). The optimism implied here is, first of all, that even if conscious human life-extensionist efforts fail, the human race can rely on evolution for increased longevity. The second source of optimism is that the amount of genetic change associated with increased longevity is rather limited (compared to the immense complexity and randomness implied in the Mutation Accumulation theory). The limited number of genes associated with aging raises the hopes to pinpoint specific intervention targets. A possible problem I could see here is that Cutler’s calculations are likely not very accurate. There are obviously huge blank spots in the hominid ancestral descendant sequence. Moreover, Cutler’s calculations of genetic change are based on Haldane’s estimation that “the maximum rate of adaptive gene substitution in mammalian evolution could not be more than one substitution per genome per 300 generations” and he assumes the fixation rate of about 6x10-3 AA/gene per 104 generations and 4x104 genes per genome. However, Cutler himself admits that estimations of adaptive gene substitutions differ by orders of magnitude among different authors. And the estimate of 40,000 genes per human genome is now known to be about twice the actual value.
Nevertheless, the proposed tendency of longevity increase is very uplifting. The prominent Russian gerontologist Vladimir Frolkis, in his Aging and Life-Prolonging Processes (1982) is truly inspired by Cutler’s findings and quotes them at least a dozen times. According to Frolkis, mainstream evolutionary theories of aging give too much emphasis on genes causing aging damage, forgetting that alongside them there evolved deliberate mechanisms prolonging life, what he calls “vitauct” roughly equivalent to “anti-aging.” These mechanisms include genes for anti-oxidant defense enzymes, enzymes for DNA repair (various types of ligases, polymerases and nucleases), mechanisms of membrane hyper-polarization (necessary for cell resting state, ATP replenishment and protein synthesis). These types of genes could be included in the 0.5% genetic change suggested by Cutler and can be reasonably manipulated.
Inconsistencies in the 3 mainstream evolutionary theories of aging made several contemporary researchers, such as Mitteldorf, Goldsmith and Skulachev, ponder a return to Weismann’s theory. According to Skulachev, there are several “deliberate” mechanisms which seem to have no other function than to cause aging and death. These mechanisms seem to be too well orchestrated and directional to be randomly accumulated mutations. In Skulachev’s metaphor, “we will not accuse a person of kleptomania if he only steals money.” Among these “deliberate” mechanisms, Skulachev lists: “1) telomere shortening due to suppression of telomerase at early stages of embryogenesis; 2) age-related deactivation of a mechanism that induces the synthesis of heat shock proteins in response to denaturing stimuli; and 3) incomplete suppression of generation and scavenging of reactive oxygen species (ROS).” By analogy to apoptosis or programmed cell death, Skulachev terms these evolved programmed mechanisms of aging of the entire organism “phenoptosis.” In organisms like salmon fish, aging is strictly programmed (they die right after spawning), while in man it is more pliable, but programmed nonetheless. Hence, Skulachev concludes that “Aging is a specific biological function rather than the result of a disorder in complex living systems.” But what biological function? The specter of teleology is raised again. Skulachev, Mitteldorf and Goldsmith offer explanations. First of all, according to these authors, an absence of aging would impair variation and thus reduce the species evolvability and adaptability. For example, an ideal DNA repair mechanism would make mutability impossible (all mutations would be immediately corrected). And without mutability, there would be no diversity and no evolution. Any new threat (e.g. a new infection) could then wipe out the entire stagnant population. (Still, improved immunity and DNA repair seem to me to provide defense against a greater range of pathogens and environmental threats, such as radiation, temperature changes and toxins, including bio-toxins, so I am personally not sure how this can be an evolutionary disadvantage). Secondly, there remains the threat of resources exhaustion. A population that cannot regulate its size through programmed “natural death” will be wiped out by resource scarcity and famine. (However, in this case, selection should rapidly operate on a group rather than on an individual, since longevity is a clear advantage for the individual. Since George Williams, the possibility of “group selection” has been hotly debated. Metchnikoff’s earlier observation that “natural death” almost never occurs in nature might be recalled as well. There is no evidence of extinction of non-aging animals, such as protozoa or the hydra.)
The belief in the “programmed,” “designed” nature of aging does not hinder Skulachev’s optimism. Academician Skulachev has been one of the leading Russian life extensionists. He is a self-avowed “fighter for human immortality,” developing super-antioxidants and hoping that “man will live hundreds of years.” He strongly believes that human beings are now at the stage when they can rise above blind Darwinian selection and create our own destiny. Moreover, he believes that because of the fact that the number of “programmed” mechanisms of aging is limited, a restricted number of specific interventions can be designed to target them. Despite the intense controversies, this is the hope (even though a distant one) that most aging researchers share. It is believed that through evolutionary investigations, factors affecting longevity (including genetic factors, pathogens and environmental conditions, constitutional and metabolic properties) can be identified and then manipulated.
