Evolutionary theories of aging

 

The Historical Evolution of Evolutionary Theories of Aging

Ilia Stambler 

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-long-lived 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 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 been long present. Its proponents included founding figures of modern biology. Thus, 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.1 In Charles 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 German biologist August Weismann (1834-1914) posited the first evolutionary theory specifically regarding aging and natural death.2 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 (1845-1916) raised several important arguments against Weismann’s theory.3 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.”4 In the 1940s, the British geneticist 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.5

In 1952, the British immunologist Peter Medawar developed this idea into a general theory of “Mutation Accumulation.”6 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.”7 Another problem is that genes that have been so far found to affect aging do not appear to be random mutations, but rather have orderly patterns.8 This issue will be discussed later on.

In 1957, the American evolutionary biologist George Williams added an important specification.9 (According to the British gerontologist Alex Comfort, writing in 1956, very similar principles were posited by the British marine biologist George Bidder in 1932.10) 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 (“calcification”) 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. Another hypothetical example Williams uses is that “a gene that favored erythrocyte longevity might be far from ideal for the maximization of oxygen-carrying capacity.”9 Other examples can be adduced along those lines. Thus, high levels of testosterone may 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, suddenly become 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 – perhaps with just a few exceptions, such as the decay-accelerating factor (DAF) genes.11 In the experiments of the British-American biogerontologist Michael Rose, some strains of extremely long-lived fruit flies were bred without any decrease in early fertility.12 Perhaps even more persuasive, arguably, are the observations showing that people who have good athletic abilities early in life also often live longer and are more active later in life.13

The propositions of the above two theories were formalized in 1966 by the British evolutionary biologist 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 the British evolutionary biologist 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.”14

Later on, in 1977, the British gerontologist Thomas Kirkwood suggested the “Disposable Soma” theory.15 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 (the organisms having a single reproductive episode before death) offer perhaps the best demonstration of this principle. Thus, 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, the British researchers Jens Rolff and Michael Siva-Jothy demonstrated that frequent mating of beetles shortens their life (“Copulation corrupts immunity” 2002).16 Also, Michael Rose showed that delayed reproduction in drosophila flies drastically increases their life-span.17 Related effects may also exist in humans. Thus, 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).18

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, Germany)19 and for humans by Davey Smith et al. (“Sex and Death: Are They Related?” 1997, UK).20 This was also the conclusion of the US Duke Longitudinal Study which showed that more sexually active people live longer.21 According to the Russian-American gerontologist 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 the British statisticians 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.22

There seems to be a large number of methodological problems on both sides of the dispute. It is generally difficult to project animal studies (e.g. 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’s et al. “Caerphilly study” (“Sex and Death: Are They Related?”)20 has become famous for suggesting that high sexual activity reduces mortality rates. It appeared in 1997 and has been making the headlines since. However, it may be argued that the Caerphilly study’s representation is rather uncertain. Its sample size is by an order of magnitude less than that of Marc Luy’s “Cloister Monks/Nuns study”18 (2006, Germany-Austria). 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 case of the French physiologist Charles-Édouard Brown-Séquard’s experiment of 1889 with self-injection of animal testicular extracts, where some transient “rejuvenation” effects were soon followed by deterioration.23) 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 the 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%.24 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.25 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)26 or Saul Kent’s The Life Extension Revolution (1983)27 – 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 are cited as the primary authority. This might be an issue of possible British-American rivalry (according to the American gerontologist 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).28 Another, perhaps even more plausible explanation that could be offered, is that the three 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.

The 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. Sacher29 posited a general formula relating the weight of an animal and the weight of its brain to its maximum life span (MLS):30

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,31 the maximal life span would be somewhere around 90-100 years.) Large animals have been long known to live longer32 (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 presumably 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 still rely on evolution for increased longevity (of course, if still granted favorable environmental conditions). 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 that may be raised in this regard 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 adaptive nucleotides fixation rate of about 6×10-3 AA/gene per 104 generations and 4×104 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.33

Nevertheless, the suggested tendency of longevity increase is very uplifting. For example, the prominent Ukrainian gerontologist Vladimir Frolkis, in his Aging and Life-Prolonging Processes (1982)34 was truly inspired by Cutler’s findings and quoted 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 called “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 three mainstream evolutionary theories of aging made several contemporary researchers, such as the Americans Josh Mitteldorf and Theodore Goldsmith and the Russian Vladimir Skulachev, ponder a return to Weismann’s theory.35 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 and death 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 may be assumed to provide improved defense against a greater range of pathogens and environmental threats, such as radiation, temperature changes and toxins, including bio-toxins, hence it seems not entirely clear how this can be an unequivocal 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, insofar as 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 the life-extensionists’ optimism – rather to the contrary. For example, academician Skulachev has been one of the leading Russian life-extensionists. He is a self-avowed “fighter for human longevity,” developing super-antioxidants aimed to correct oxidative damage at its source within the mitochondria, and hoping that “man will live hundreds of years.”36 He strongly believes that human beings are now at the stage when they can rise above the 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. Even under the mainstream “evolutionary neglect” paradigm, there is still a hope of intervention, for example by eliminating accumulated damage before it becomes pathological and irreparably harms the organism’s regulation,37 or by environmental adjustments aimed to induce prolongevity epigenetic effects.38

