Evolution of ageing

Old man at a nursing home in Norway.

Enquiry into the evolution of ageing aims to explain why survival, reproductive success, and functioning of almost all living organisms decline at old age. Leading hypotheses [1][2] suggest that a combination of limited resources, and an increasing risk of death by environmental causes determine an "optimal" level of self-maintenance, i.e. the repair of molecular and cellular level damage that accumulates over time. Allocation of limited resources into such damage repair is traded-off with investment into reproduction, which determines the individual's Darwinian fitness. In consequence, traits that improve an individual's performance in early life are favored by selection, even if the same traits have negative effects late in life, when the individual has already passed on their genes to the next generation.

History

August Weismann was responsible for interpreting and formalizing the mechanisms of Darwinian evolution in a modern theoretical framework. In 1889, he theorized that ageing was part of life's program because the old need to remove themselves from the theatre to make room for the next generation, sustaining the turnover that is necessary for evolution.[3] This theory again has much intuitive appeal, but it suffers from having a teleological or goal-driven explanation. In other words, a purpose for ageing has been identified, but not a mechanism by which that purpose could be achieved. Ageing may have this advantage for the long-term health of the community; but that doesn't explain how individuals would acquire the genes that make them get old and die, or why individuals that had ageing genes would be more successful than other individuals lacking such genes. (In fact, there is every reason to think that the opposite is true: ageing decreases individual fitness.) Weismann later abandoned his theory.

Theories suggesting that deterioration and death due to ageing are a purposeful result of an organism's evolved design (such as Weismann's "programmed death" theory) are referred to as theories of programmed ageing or adaptive ageing. The idea that the ageing characteristic was selected (an adaptation) because of its deleterious effect was largely discounted for much of the 20th century, but a theoretical model suggests that altruistic ageing could evolve if there is little migration among populations.[4]

Mutation accumulation

The first modern theory of mammal ageing was formulated by Peter Medawar in 1952. It formed from discussions in the previous decade with J. B. S. Haldane and the selection shadow concept. Their idea was that ageing was a matter of neglect. Nature is a highly competitive place, and almost all animals in nature die before they attain old age. Therefore, there is not much reason why the body should remain fit for the long haul – not much selection pressure for traits that would maintain viability past the time when most animals would be dead anyway, killed by predators, disease, or accident.[5]

Medawar's theory is referred to as Mutation Accumulation. The mechanism of action involves random, detrimental germline mutations of a kind that happen to show their effect only late in life. Unlike most detrimental mutations, these would not be efficiently weeded out by natural selection. On the grand scale, senescence would just be the summation of deleterious genes that only present in older individuals.[6] Hence they would 'accumulate' and, perhaps, cause all the decline and damage that we associate with ageing.[7][8]

Modern genetics science has disclosed a possible problem with the mutation accumulation concept in that it is now known that genes are typically expressed in specific tissues at specific times (see regulation of gene expression). Expression is controlled by some genetic "program" that activates different genes at different times in the normal growth, development, and day-to-day life of the organism. Defects in genes cause problems (genetic diseases) when they are not properly expressed when required. A problem late in life suggests that the genetic program called for expression of a gene only in late life and the mutational defect prevented proper expression. This implies existence of a program that called for different gene expression at that point in life. Why, given Medawar's concept, would there exist genes only needed in late life or a program that called for different expression only in late life? The maintenance mechanism theory (discussed below) avoids this problem.

Medawar's concept suggested that the evolution process was affected by the age at which an organism was capable of reproducing. Characteristics that adversely affected an organism prior to that age would severely limit the organism's ability to propagate its characteristics and thus would be highly "selected against" by natural selection. Characteristics that caused the same adverse effects that only appeared well after that age would have relatively little effect on the organism's ability to propagate and therefore might be allowed by natural selection. This concept fits well with the observed multiplicity of mammal life spans (and differing ages of sexual maturity) and is important to all of the subsequent theories of ageing discussed below.

Role of extrinsic mortality

Young cohorts, not depleted in numbers yet by extrinsic mortality, contribute far more to the next generation than the few remaining older cohorts, so the force of selection against late-acting deleterious mutations, which affect only these few older individuals, is very weak. The mutations may not be selected against, therefore, and may spread over evolutionary time into the population.