Appendix. Brief biographic sketches of authors mentioned in the presentation
Bichat, Xavier (1771-1802). French anatomist and physiologist, considered to be the father of modern histology and pathology. Worked as a surgeon in Lyon and Paris.
Buffon, Georges-Louis (1707-1788). French naturalist, mathematician, biologist, cosmologist and fiction writer, a great influence on Jean-Baptiste Lamarck and Darwin. Darwin, in his foreword to the 6th edition of the Origin of Species, claimed that "the first author who in modern times has treated [natural selection] in a scientific spirit was Buffon". He became member of the French Academy of Science at the age of 27, and since 1737 worked as the keeper of Jardin du Roi (Royal Garden) in Paris.
Comfort, Alexander (1920-2000). British (Cambridge) physician and gerontologist (a sworn life-extensionist), a poet and a writer. Well known for his anarchist and pacifist views, and most famous for his The Joy of Sex (1972) that played an important role in the so called “sexual revolution”. Comfort’s The Biology of Aging (first published in 1956 and republished several times through 1970) is his major comprehensive treatise on gerontology.
Cutler, Richard G Ph.D. from the University of Houston. Worked as an assistant professor at the Institute for Molecular Biology at the University of Texas at Dallas, was a NIH principle investigator with the Intramural Program of the National Institute on Aging, USA. He also worked as the senior scientist at the Kronos Longevity Research Institute, Phoenix, Arizona, USA.
Cuvier, Georges (1769-1832). French naturalist and zoologist. Made major contributions in comparative anatomy and paleontology, a major proponent of “catastrophism” and opponent of early evolutionary theories.. He was a member of Institut de France, Paris.
Darwin, Charles (1809–1882). The author of the theory of evolution by natural selection (On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, 1859). Worked in Cambridge.
Fisher, Ronald Aylmer (Sir, 1890-1962). English statistician, evolutionary biologist and geneticist. Worked at Rothamsted Experimental Station in Harpenden, Hertfordshire, England. Then became Professor of Eugenics at University College, London. A staunch supported of eugenics, very active at the British Eugenics Society.
Frolkis, Vladimir Veniaminovich (1924—1999) For several decades was head of the Faculty of the Physiology of Aging, at the Institute of Gerontology, the Academy of Medical Sciences, Kiev, Ukraine. Member of the Academy of Sciences (the first academician in gerontology).
Gavrilov, Leonid. Russian evolutionary biologist, geneticist and gerontologist. Until 1997 Principal Research Scientist at A. N. Belozersky Institute for Physical-Chemical Biology, Moscow State University, Moscow, Russia. Then he has worked at the Center on Aging, Nutrition Obesity Research Center (NORC) and the University of Chicago, US.
Haldane, John Burdon (1892-1964). British geneticist and evolutionary biologist, one of the founders of population genetics. Born in Edinburg, Scotland, to physiologist John Scott Haldane and Louisa Kathleen Haldane, descended from Scottish aristocrats. A staunch socialist (in youth a communist) and a great believer in scientific progress (e.g. Daedalus or Science and the Future, 1923). He worked as a professor of genetics in New College, then Cambridge University (until 1932), then University College, London.
Hamilton, William Donald (1936-2000). British evolutionary biologist, a major theorist of evolutionary theory. Until 2000, he was a Royal Society Research Professor at Oxford University.
Kent, Saul has been a prominent life-extension activist, and co-founder of the Life Extension Foundation, now the greatest Life Extension grass roots organization in the world (over 100,000 members). A promoter of anti-aging research. He has also been a board member of the cryonics organization Alcor Life Extension Foundation.
Kirkwood, Thomas (born 1951 in Durban, South African, moved to England in 1954). MSc in applied statistics from Oxford, PhD in biology from Cambridge. Has worked as a Professor of biogerontology at the of University of Newcastle upon Tyne UK. A foremost researcher of evolution and genetics of aging, famous for his “disposable soma theory.”
Linnaeus, Carl (1707-1778). Swedish botanist, physician and zoologist, considered to be the “father” of modern taxonomy and ecology. For some periods worked in the Netherlands, at the University of Harderwijk and at Heemstede, but mainly in Sweden, at the Universities of Stockholm and Uppsala.