Whatever theory prevails, a deep and practical understanding of evolutionary mechanisms of aging and longevity entails a hope for positive ameliorative interventions. 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 to improve human health and longevity.

 References and notes

  1. William Randall Albury, “Ideas of Life and Death,” in Companion Encyclopedia of the History of Medicine, Edited by William F. Bynum and Roy Porter, Routledge, London and NY, 2001, pp. 253-254.
  2. August Weismann, “Ueber die Dauer des Lebens” (On the duration of life), Jena, 1882; August Weismann, “Ueber Leben und Tod” (On life and death), Jena, 1884. These works appear in English translation in August Weismann, On Heredity, Claredon Press, Oxford, 1891.
  3. 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.
  4. Aubrey de Grey, “Do we have genes that exist to hasten aging? New data, new arguments, but the answer is still no.” Current Aging Science, 8(1), 24-33, 2015.
  5. John B.S. Haldane, New Paths in Genetics, George Allen and Unwin, London, 1941.
  6. Peter Brian Medawar, An Unsolved Problem of Biology, H.K. Lewis, London, 1952.
  7. Ronald D. Lee, “Rethinking the evolutionary theory of aging: transfers, not births, shape senescence in social species,” Proceedings of the National Academy of Sciences USA, 100(16), 9637-9642, 2003.
  8. 8. Jeff Bowles, “Shattered: Medawar’s test tubes and their enduring legacy of chaos,” Medical Hypotheses, 54(2), 326–339, 2000.
  9. George C. Williams, “Pleiotropy, natural selection and the evolution of senescence,” Evolution, 11, 398-411, 1957.
  10. George P. Bidder, “The mortality of plaice,” Nature, 115, 495, 1925; George P. Bidder, “Senescence,” British Medical Journal, 2, 5831, 1932, quoted in Alexander Comfort, The Biology of Senescence, Butler & Tanner, London, 1956, pp. 11-12.
  11. Cynthia J. Kenyon, “The genetics of ageing,” Nature, 464, 504-512, 2010; Jacob J.E. Koopman, Jeroen Pijpe, Stefan Böhringer, et al., “Genetic variants determining survival and fertility in an adverse African environment: a population-based large-scale candidate gene association study,” Aging (Albany NY), 8(7), 1364-1374, 2016.
  12. Michael R. Rose, Evolutionary Biology of Aging, Oxford University Press, New York, 1991.
  13. Some studies indicating the enhanced longevity of athletes include: 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, e.g.: 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.

The results also vary widely depending on the type of sports, level of athleticism, period of practice, and many other factors. (Anthony P. Polednak (Ed.), The Longevity of Athletes, Charles C. Thomas, Springfield IL, 1979.)