The major testable prediction made by this model is that species that have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is borne out among mammals, the best-studied in terms of life history. There is a correlation among mammals between body size and lifespan, such that larger species live longer than smaller species under controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are of similar size, yet bats live much longer. For instance, the little brown bat, half the size of a mouse, can live 30 years in the wild. A mouse will only live 2–3 years even under optimum conditions. The explanation is that bats have fewer predators, and therefore low extrinsic mortality. More individuals survive to later ages, so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations equates to lower mortality and therefore a longer lifespan. Birds are also warm-blooded and are similar in size to many small mammals, yet often live 5–10 times as long. They have less predation pressure than ground-dwelling mammals. Seabirds, which, in general, have the fewest predators of all birds, live longest.

When examining the body-size vs. lifespan relationship, one also observes that predatory mammals tend to live longer than prey mammals in a controlled environment, such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys, and apes) relative to body size is that their intelligence, and often their sociality, help them avoid becoming prey. High position in the food chain, intelligence and cooperativeness all reduce extrinsic mortality in species.

Antagonistic pleiotropy

Medawar's theory was further developed by George C. Williams in 1957, who noted that senescence may be causing many deaths, even if animals are not 'dying of old age.' In the earliest stages of senescence, an animal may lose a bit of its speed, and then predators will seize it first, while younger animals flee successfully. Or its immune system may decline, and it becomes the first to die of a new infection. Nature is such a competitive place, said Williams, (turning Medawar's argument back at him), that even a little bit of senescence can be fatal; hence natural selection does indeed care; ageing isn't cost-free.

Williams's objection has turned out to be valid: Modern studies of demography in natural environments demonstrate that senescence does indeed make a substantial contribution to the death rate in nature. These observations cast doubt on Medawar's theory. Another problem with Medawar's theory became apparent in the late 1990s, when genomic analysis became widely available. It turns out that the genes that cause ageing are not random mutations; rather, these genes form tight-knit families that have been around as long as eukaryotic life. Baker's yeast, worms, fruit flies, and mice all share some of the same ageing genes.[9]

Williams (1957) proposed his own theory, called antagonistic pleiotropy. Pleiotropy means one gene that has two or more effects on the phenotype. In antagonistic pleiotropy, one of these effects is beneficial and another is detrimental. In essence, this refers to genes that offer benefits early in life, but exact a cost later on. If evolution is a race to have the most offspring the fastest, then enhanced early fertility could be selected even if it came with a price tag that included decline and death later on.[1] Because ageing was a side effect of necessary functions, Williams considered any alteration of the ageing process to be "impossible."

Antagonistic pleiotropy is a prevailing theory today, but this is largely by default, and not because the theory has been well verified. In fact, experimental biologists have looked for the genes that cause ageing, and since about 1990 the technology has been available to find them efficiently. Of the many ageing genes that have been reported, some seem to enhance fertility early in life, or to carry other benefits. But there are other ageing genes for which no such corresponding benefit has been identified. This is not what Williams predicted. This may be thought of as partial validation of the theory, but logically it cuts to the core premise: that genetic trade-offs are the root cause of ageing.

Another difficulty with antagonistic pleiotropy and other theories that suppose that ageing is an adverse side effect of some beneficial function is that the linkage between adverse and beneficial effects would need to be rigid in the sense that the evolution process would not be able to evolve a way to accomplish the benefit without incurring the adverse effect even over a very long time span. Such a rigid relationship has not been experimentally demonstrated and, in general, evolution is able to independently and individually adjust myriad organism characteristics.