Martin, George M. Professor at Departments of Pathology, Genetics and Alzheimer’s Research Center, at Washington University, Seattle, WA, US. Researcher of the biology, pathology, and chemistry of aging. His program mainstay is Gene Action in the Pathobiology of Aging.
Medawar, Peter Brian, Sir (1915-1987). A Brazilian-born British scientist (born of a British mother and a Lebanese father). Worked on immune system rejection, and suggested means for immunosuppression (cortisone) necessary for organ transplantation. Nobel laureate in Medicine of 1960 (together with Frank Macfarlane Burnet). Medawar worked at Magdalen College, Oxford (1932-1946), was professor of zoology at the University of Birmingham (1947-51) and University College London (1951-62). In 1962 he was appointed director of the National Institute for Medical Reserch, UK, and was a professor of experimental medicine at the Royal Institution (1977-83), and president of the Royal Postgraduate Medical School (1981-87). His article “An unsolved problem of biology” (1952) is a major foundation for the evolutionary theories of aging.
Metchnikoff, Elie (1845-1916). Prominent Russian zoologist, immunologist and microbiologist. Born in Kharkov, Ukraine, of a Jewish mother and a Russian father. The discoverer of phagocytosis. Nobel Laureate of 1908 (together with Paul Ehrlich). Worked as a professor of zoology in Russia: in Kharkov, St. Petersburg and Odessa Universities, and abroad in Messina, Gottingen and Munich. Since 1888, a vice director of the Pasteur Institute in Paris.
Pearson, Durk. A famous longevity advocate and consultant to nutritional supplement industry, though not himself an academic. He has had patents in the areas of oil shale recovery, lasers, holography, and functional food. Worked on the manned aerospace programs from Gemini to the Shuttle (wrote the safety manual for the Materials Processing Laboratory on the Shuttle). Graduated MIT in 1965 with a triple major (physics, biology, and psychology) and a triple minor (electrical engineering, computer science, and chemistry). Most famous for his books advocating life extension and successful law suits against Food and Drug Administration.
Pearson, Karl (1857-1936). British statisticin, in fact established the discipline of mathematical statistics. In 1911, he founded the world’s first university statistics department at University College, London. He was a proponent of eugenics, and a protégé and biographer of Sir. Francis Galton. He was also a socialist.
Rose, Michael. Professor of ecology and evolutionary biology at UC Irvine, US. He has been a foremost authority on evolutionary development of aging. By delaying reproduction in drosophila flies, he was able to select strains of flies living up to twice their normal life span. A staunch immortalist, believing human beings will be able to reach “a plateau of immortality”.
Sacher, George A (1917-1981). American gerontologist. Professor of biology with the Argonne National Laboratory, Argonne, Illinois.
Skulachev, Vladimir Petrovich (born 1935). Prominent Russian biochemist, member of the Russian Academy of Sciences. Director of the Institute for Physio-Chemical Biology in Moscow, Founder and Dean of the Faculty of Bioinformatics and Bioengineering at Moscow University. He has played a leading role in Russian Life-extensionism, a self-described “fighter for human immortality.”
Weismann, August (1834-1914). German biologist, ranked by Ernst Mayr, “the second most notable evolutionary theorist of the 19th century, after Charles Darwin.” For most of his career (1863-1912) he was a professor of zoology and director of the zoological institute at Albert Ludwig University of Freiburg in Breisgau, Germany.
Williams, George (1926-2010). American evolutionary biologist. PhD from University of California, Los Angeles. Has worked as a professor of biology at the State University of New York at Stony Brook. A prominent critic of group selection. Author of many works on the evolution of sex.
 W.R. Albury, “Ideas of Life and Death”, pp. 253-254, in Companion Encyclopedia of the History of Medicine, Edited by W.F. Bynum and Roy Porter, Routledge, London and NY, 2001.
 Ibid. pp. 255-256.
 August Weismann, “Ueber die Dauer des Lebens” (On the duration of life), Jena, 1882; “Ueber Leben und Tod” (On life and death), Jena, 1884. Appears in English translation in August Weismann, On Heredity, Claredon Press, Oxford, 1891.
 Elie Metchnikoff, Etudy o Prirode Cheloveka (Etudes On the Nature of Man), The USSR Academy of Sciences Press, Moscow, 1961. First published in 1903. “An introduction to the scientific study of death” pp. 214-245.