  1. Brian Charlesworth, “Fisher, Medawar, Hamilton and the Evolution of Aging,” Genetics, 156, 927-931, 2000; William D. Hamilton, “The moulding of senescence by natural selection,” Journal of Theoretical Biology, 12(1), 12-45, 1966.
  2. Thomas B.L. Kirkwood, “Evolution of aging,” Nature, 270, 301-304, 1977; Fotios Drenos, Thomas B.L. Kirkwood, “Modelling the disposable soma theory of ageing,” Mechanisms of Ageing and Development, 126(1), 99-103, 2005.
  3. Jens Rolff, Michael Siva-Jothy, “Copulation corrupts immunity,” Proceedings of the National Academy of Sciences USA, 99, 9916-9918, 2002.
  4. Michael R. Rose and Theodore J. Nusbaum, “Prospects for postponing human aging,” The FASEB Journal, 8, 925-928, 1994; Ricki L. Rusting, “Why Do We Age,” Scientific American, 87-95, December 1992.
  5. 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, part of Klosterstudie zur Lebenserwartung von Nonnen und Mönchen (The “Closter” study of life-expectancy in nuns and monks) http://www.klosterstudie.de/; Bartosz Jenner, “Changes in average life span of monks and nuns in Poland in the years 1950-2000,” Przegl Lek, 59(4-5), 225-229, 2002; de Gouw H.W., Westendorp R.G., Kunst A.E., Mackenbach J.P., Vandenboucke J.P., “Decreased mortality among contemplative monks in The Netherlands,” American Journal of Epidemiology, 141(8), 771-775, 1995.
  6. Alexandra Schrempf, Jürgen Heinze, Sylvia Cremer, “Sexual cooperation: mating increases longevity in ant queens,” Current Biology, 15, 267-270, 2005.
  7. George Davey Smith, Stephen Frankel, John Yarnell, “Sex and Death: Are They Related?” British Medical Journal, 315, 1641-1644, 1997.
  8. Maxon P.J., Gold C.H., Berg S., “Characteristics of long-surviving men: results from a nine-year longitudinal study,” Aging (Milano), 9(3), 214-220, 1997; Ostbye T., Krause K.M., Norton M.C., 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,” Journal of the American Geriatrics Society, 54(2), 199-209, 2006; Linda George and Stephen Weiler, “Sexuality in Middle and Late Life” pp. 12-19, Erdman B. 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.
  9. Natalia S. Gavrilova, Leonid A. Gavrilov, “Human longevity and Reproduction. An evolutionary perspective,” in Grandmotherhood: The Evolutionary Significance of the Second Half of Female Life, Rutgers University Press, New Brunswick, NJ, USA, 2005, pp. 59-80.
  10. Ilia Stambler, A History of Life-Extensionism in the Twentieth Century, Longevity History, 2014, http://www.longevityhistory.com/.
  11. Richard Weindruch, Rajindar S. Sohal, “Caloric intake and aging,” New England Journal of Medicine, 337(14), 986–994, 1997.
  12. Leonid Gavrilov, Natalia Gavrilova, Biologia Prodolzhitelnosti Zhizni (Biology of the Lifespan), Vladimir Skulachev (Ed.), Nauka, Moscow, 1991, Ch. 4.1; Vladimir Anisimov, Molekuliarnie i Physiologicheskie Mechanismy Starenia (Molecular and Physiological Mechanisms of Aging), Nauka, St. Petersburg, 2003, Ch. 1.3. Accessible at: http://gerontology.bio.msu.ru/notourpublications.htm, http://gerontology-explorer.narod.ru/.

See also: Wikipedia, “Senescence” http://en.wikipedia.org/wiki/Senescence, “Evolution of Aging,” http://en.wikipedia.org/wiki/Evolution_of_ageing; 

João Pedro de Magalhães, “The Evolutionary Theory of Aging,” http://www.senescence.info/evolution_of_aging.html.

  1. Durk Pearson, Sandy Shaw, Life Extension. A Practical Scientific Approach, Warner Books, NY, 1982, Part 1, Ch. 1. “The Evolution of Aging,” pp. 18-23.
  2. 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.
  3. George M. Martin, “How is the evolutionary biological theory of aging holding up against mounting attacks?” American Aging Association Newsletter, March 2005, http://web.archive.org/web/20160328164647/http://www.americanaging.org/news/mar05.html.
  4. 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, 28(8), 497-501, 1978.
  5. Richard Cutler, “Evolution of human longevity and the genetic complexity governing aging rate,” Proceedings of the National Academy of Sciences USA, 72(11), 4664-4668, 1975, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC388784/.
  6. Miller A.K., Corsellis J.A., “Evidence for a secular increase in human brain weight during the past century,” Annals of Human Biology, 4(3), 253-257, 1977.
  7. William A. Calder, Size, Function, and Life History, Harvard University Press, Cambridge, 1984; Knut Schmidt-Nielsen, Scaling: Why is Animal Size So Important? Cambridge University Press, Cambridge, 1984; João Pedro de Magalhães, “Comparative Biology of Aging,” Senescence Info, http://www.senescence.info/comparative_biology.html.
  8. International Human Genome Sequencing Consortium, “Finishing the euchromatic sequence of the human genome,” Nature 431(7011), 931-45, 2004, http://www.nature.com/nature/journal/v431/n7011/full/nature03001.html.
  9. Vladimir Frolkis, Aging and Life-Prolonging Processes, Springer-Verlag, Wien, 1982.
  10. Theodore C. Goldsmith, “Aging as an Evolved Characteristic – Weismann’s Theory Reconsidered,” Medical Hypotheses, 62(2), 304-308, 2004; Joshua Mitteldorf, “Ageing selected for its own sake,” Evolutionary Ecology Research, 6, 937-953, 2004; Vladimir Skulachev, “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 (Moscow), 62(11), 1191-1195, 1997, http://humbio.ru/humbio/phenopt/00000934.htm.
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