In breeding experiments, Michael R. Rose selected fruit flies for long lifespan. Based on antagonistic pleiotropy, Rose expected that this would surely reduce their fertility. His team found that they were able to breed flies that lived more than twice as long as the flies they started with, but to their surprise, the long-lived, inbred flies actually laid more eggs than the short-lived flies. This was another setback for pleiotropy theory, though Rose maintains it may be an experimental artefact.[10]

Disposable soma theory

A third mainstream theory of ageing, the ''Disposable soma theory, proposed in 1977 by Thomas Kirkwood, presumes that the body must budget the amount of energy available to it. The body uses food energy for metabolism, for reproduction, and for repair and maintenance. With a finite supply of food, the body must compromise, and do none of these things quite as well as it would like. It is the compromise in allocating energy to the repair function that causes the body gradually to deteriorate with age.[11] A caveat to the disposable soma theory suggests that time, rather than energy, is a limiting resource that may be critical to an organism. The concept is that each organism must reproduce in an optimal period in order to ensure the greatest chance of success for the offspring. This optimal period is dictated by the ecological niche of the organism but in essence, it limits the time that any given organism can devote to growth and development prior to bearing offspring. Thus, developmental rate and gestational rate are subject to evolutionary pressure. The need to accelerate gestation limits the time allocated to damage repair at the cellular level, resulting in an accumulation of damage and a decreased lifespan relative to organisms with longer gestation. This concept stems from a comparative analysis of genomic stability in mammalian cells.[12]

There are arguments against the disposable soma theory. The theory clearly predicts that a shortage of food should make the compromise more severe all around; but in many experiments, ongoing since 1930, it has been demonstrated that animals live longer when fed substantially less than controls. This is the caloric restriction (CR) effect,[13][14][15] and it cannot be easily reconciled with the Disposable Soma theory. Though by decreasing energy expenditure the damage generated (by free radicals, for instance) is expected to be reduced and the total energy budget might indeed be reduced, but the investment in repair function might still be relatively the same. But dietary restriction has not been shown to increase lifetime reproductive success (fitness), because when food availability is lower, reproductive output is also lower. So CR does thus not completely dismiss disposable soma theory.

With respect to such limitations Kriete[16] proposed consideration of systems-level properties like robustness to characterize ageing as a robustness tradeoff. According to this concept living systems evolve into a state of highly optimized tolerance promoting traits beneficial for survival and fitness at the cost of fragilities driving the ageing phenotype. The view is compatible with aspects of the antagonistic pleiotropy and the disposable soma theory, but offers additional mechanisms rooted in complex systems theory.

Other problems with the classical ageing theories

A raised criticism for all three mainstream theories based on classical evolutionary process concepts is the potential existence of 'deliberate' metabolic mechanisms that work to promote death.

One is apoptosis, or programmed cell death. Apoptosis is responsible for killing infected cells, cancerous cells, and cells that are simply in the wrong place during development. There are clear benefits to apoptosis, so the existence of apoptosis isn't a problem for evolutionary theory. The problem is that apoptosis seems to ramp up late in life and kill healthy cells, causing weakness and degeneration . And, paradoxically, apoptosis has been observed as a kind of 'altruistic suicide' in colonies of yeast under stress.[17] This seems to be a direct hint that senescence arose because it conferred a direct evolutionary advantage, rather than some kind of side effect of genes that have other evolutionary advantages (pleiotropy).

A second 'deliberate' mechanism is called replicative senescence or cellular senescence. Metaphorically, a cell may be said to 'count' (with its telomeres) the number of times that it has divided, and after a set number of replications, it languishes and dies. It has been proposed that this mechanism evolved to suppress cancer.[18][19] Many invertebrates experience replicative senescence, though they never die of cancer. Even one-celled organisms count replications, and will die if they don't replenish their telomeres with conjugation (sex).[20]

More strictly, cells cannot 'count' the number of times they have divided . Telomeres are not a counting mechanism , though they may be used to indicate the number of times a particular chromosome has been replicated. Cellular processes for genetic material replication occur in both directions along DNA, 5' to 3' and on the other strand, 3' to 5'. As the 3' or 5' end is impossible for DNA polymerase to grab at the 1 base pair mark, a handful of basepairs (10-15) are cut off each replication. Over time, this cutting short of the DNA results in no telomeres, and the cell is unable to replicate that chromosome without cutting into genes.