 Charlesworth, B. "Fisher, Medawar, Hamilton and the evolution of aging." Genetics 156(3):927-931, 2000; Hamilton, W. D. "The moulding of senescence by natural selection." J Theor Biol 12(1):12-45, 1966.
 Medawar, P.B. An Unsolved Problem of Biology. London: H.K. Lewis, 1952.
 Lee, R. D. "Rethinking the evolutionary theory of aging: transfers, not births, shape senescence in social species." Proc Natl Acad Sci U S A 100(16):9637-9642, 2003. .
 J. Bowles Shattered, “Medawar’s test tubes and their enduring legacy of chaos,” Medical Hypotheses 54(2): 326–339, 2000.
 Williams, G.C. “Pleiotropy, natural selection and the evolution of senescence,” Evolution, 11:398-411, 1957.
 Alex Comfort, The Biology of Aging, Rinehart & Company, NY, 1956, p. 13.
 Rose, M. R, Evolutionary Biology of Aging, Oxford University Press, New York, 1991.
 On longevity of athletes: Louis Dublin, “Longevity of College Athletes,” Harper’s Monthly Magazine, 157: 229-238, July 1928; Marti Karvonen, “Endurance sports, Longevity and Health,” Annals of the New York Academy of Sciences, 301: 653-655, 1977. However, contrary data exist as well pointing out life-shortening effects of strenuous physical activity: Peter Kaprovich, “Longevity and Athletics,” Research Quarterly, 12: 451-455, 1941; Henry Montoye et al. The Longevity and Morbidity of College Athletes, Indianapolis, Phi Epsilon Kappa, 1957; Anthony Polednak and Albert Damon, “College Athletics, Longevity and Cause of Death,” Human Biology, 42: 28-46, 1970; Charles Rose and Michel Cohen, “Relative importance of physical activity for longevity,” Annals of the New York Academy of Sciences, 301: 671-702, 1977.
 Brian Charlesworth, “Fisher, Medawar, Hamilton and the Evolution of Aging,” Genetics 156: 927–931 (November 2000).
 Kirkwood, T.B.L. “Evolution of aging,” Nature, 270: 301-304, 1977; Drenos F, Kirkwood TB, “Modelling the disposable soma theory of ageing,” Mechanisms of Ageing and Development, 126(1):99-103, Jan 2005.
 Jens Rolff and Michael Siva-Jothy, “Copulation corrupts immunity,” Proc Natl Acad Sci USA, 99: 9916-8, 2002.
 Michael R. Rose and Theodore J. Nusbaum, “Prospects for postponing human aging,” The FASEB Journal, 8: 925-928, Sept 1994; “Why Do We Age” Scientific American, 87-95, December 1992.
 Marc Luy, “Leben Frauen länger oder sterben Männer früher?“ (Do women live longer or do men die earlier?), Public Health Forum 14(50): S. 18-20, 2006. In Klosterstudie zur Lebenserwartung von Nonnen und Mönchen (The “Closter” study of life-expectancy in nuns and monks) http://www.klosterstudie.de/; Jenner B, “Changes in average life span of monks and nuns in Poland in the years 1950-2000,” Przegl Lek. 59(4-5):225-9, 2002; de Gouw HW, Westendorp RG, Kunst AE, Mackenbach JP, Vandenboucke JP, “Decreased mortality among contemplative monks in The Netherlands,” Am J Epidemiol. 141(8):771-5, April 1995.
 Schrempf A, Heinze J, and Cremer S, “Sexual cooperation: mating increases longevity in ant queens,” Curr Biol. 15:267-7, 2005.
 Davey Smith G et al. “Sex and Death: Are They Related?” Br Med J, 315: 1641-1644, 1997.
 Maxon PJ, Gold CH, Berg S, “Characteristics of long-surviving men: results from a nine-year longitudinal study,” Aging (Milano), 1997 Jun, 9(3):214-20; Ostbye T, Krause KM, Norton MC et al. “Ten dimensions of health and their relationships with overall self-reported health and survival in a predominately religiously active elderly population: the cache county memory study,” J Am Geriatr Soc, 2006 Feb, 54(2):199-209; Linda George and Stephen Weiler, “Sexuality in Middle and Late Life” pp. 12-19, Erdman Palmore “Predictors of the Longevity Difference” pp. 20-29, in Normal Aging: Reports from the Duke Longitudinal Study By Duke University Center for the Study of Aging and Human Development, Duke University Press, Durham NC, 1985.
