User:Mitteldorf/Evolution of aging
Why do almost all living things weaken and die with age? There is not yet agreement in the academic community on a single answer. The evolutionary origin of senescence remains a fundamental, unsolved problem of biology.
Historically, aging was first likened to ‘wear and tear’: Our bodies get weak for the same reason that a knife gets dull or metal rusts. But this idea was discredited in the 19th century when the Second Law of Thermodynamics was formalized. Entropy (disorder) must increase inevitably within a closed system, but living beings are not closed systems. In fact, it is a defining feature of life that we take in free energy from the environment and unload our entropy as waste. Living systems routinely repair themselves, and, in fact, can build themselves up from seed. There is no thermodynamic necessity for senescence. (Nevertheless, the idea of ‘wearing out’ has so much intuitive appeal that even experts will lapse into thinking that way from at times.)
August Weismann was responsible for interpreting and formalizing the mechanisms of Darwinian evolution in a modern theoretical framework. In 1889, he theorized that aging was part of life’s program because the old need to remove themselves from the theater to make room for the next generation, sustaining the turnover that is necessary for evolution. This theory again has much intuitive appeal, but it suffers from ‘teleological thinking’. In other words, a purpose for aging has been identified, but not a mechanism by which that purpose could be achieved. Aging 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 aging genes would be more successful than other individuals lacking such genes. (In fact, there is every reason to think that the opposite is true: aging decreases individual fitness.) Weismann disavowed his own theory before his life was over.
The first modern, successful theory of aging was formulated by Peter Medawar in 1952. His idea was that aging 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 motivation to keep the body 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 or disease or by accident.
Medawar’s theory is referred to as Mutation Accumulation. The mechanism of action involves random, detrimental 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. Hence they would ‘accumulate’ and, perhaps, cause all the decline and damage that we associate with aging.
This theory was criticized by George 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; aging 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 the Medawar’s theory. Another problem with this theory became apparent in the late 1990s, when genomic analysis became widely available. It turns out that the genes that cause aging are not random mutations; rather, these genes form tight-knit families that have been around as long as eukaryotic life. Baker’s yeast, worms, fruitflies, and mice all share some of the same aging genes!
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. Suppose there are 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.
Antagonistic pleiotropy is the 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 aging, and since about 1990 the technology has been available to find them efficiently. Of the many aging genes that have been reported, some seem to enhance fertility early in life, or to carry other benefits. But there are other aging genes for which no such corresponding benefit has been identified. This is not what Williams predicted. You may think of it as partial validation of the theory, but logically it cuts to the core premise: that genetic tradeoffs are the root cause of aging.
In breeding experiments, Michael Rose selected fruitflies for long life span. 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 must be an experimental artifact.
There is a third mainstream theory of aging, which also has its proponents. In 1977, Thomas Kirkwood proposed the Disposable soma theory, which is all about the body’s energy budget. 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.
The disposable soma theory has great appeal because its basis is so sensible and intuitive, but it cannot be correct. 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 the less they are fed. This is the caloric restriction effect, and it cannot be reconciled with the Disposable Soma theory. Still, many scientists defend the theory, and say that ‘energy’ here is just a metaphor for whatever it is that the body does not have enough of. They are saying that there must be some tradeoff that causes repair functions to be shortchanged, even if we can’t identify exactly what it is that is being traded. They take the Disposable Soma theory to be a kind of pleiotropy, but acting through metabolism rather than directly through phenotype. It’s a promising paradigm, awaiting a mechanism to be proposed that doesn’t involve food energy.
Because it is so robust and ubiquitous in the animal kingdom, the caloric restriction effect presents a dilemma for any of the pleiotropic theories. How can it be that an animals can lengthen its life span under stress, but fails to do so without stress? The answer from pleiotropy theory is that the stress changes the relative values of the fundamental tradeoff, and induces the animal to sacrifice fertility for longevity. In pleiotropy theory, all of the capacity to lengthen life span comes directly from forgone fertility. Experimentally, some animals lose fertility when their life spans are extended by CR and some suffer no appreciable loss. Males, for example, typically remain fertile when underfed, while females do not. And even females present an enigma because their fertility decline is not tightly coupled to their longevity gain. For example, in female mice that are restricted to 60% of a free-feeding diet, reproduction is shut down altogether. But female life span continues to increase linearly right up to the threshold of starvation – around 30% of free-feeding levels.