The dilemma is that classical evolutionary theory says that what is maintained in a lineage is that which ensures the viability of an organism and its offspring. Ageing can only cut off an individual's capacity to reproduce. So, according to classical theory, ageing could only evolve as a side effect, or epiphenomenon of selection. The disposable soma theory and antagonistic pleiotropy theory are examples in which a compensating individual benefit, compatible with classical evolution theory (See neo-Darwinism) is proposed. Nevertheless, there is accumulated evidence that ageing looks like an adaptation in its own right, selected for its own sake.[21][22]

Semelparous organisms and others that die suddenly following reproduction (e.g. salmon, octopus, marsupial mouse (brown antechinus), etc.) also represent instances of organisms who incorporate a lifespan-limiting feature. Sudden death is more obviously an instance of programmed death or a purposeful adaptation than gradual ageing. Biological elements clearly associated with evolved mechanisms such as hormone signalling have been identified in the death mechanisms of organisms such as the octopus.[23]

Impact of new evolution concepts on ageing theories

At the time most of the non-programmed ageing theories were developed, there was very little scientific disagreement with classical theories (i.e. Neo-Darwinism) regarding the process of evolution. However, in addition to suicidal behaviour of semelparous species (not handled by the classical ageing theories) other apparently individually adverse organism characteristics such as altruism and sexual reproduction were observed. In response to these other conflicts, adjustments to classical theory were proposed:

  • Various group selection theories (beginning in 1962) propose that benefit to a group could offset the individually adverse nature of a characteristic such as altruism. The same principle could be applied to characteristics that limited life span and theories proposing group benefits for limited lifespans appeared.
  • Evolvability theories (beginning in 1995) suggest that a characteristic that increased an organism's ability to evolve could also offset an individual disadvantage and thus be evolved and retained. Multiple evolvability benefits of a limited lifespan were subsequently proposed in addition to those originally proposed by Weismann.

Ageing theories based on group selection

Group selection is often criticized to be too slow to happen in real biology. However, Jiang-Nan Yang[4] recently showed with an individual-based model that the evolution of altruistic ageing occurs under fairly general conditions by kin/group selection. Group selection can be based on population viscosity (limited offspring dispersal, first proposed by Hamilton (1964) for kin selection) that is widely present in natural populations. This population structure builds a continuum between individual selection, kin selection, kin group selection and group selection without a clear boundary for each level. Although early theoretical models by D.S. Wilson et al. (1992)[24] and Taylor (1992)[25] showed that pure population viscosity cannot lead to cooperation/altruism because of the exact cancelling out of the benefit of kin cooperation and the cost of kin competition, this exact cancelling out also suggests that any additional benefit of local cooperation would be sufficient for the evolution of cooperation.[4] Mitteldorf and D.S. Wilson (2000) later showed that if the population is allowed to fluctuate, then local populations can temporarily store the benefit of local cooperation and promote the evolution of altruism.[26] By assuming individual differences in adaptations, Yang (2013) further showed that the benefit of local altruism can be stored in the form of offspring quality and thus promote the evolution of altruistic ageing even if the population does not fluctuate, this is because local competition among the young will result in an increased average local inherited fitness of survived progenies after the elimination of the less adapted by natural selection, since the young do not have strong age-associated abilities and have to depend more on inherited abilities to compete.[4] In Yang (2013)'s model, altruistic ageing is stabilized by higher-level selection instead of just kin selection.[4]

Mitteldorf[27] proposed a group benefit of a limited lifespan involving regulation of population dynamics. Populations in nature are subject to boom and bust cycles. Often overpopulation can be punished by famine or by epidemic. Either one could wipe out an entire population. Senescence is a means by which a species can 'take control' of its own death rate, and level out the boom-bust cycles. This story may be more plausible than the Weismann hypothesis as a mechanistic explanation, because it addresses the question of how group selection can be rapid enough to compete with individual selection.

Libertini[28] also suggests benefits for adaptive ageing.