 Natalia S Gavrilova and Leonid A Gavrilov, “Human longevity and Reproduction. An evolutionary perspective,” Published in: Grandmotherhood: The Evolutionary Significance of the Second Half of Female Life. Rutgers University Press, New Brunswick, NJ, USA, 2005, 59-80.
 Vladimir Frolkis, Aging and Life-Prolonging Processes, Springer-Verlag, Wien, 1982, Ch. 14. “Experimental Life Prolongation” pp. 306-341.
 Леонид Анатольевича Гаврилов и Наталья Сергеевна Гаврилова, "Биология продолжительности жизни". Ответственный редактор: академик Владимир Петрович Скулачев. Москва, изд. "Наука", 1991 г. 4.1. Обзор Представлений о Видовой Продолжительности Жизни. (Leonid Gavrilov and Nataliа Gavrilov, The Biology of Life-Span, Nauka, Moscow, 1991). Владимир Николаевич Анисимов "Молекулярные и физиологические механизмы старения" Рецензенты: академик Владимир Петрович Скулачев, профессор А.И. Яшин. Издательство "Наука", 2003 г., Санкт-Петербург 1.3. Репродуктивное поведение и эволюция продолжительности жизни. (Vladimir Anisimov, Molecular and Physiological Mechanisms of Aging, Nauka, St. Petersburg, 2003). http://biblioteka.starenie.ru/, http://gerontology.bio.msu.ru/notourpublications.htm , http://gerontology-explorer.narod.ru/.
See also Wikipedia, “Senescence”, “Evolution of Aging” http://en.wikipedia.org/wiki/Senescence http://en.wikipedia.org/wiki/Evolution_of_ageing ; João Pedro de Magalhães, “The Evolutionary Theory of Aging” http://www.senescence.info/evolution.html ; Sharon Phaneuf, “Evolutionary Theories of Aging” http://grove.ufl.edu/~cleeuwen/Theory.pdf; George M. Martin, “How is the evolutionary biological theory of aging holding up against mounting attacks?” American Aging Association Newsletter, March 2005 http://www.americanaging.org/news/mar05.html
 Durk Pearson and Sandy Shaw, Life Extension. A Practical Scientific Approach, Warner Books, NY, 1982, Part 1, Ch. 1. “The Evolution of Aging”, pp.18-23.
 Saul Kent, The Life-Extension Revolution. The Source Book for Optimum Health and Maximum Life-span, Quill, NY, 1983, Ch. 1, “Why do we grow old and die?” pp. 19-20.
 George M. Martin (MD, University of Washington) “How is the evolutionary biological theory of aging holding up against mounting attacks?” American Aging Association Newsletter, March 2005 http://www.americanaging.org/news/mar05.html
 George A. Sacher, “Relationship of lifespan to brain weight and body weight in mammals,” in Ciba Foundation Colloquia on Aging, Churchill, London, 1959,Vol. 5, pp. 115-133. George A. Sacher “Longevity and Aging in Vertebrate Evolution,” BioScience, Vol. 28, No. 8, Aug, 1978, pp. 497-501.
 Quoted in Richard Cutler, “Evolution of human longevity and the genetic complexity governing aging rate,” Proc. Nat. Acad. Sci. USA, Vol. 72, No. 11, pp. 4664-4668, November 1975.
 Calder, W. A. Size, Function, and Life History. Harvard University Press, Cambridge, 1984.
Schmidt-Nielsen, K, Scaling: Why is Animal Size So Important? Cambridge University Press, Cambridge, 1984; João Pedro de Magalhães. “Comparative Biology of Aging,” http://www.senescence.info/comparative.html
 International Human Genome Sequencing Consortium, "Finishing the euchromatic sequence of the human genome," Nature 431 (7011): 931-45, 2004.
 Vladimir Frolkis, Aging and Life-Prolonging Processes, Springer-Verlag, Wien, 1982.
 Mitteldorf, J. “Ageing selected for its own sake,” Evol. Ecol. Res., 6:937-953 2004; Goldsmith, T. “Aging as an Evolved Characteristic – Weismann’s Theory Reconsidered,” Medical Hypotheses, 62(2): 304-308, 2004; Skulachev, VP. “Aging is a Specific Biological Function Rather than the Result of a Disorder in Complex Living Systems: Biochemical Evidence in Support of Weismann's Hypothesis,” Biochemistry (Mosc), 62(11), 1191-1195, Nov 1997. http://humbio.ru/humbio/phenopt/00000934.htm