A fundamental embarrassment for all three mainstream theories is that there appear to be ‘deliberate’ metabolic features, mechanisms that seem to have no other purpose than to cause death.
One is apoptosis, or programmed cell death. Apoptosis is responsible for killing infected cells and 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. This seems to be a direct hint that senescence is a ‘design feature’ of evolution, rather than some kind of side-effect of genes that have other purposes (pleiotropy).
A second ‘deliberate’ mechanism is called replicative senescence or cellular senescence. A cell counts (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 is a last-ditch protective mechanism against cancer. But this hypothesis fails because replicative senescence is far older than cancer. 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).
The body’s inflammation process exists to fight disease; but in old age, the system can turn against us, causing heart disease and arthritis. This happens reliably enough that a low dose of aspirin each day (slightly toning down the inflammatory response in general) is sufficient to measurably reduce incidence of disease and death in older people. Is inflammation a function that goes haywire after a certain age? Or is this attack on the self part of nature’s plan: self-destruction as an adaptation?
Here’s the dilemma: Evolutionary theory says that what evolves is what helps an individual to have more offspring, faster. Aging can only cut off an individual’s capacity to reproduce. So, according to theory, aging could only evolve as a side-effect, or epiphenomenon of selection. Nevertheless, there is accumulated evidence that aging looks like an adaptation in its own right, selected for its own sake.
For replicative senescence in one-celled organisms, telomeric aging is clearly ‘feature’ of the genetic software, not a bug. If aging could evolve in one-celled organisms for the long-term good of the species, and despite its cost to the individual, then why not other forms of aging that affect higher animals?
In response to this dilemma, there are theorists who advocate a return to the ideas of Weismann: ‘making room’ for the next generation. Aging helps keep the population diverse, mitigating the problem of inbreeding depression, the well-known tendency for offspring of closely-related parents to have excessive genetic defects. The problem with such theories is the same one that troubled Weismann: a good evolutionary theory should be about mechanisms, not purposes.
A promising theoretical path invokes 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.
Is this a plausible mechanism for evolution of senescence? Does natural selection act at the level of the larger population, and not just one individual at a time? To accept group selection as an important and general mechanism of evolution would call into question a great body of evolutionary theory. The consensus among evolutionary biologists is that it is more conservative to deal with the experimental anomalies of aging one at a time, with special explanations that don’t require a revamping of evolutionary theory.
Because of the tension between theory and experiment, this is one of the most dynamic areas of modern biology. Stay tuned...--Mitteldorf 13:27, 8 June 2006 (UTC)
Making room for the young:
Weismann A. 1889. Essays upon heredity and kindred biological problems. Clarendon Press, Oxford.
Medawar, P.B. 1952. An Unsolved Problem of Biology. London: H.K. Lewis.
Edney, E.B. and Gill, R.W. 1968. Evolution of senescence and specific longevity. Nature, 220: 281–282.
Williams, G.C. 1957. Pleiotropy, natural selection and the evolution of senescence. Evolution, 11:398-411.
Kirkwood, T.B.L. 1977. Evolution of aging. Nature, 270: 301–304.
Caloric Restriction: Weindruch, R. and Walford, R.L. 1986. The Retardation of Aging and Disease by Dietary Restriction. Springfield, IL: Thomas.
Masoro, E.J. 2005. Overview of caloric restriction and ageing. Mechanisms of Ageing and Development 126: 913-922.
Aging genes in common across species:
Guarente, L and Kenyon, C. 2000. Genetic pathways that regulate ageing in model organisms. Nature 408:255-262
Flies that live longer and lay more eggs:
Leroi, A.M., Chippindale, A.K. and 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: 1244–1257.
Telomeres and programed death:
Clark, W.R. 1999. A Means to an End: The biological basis of aging and death. New York: Oxford University Press.
On group selection:
Williams, G. 1966. Adaptation and Natural Selection. Princeton, NJ: Princeton University Press.
Sober, E. & Wilson, D.S. 1998. Unto Others, Cambridge, Harvard University Press.
On the tension between experiment and evolutionary theory of aging:
Mitteldorf, J. 2004. Ageing selected for its own sake. Evol. Ecol. Res., 6:937-953.
Bredesen, D.E. 2004. The non-existent aging program: how does it work? Aging Cell. 3:255-259
On population dynamics as a mechanism for evolving aging:
Mitteldorf, J. 2006. Chaotic population dynamics and the evolution of ageing: proposing a demographic theory of senescence. Evol. Ecol. Res., 8:561-574