Inversely, within a Negative Senescence Theory R.D. Lee (similarly J.W. Vaupel) considered positive group effects performing a selection force directed to survival beyond the age of fertility.[29] Often also postreproductive individuals make intergenerational transfers: bottlenose dolphins and pilot whales guard their grandchildren; there is cooperative breeding in some mammals, many insects and about 200 species of birds; sex differences in the survival of anthropoid primates tend to correlate with the care to offspring; or an Efe infant is often attended by more than 10 people. Lee developed a formal theory integrating selection due to transfers (at all ages) with selection due to fertility.[30]

Ageing theories based on evolvability

Goldsmith[31] proposed that in addition to increasing the generation rate, and thereby evolution rate, a limited lifespan improves the evolution process by limiting the ability of older individuals to dominate the gene pool. Further, the evolution of characteristics such as intelligence and immunity may specially require a limited lifespan because otherwise acquired characteristics such as experience or exposure to pathogens would tend to override the selection of the beneficial inheritable characteristic. An older and more experienced, but less intelligent animal would have a fitness advantage over a younger, more intelligent animal except for the effects of ageing.

Skulachev[32] has suggested that programmed ageing assists the evolution process by providing a gradually increasing challenge or obstacle to survival and reproduction, and therefore enhancing the selection of beneficial characteristics. In this sense, ageing would act in a manner similar to that of mating rituals that take the form of contests or trials that must be overcome in order to mate (another individually adverse observation). This suggests an advantage of gradual ageing over sudden death as a means of lifespan regulation.

Weissmann's 1889 ageing theory was essentially an evolvability theory. Ageing or otherwise purposely limited lifespan helps evolution by freeing resources for younger, and therefore, presumably better-adapted individuals.

Yang (2013)'s model[4] is also based on mechanisms of evolvability. Ageing accelerates the accumulation of novel adaptive genes in local populations. However, Yang changed the terminology of "evolvability" into "genetic creativity" throughout his paper to facilitate the understanding of how ageing can have a shorter-term benefit than the word "evolvability" would imply.

Lenart and Vašku (2016) [33] have also invoked evolvability as the main mechanism driving evolution of aging. However, they proposed that even though the actual rate of aging can be an adaptation the aging itself is inevitable. In other words, evolution can change speed of aging but some aging no matter how slow will always occur.

Mechanism

If organisms purposely limit their lifespans via ageing or semelparous behaviour, the associated evolved mechanisms could be very complex, just as mechanisms that provide for mentation, vision, digestion, or other biological function are typically very complex. Such a mechanism could involve hormones, signalling, sensing of external conditions, and other complex functions typical of evolved mechanisms. Such complex mechanisms could explain all of the observations of ageing and semelparous behaviours as described below.

It is typical for a given biological function to be controlled by a single mechanism that is capable of sensing the germane conditions and then executing the necessary function . The mechanism signals all the systems and tissues that need to respond to that function by means of organism-wide signals (hormones). If ageing is indeed a biological function, we would expect all or most manifestations of ageing to be similarly controlled by a common mechanism. Various observations (listed below) indeed suggest the existence of a common control mechanism.

It is also typical for biological functions to be modulated by or synchronized to external events or conditions. The circadian rhythm and synchronization of mating behaviour to planetary cues are examples. In the case of ageing seen as a biological function, the caloric restriction effect may well be an example of the ageing function being modulated in order to optimize organism lifespan in response to external conditions. Temporary extension of lifespan under famine conditions would aid in group survival because extending lifespan, combined with less-frequent reproduction, would reduce the resources required to maintain a given population.

Theories to the effect that ageing results by default (mutation accumulation) or is an adverse side effect of some other function are logically much more limited and suffer when compared to empirical evidence of complex mechanisms. The choice of ageing theory therefore is logically essentially determined by one's position regarding evolutionary processes, and some theorists reject programmed ageing based entirely on evolutionary process considerations.[34]

Maintenance theories

It is generally accepted that deteriorative processes (wear, other molecular damage) exist and that living organisms have mechanisms to counter deterioration. Wounds heal; dead cells are replaced; claws regrow.

