Ageing occurs in organisms that range from yeast to humans, but also in non-living systems such as automobiles.
Do organisms become "rusty" and age like cars or is there a genetic program that guarantees that a specific age is reached?
Gerontologists widely support theories of ageing that are based on the non-adaptive accumulation of stochastic damage to macromolecules that is caused by oxygen and other toxic species following the decline of the force of natural selection and the consequent decline in protection and repair mechanisms with increasing age.
However, a series of pioneering genetic studies that were carried out in yeast, worms, flies and mice over the past 15 years have shown that lifespan can be extended by threefold or more through mutations that force entry into phases that are normally entered under conditions of starvation.
These findings indicate that a genetic program might regulate the level of protection against stochastic damage, and therefore the length of time an organism remains healthy.
Another possibility is that a program can promote ageing and death for altruistic reasons (the "programmed and altruistic ageing" theory).
There are two possible explanations for such altruistic behavior – one explanation is that it benefits closely related organisms that have acquired mutations that increase their ability to grow and survive, the other is that it benefits the group as a whole.
Recent studies of the unicellular organism Saccharomyces cerevisiae raise the controversial possibility that programmed and altruistic ageing might occur, and that this might be an adaptive process that benefits small sub-populations of closely related mutants.
The programmed and altruistic ageing theory
The programmed and altruistic ageing theory presented here proposes that ageing is programmed so that organisms age and die to benefit related individuals or their group.
An ageing and death program that benefits closely related organisms can be explained by kin selection.
By contrast, death for the benefit of unrelated organisms is explained by group selection.
Theoretically, ageing could provide longterm benefits at the group or population level that include population stabilization, enhanced genetic diversity, a shortening of the effective generation cycle and acceleration of the pace of adaptation.
Local extinctions from overpopulation might support a kind of population-level selection that is strong and rapid enough to overpower the individual costs of programmed ageing.
Altruism and group selection
Darwin proposed that natural selection can operate at more than one level, but most evolutionary biologists generally believe that selection operates on the level of individual organisms.
Group selectionism enjoyed some support before the 1960s but almost disappeared from the literature after Williams, Maynard Smith and Hamilton provided alternative explanations for the observations that were made by Wynne-Edwards and others in support of altruistic behavior.
Wynne-Edwards had concluded that animal population numbers remain stable because animals regulate reproduction on the basis of nutrient availability.
For this regulation to occur, the individual would have to consider the welfare of the group before deciding whether to reproduce or not.
Maynard Smith argued that even if certain groups altruistically reduced reproduction, an egoist would eventually infect and take over the altruistic group.
Great advances have been made since the contributions of Williams and Maynard Smith.
Based on the Price equation, a theory of multilevel selection has developed, which was spearheaded by the work of Wilson.
Nevertheless, the individual cost of programmed death is sufficiently great and the group benefit sufficiently diffuse that quantitative models that are based on multilevel selection do not support the evolution of ageing programs through these mechanisms.
Theory and observation both indicate that when populations outgrow their food supply, mass starvation can be rapid and lethal.
Local extinctions that result from overpopulation might support a kind of population-level selection that is strong and rapid enough to overpower the individual costs of programmed ageing.
It is possible that even if most of the altruistic groups are invaded by a selfish organism, the remaining altruistic groups would have an advantage over the non-altruist, provided that the disadvantage created by egoism eventually causes extinction.
It is also possible that the altruistic groups have evolved protective systems that are aimed at keeping the selfish organisms out.
Therefore, altruistic genes could be inherited together with a protective or surveillance system with the purpose of keeping the selfish organisms out.
In fact, when programmed ageing occurs in the altruistic Saccharomyces cerevisiae, the medium is acidified to pH 3.5 which prevents the growth of competing organisms.
Theoretical arguments against programmed ageing
Most evolutionary biologists believe that programmed ageing cannot result from natural selection, as it is currently understood to operate.
Almost 50 years ago, evolutionary theorists established several arguments against this theory.
First, the contribution of ageing to individual fitness is wholly negative.
Second, the contribution of ageing to population-level fitness is too indirect and too diffuse to be important in selection dynamics, and therefore ageing cannot be affirmatively selected as an adaptation.
Third, ageing can be readily understood in terms of the declining force of selection pressure with age.
Fourth, selection that operates on genetic trade-offs is predicted to favour early fertility at the expense of robust protection against deterioration (this is known as antagonistic pleiotropy).
Fifth, metabolic trade-offs constitute another opportunity for the body to divert energy towards early fertility at the expense of repair and maintenance functions (this is known as the disposable soma theory).
And finally, even without trade-offs, genetic load would be expected to be heaviest in the genes for which their deleterious effects manifest only late in life (this is known as the mutation accumulation theory).
Important requirements for demonstrating the theory of programmed ageing: the identification of mutations that can significantly extend lifespan; the similarities between normal ageing and mammalian apoptosis; evidence for the benefit that is provided by the ageing program (for example, a correlation between lifespan and the ability of a population to adapt to changing environments); the identification of a sequence of molecular processes that are required to cause normal ageing and death; and the demonstration that the program occurs both under conditions that mimic those encountered in natural environments and in organisms that are isolated from natural environments.