A non-programmed theory of mammal ageing[35] that fits with classical evolution theory and Medawar's concept is that different mammal species possess different capabilities for maintenance and repair. Longer-lived species possess many mechanisms for offsetting damage due to causes such as oxidation, telomere shortening, and other deteriorative processes that are each more effective than those of shorter-lived species. Shorter-lived species, having earlier ages of sexual maturity, had less need for longevity and thus did not evolve or retain the more-effective repair mechanisms. Damage therefore accumulates more rapidly, resulting in earlier manifestations and shorter lifespan. Since there are a wide variety of ageing manifestations that appear to have very different causes, it is likely that there are many different maintenance and repair functions.

A corresponding programmed maintenance theory based on evolvability[36] suggests that the repair mechanisms are in turn controlled by a common control mechanism capable of sensing conditions, such as caloric restriction, and also capable of producing the specific lifespan needed by the particular species. In this view, the differences between short- and long-lived species are in the control mechanisms, as opposed to each individual maintenance mechanism.

DNA damage theory

The DNA damage theory of aging is a prominent explanation for aging at the molecular level. This theory postulates that DNA damage is ubiquitous in the biological world and is the primary cause of aging.[37] Consistent with this theory, genetic elements that regulate repair of DNA damage in somatic cells were proposed to have pleiotropic effects that are beneficial during early development but allow deleterious consequences later in life.[37][38][39] As an example, studies of mammalian brain and muscle have shown that DNA repair capability is relatively high during early development when cells are dividing mitotically, but declines substantially as cells enter the post-mitotic state.[40][41][42] The reduction in DNA repair capability presumably reflects an evolutionary adaptation for diverting resources from cell duplication and repair to more essential neuronal and muscular functions.[37] The effect of reducing expression of DNA repair capability is to allow increased accumulation of DNA damage. This then impairs gene transcription and causes the progressive loss of cellular and tissue functions that define aging.

Evidence

  • Complex programmed death mechanisms exist in semelparous species (e.g. octopus), including hormone signalling, nervous system involvement, etc. If a limited lifespan is generally useful as predicted by the programmed ageing theories, it would be unusual for an octopus to possess a more complex mechanism for accomplishing that function than a mammal.
  • "Ageing genes" with no other apparent function. However to date no evidence that such genes exist has been found.
  • Caloric restriction effect: reduction of available resources increases lifespan. This behavior has a plausible group benefit in enhancing the survival of a group under famine conditions and also suggests common control.
  • Progeria and Werner syndrome are both single-gene genetic diseases that cause acceleration of many or most symptoms of ageing. The fact that a single gene malfunction can cause similar effects on many different manifestations of ageing suggests a common mechanism. However, both genes affected influence DNA stability and so can be explained by stochastic theories of ageing that attribute ageing to accumulation of DNA damage.
  • Although mammal lifespans vary over an approximately 100:1 range, manifestations of ageing (cancer, arthritis, weakness, sensory deficit, etc.) are similar in different species. This suggests that the deterioration mechanisms and corresponding maintenance mechanisms operate over a short period (less than the lifespan of a short-lived mammal). All the mammals therefore need all the maintenance mechanisms. This suggests that the difference between mammals is in a control mechanism or repair efficiency.
  • Lifespan varies greatly among otherwise very similar species (e.g. different varieties of salmon 3:1, different fish 600:1) suggesting that relatively few genes control lifespan and that relatively minor changes to genotype could cause major differences in lifespan. This could be consistent with a common control mechanism for lifespan but note that this does not in itself provide evidence for programmed aging but is equally consistent with traditional theories.

Problems with programmed ageing theories

Contrary to the theory of programmed death by ageing, individuals from a single species usually live much longer in a protected (laboratory, domestic, civilized) environment than in their wild (natural) environment, reaching ages that would be otherwise practically impossible. Also, in the majority of species, there doesn't exist any critical age after which death rates change dramatically, as intended by the programmed death by ageing, but the age-dependence of death rates is very smooth and monotonic. However, as mentioned above, V.P. Skulachev[43] explained that a process of gradual ageing has the advantage of facilitating selection for useful traits by allowing old individuals with a useful trait to live longer. It is also easy to imagine that animals with gradual ageing will live longer in a protected environment.