The lives of many cells in multicellular organisms seem to follow a Samurai principle: it is better to die than to be wrong.
Complex biological systems are equipped with programs that eliminate portions of the system that become dangerous or unnecessary for the system as a whole.
One mechanism of programmed cell death is apoptosis – this is characterized by distinctive morphological changes in the DNA, nucleus and cytoplasm.
Apoptosis is involved in ontogenic development, anticancer defense, immune responses and other physiological processes.
For unicellular organisms, the idea of programmed cell death becomes theoretically problematic because we are talking about the death of a whole organism – or phenoptosis.
However, in the past 10 years, several studies have indicated that a form of programmed death that is similar to mammalian apoptosis occurs in the unicellular organism S. cerevisiae.
When the anti- or pro-apoptotic mammalian proteins BCL2 (B-cell leukaemia/lymphoma) or BAX (BCL2-associated X protein) are expressed in S. cerevisiae they rescue cells from death or stimulate it, respectively.
Indeed, the overexpression of the human anti-apoptotic BCL2 protein in yeast delays ageing and death in both wild-type cells and cells that lack superoxide dismutases.
In addition, certain mutations in the S. cerevisiae genome cause death that is similar to mammalian cellular apoptosis, and harsh treatments (such as H2O2 and acetic acid) induce a form of death in yeast that also resembles apoptosis.
More recently, the identification of an S. cerevisiae caspase-like protease that is involved in the apoptotic cascade strengthened the claim that apoptosis occurs in yeast.
Other studies indicate that the plant antibiotic osmotin and yeast sexual pheromone can cause the death of yeast in an apoptosis-like manner.
Pheromone-dependent death in yeast has been shown to involve several consecutive components that share features with apoptosis.
These include pheromone receptor activation; a mitogen activated protein kinase cascade; protein synthesis; stimulation of mitochondrial respiration and an increase in energy coupling; a strong elevation of mitochondrial membrane potential; a burst of production of reactive oxygen species in the mitochondrial respiratory chain; the decomposition of mitochondrial filaments; and the collapse of the mitochondrial membrane potential and cytochrome c release from mitochondria.
These biochemical changes are similar to those that were previously identified in studies of chronologically ageing S. cerevisiae, which included activation of the Ras and Sch9 pathways, mitochondrial superoxide generation and loss of mitochondrial function.
Notably, a form of programmed death has also been described for bacteria: it was shown that damaged DNA activates a signalling pathway that causes autolysin-mediated death.
Benefits of ageing for kin or for the group
Several studies support the hypothesis that the programmed ageing and death of populations of billions of S. cerevisiae can promote the adaptation of some members of the population to changing environments by affecting DNA-mutation frequency and the nutritional environment.
As in higher eukaryotes, chronological ageing in yeast is determined by monitoring time-dependent mortality and loss of functions such as reproduction.
Chronological lifespan is normally determined by measuring the survival of a population of billions of non-dividing yeast that are grown in a glucose or ethanol-containing medium.
Ageing in yeast can also be measured by counting the number of daughter cells that are generated by an individual mother cell (this is called replicative lifespan).
In studies of chronologically ageing yeast, after 90–99% of the population dies, a small sub-population of better-adapted mutants regrow by using nutrients that are released from the dead cells.
This regrowth phenomenon (the doubling of viable organisms within a chronologically ageing population) might be similar to the "gasping" phenomenon that can be observed in chronologically ageing bacteria.
It is possible that the composition of the growth medium changes as a consequence of the non-adaptive death of old cells, selecting for rare mutants that previously had low fitness.
However, the results indicate that the death of most of the population and regrowth of the mutants is part of an evolved program.
The wide skepticism about group selection and the difficulties associated with the experimental demonstration of programmed and altruistic ageing eclipsed the ideas of pioneers of evolutionary biology such as Wallace, who first proposed that death can be programmed, and Weismann, who later developed the idea.
Today, Wallace and Weismann’s critics often cite Medawar to conclude that ageing could not be an evolved process because, under natural conditions, most organisms die of diseases or predation before they become old.
However, we feel that the evidence that populations of S. cerevisiae die to benefit a few mutants indicates that population genetic theory could be underestimating the potency of group selection.
Could a putative ageing program also have evolved to make older higher eukaryotes less competitive than younger ones?
Could a similar strategy have evolved in mammals that normally die before reaching old age?
Because a small loss of function can cause a statistically significant increase in death rate, the effect of ageing in wild animals could begin in relatively young individuals, which is confirmed by the increase in death rates in wild animals that begins at puberty.
Because ageing contributes to death that is caused by, for example, predators and infections before middle age, the existence of programmed ageing in mammals cannot be ruled out on the basis that most organisms die of disease or predation before they become old.
Although any claim that humans are programmed to age and die would be highly speculative, it is believed that as a hypothesis it suggests fruitful avenues for biological and even medical research.
"There can be no doubt that a tribe including many members who were always ready to aid one another, and to sacrifice themselves for the common good would be victorious over most other tribes; and this would be natural selection."