The death rates at extreme old ages start to slow down, which is the opposite of what would be expected if death by ageing was programmed. From an individual-selection point of view, having genes that would not result in a programmed death by ageing would displace genes that cause programmed death by ageing, as individuals would produce more offspring in their longer lifespan and they could increase the survival of their offspring by providing longer parental support.[44]

Biogerontology considerations

Theories of ageing affect efforts to understand and find treatments for age-related conditions (see biogerontology):

  • Those who believe in the idea that ageing is an unavoidable side effect of some necessary function (antagonistic pleiotropy or disposable soma theories) logically tend to believe that attempts to delay ageing would result in unacceptable side effects to the necessary functions. Altering ageing is therefore "impossible",[1] and study of ageing mechanisms is of only academic interest.
  • Those believing in default theories of multiple maintenance mechanisms tend to believe that ways might be found to enhance the operation of some of those mechanisms. Perhaps they can be assisted by anti-oxidants or other agents.
  • Those who believe in programmed ageing suppose that ways might be found to interfere with the operation of the part of the ageing mechanism that appears to be common to multiple symptoms, essentially "slowing down the clock" and delaying multiple manifestations. Such effect might be obtained by fooling a sense function. One such effort is an attempt to find a "mimetic" that would "mime" the anti-ageing effect of calorie restriction without having to actually radically restrict diet.[45]

See also

References

  1. 1 2 3 Williams, G.C. (1957). "Pleiotropy, natural selection and the evolution of senescence" (PDF). Evolution. 11 (4): 398–411. doi:10.2307/2406060. JSTOR 2406060. Archived from the original (PDF) on 2006-07-13. Paper in which Williams describes his theory of antagonistic pleiotropy.
  2. ↑ Kirkwood, TB (24 November 1977). "Evolution of ageing". Nature. 270 (5635): 301–4. Bibcode:1977Natur.270..301K. doi:10.1038/270301a0. PMID 593350.
  3. ↑ Weismann A. (1889). Essays upon heredity and kindred biological problems. Oxford: Clarendon Press. Work that describes Weismann's theory about making room for the young.
  4. 1 2 3 4 5 6 Yang, Jiang-Nan (2013). "Viscous populations evolve altruistic programmed ageing in ability conflict in a changing environment". Evolutionary Ecology Research. 15: 527–543.
  5. ↑ Fabian, Daniel; Flatt, Thomas (2011). "The Evolution of Aging". Scitable. Nature Publishing Group. Retrieved May 20, 2014.
  6. ↑ Monaco, Thiago Oliveira; Silveira, Paulo Sergio Panse (May 2009). "Aging is not Senescence: A Short Computer Demonstration and Implications for Medical Practice". Clinics (Sao Paulo, Brazil). 64 (5): 451–457. doi:10.1590/S1807-59322009000500013. ISSN 1807-5932. PMC 2694250. PMID 19488612.
  7. ↑ Medawar, P.B. (1952). An Unsolved Problem of Biology. London: H.K. Lewis. Edney, E.B. and Gill, R.W. 1968. Delineates the theory of mutation accumulation.
  8. ↑ Edney EB, Gill RW (October 1968). "Evolution of senescence and specific longevity". Nature. 220 (5164): 281–2. Bibcode:1968Natur.220..281E. doi:10.1038/220281a0. PMID 5684860. Further describes theory of mutation accumulation.
  9. ↑ Guarente L, Kenyon C (November 2000). "Genetic pathways that regulate ageing in model organisms". Nature. 408 (6809): 255–62. doi:10.1038/35041700. PMID 11089983. Shows similarities between ageing genes in model organisms.
  10. ↑ Leroi, A.M.; Chippindale, A.K.; Rose, M.R. (1994). "Long-term laboratory evolution of a genetic life-history tradeoff in Drosophila melanogaster. 1. The role of genotype-by-environment interaction". Evolution. 48 (4): 1244–57. doi:10.2307/2410382. JSTOR 2410383.
  11. ↑ Kirkwood TB (November 1977). "Evolution of ageing". Nature. 270 (5635): 301–4. Bibcode:1977Natur.270..301K. doi:10.1038/270301a0. PMID 593350. Origin of the disposable soma theory.
  12. ↑ Lorenzini, A, Stamato, T. Sell, C. (2011). "The disposable soma theory revisited: Time as a resource in the theories of aging". Cell Cycle. 15: 3853–3856. doi:10.4161/cc.10.22.18302.
  13. ↑ Weindruch, R.; Walford, R.L. (1986). The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: Thomas.
  14. ↑ Weindruch R (1996). "The Retardation of Aging by Caloric Restriction: Studies in Rodents and Primates". Toxicologic Pathology. 24 (6): 742–5. doi:10.1177/019262339602400618. PMID 8994305.
  15. ↑ Masoro EJ (September 2005). "Overview of caloric restriction and ageing". Mech. Ageing Dev. 126 (9): 913–22. doi:10.1016/j.mad.2005.03.012. PMID 15885745. Overview of caloric restriction and aging.
  16. ↑ Kriete, A. (2013). "Robustness and aging-a systems-level perspective". Biosystems. 112: 37–48. doi:10.1016/j.biosystems.2013.03.014. PMID 23562399.
  17. ↑ Gourlay CW, Du W, Ayscough KR (December 2006). "Apoptosis in yeast--mechanisms and benefits to a unicellular organism". Mol. Microbiol. 62 (6): 1515–21. doi:10.1111/j.1365-2958.2006.05486.x. PMID 17087770.
  18. ↑ Blasco, M.; Pelengaris, S. (2006-02-28). The molecular biology of cancer?. Blackwell. p. 285. ISBN 978-1-4051-1814-9. OCLC 263712202. This has resulted in speculation that cellular senescence evolved as a cancer suppression mechanism at a time when the life expectancy for humans was far shorter than it is today.
  19. ↑ Stewart, S. A.; Weinberg, R. A. (2002). "Does senescence function as an anti-neoplastic mechanism in vivo?" (PDF). Oncogene. 21 (4): 627–630. doi:10.1038/sj.onc.1205062. Senescence has been postulated to serve as a tumor-suppressing mechanism that is responsible for limiting the replicative potential of pre-neoplastic cells. This notion, attractive in concept, remains to be proven.
  20. ↑ Clark, W.R. (1999). A Means to an End: The biological basis of aging and death. New York: Oxford University Press. About telomeres and programmed cell death.
  21. ↑ Mitteldorf, J. (2004). "Ageing selected for its own sake" (PDF). Evol. Ecol. Res. 6: 937–53. On the tension between experimental data and evolutionary theory.
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Further reading

  • Fabian, D. & Flatt, T. (2011) The Evolution of Aging. Nature Education Knowledge 3(10):9
  • Gavrilova, N.S., Gavrilov, L.A. Human longevity and reproduction: An evolutionary perspective. In: Voland, E., Chasiotis, A. & Schiefenhoevel, W. (eds.): Grandmotherhood - The Evolutionary Significance of the Second Half of Female Life. Rutgers University Press. New Brunswick, NJ, USA, 2005, 59-80.
  • Gavrilova NS, Gavrilov LA, Semyonova VG, Evdokushkina GN (2004). "Does Exceptional Human Longevity Come With High Cost of Infertility? Testing the Evolutionary Theories of Aging". Annals of the New York Academy of Sciences. 1019: 513–517. Bibcode:2004NYASA1019..513G. doi:10.1196/annals.1297.095. PMID 15247077.
  • Gavrilova, N.S., Gavrilov, L.A. Evolution of Aging. In: David J. Ekerdt (ed.) Encyclopedia of Aging, New York, Macmillan Reference USA, 2002, vol.2, 458-467.
  • Gavrilov L.A.; Gavrilova N.S. (2002). "Evolutionary theories of aging and longevity". The Scientific World Journal. 2: 339–356. doi:10.1100/tsw.2002.96.
  • Gavrilova N.S.; Gavrilov L.A.; Evdokushkina G.N.; Semyonova V.G.; Gavrilova A.L.; Evdokushkina N.N.; Kushnareva Yu.E.; Kroutko V.N.; Andreyev A.Yu; et al. (1998). "Evolution, mutations and human longevity". Human Biology. 70 (4): 799–804. PMID 9686488.
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