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At the most basic level, the function of sex cells is to pass on undamaged DNA to the next generation, while the function of the soma, the body, is to be selected for vigour, not to be perpetuated itself. The origins of this differentiation between sex cells and somatic cells stretch back to the earliest days of sex. How the differentiation came about is unknown, but its relationship to sex is discussed by William Clark, an immunologist at the University of California, Los Angeles, in his book Sex and the Origins of Death. Clark cites the tiny animalcule Paramecium, a single-celled eukaryote living in freshwater ponds, as an example of what might have been the first evolutionary links between differentiation (within a single cell in this case), sex, senescence and death.
Paramecium reproduces both sexually and asexually. Asexual reproduction is achieved by budding from the mother cell. However, budding
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cannot continue indefinitely. After about 30 cell divisions, a culture of Paramecium shows signs of senescence, even given perfect conditions for growth. Their growth rate slows down, they cease to divide, and the population dies unless reinvigorated by sex. This is quite unlike bacterial populations, which are theoretically immortal, even if many individual cells die. In the case of Paramecium, whole populations are evidently mortal.
This peculiar state of affairs is explained by the complex life cycle of Paramecium. A single Paramecium has two nuclei, a large one called the macronucleus and a small one called the micronucleus. The macronucleus is in charge of the daily running of the cell, while the micronucleus wraps its DNA tightly in proteins and shuts itself off. When a Paramecium divides asexually, the micronucleus flickers to life briefly, replicates its DNA and divides to provide a micronucleus for each daughter cell, then shuts down again. At the same time, the macronucleus divides to provide a working macronucleus for each daughter cell.
It seems that it’s the macronucleus that finally gives up the ghost and becomes senescent. Exactly what causes this senescence is uncertain.
Despite leaning towards a theory of programmed ageing (in which I think he is wrong), Clark ascribes the demise of the macronucleus to wear and tear — the accumulation of random genetic mutations over 30 generations. Whatever the reason for the senescence, the Paramecium must now indulge in sex to reset its biological clock to zero. When two suitable cells conjugate, the micronucleus in each one springs to life, dividing in two by meiosis to produce two haploid micronuclei for each cell. One nucleus from each cell is exchanged, and the newly shuffled pairs of haploid nuclei fuse to produce one diploid micronucleus for each cell. These then divide by mitosis to form a new diploid macronucleus for each cell. The new micronucleus shuts down and the new macronucleus takes over running the reinvigorated cells. The old macronucleus disintegrates in an orderly, programmed fashion and its constituents are recycled for use by the rejuvenated cells. Paramecium therefore combines the speed of reproduction by asexual budding with the periodic genetic cleansing of sex, gaining benefits from each.
The disintegration of the old macronucleus echoes what must have been a pivotal moment in evolution. For the first time, we encounter DNA that is deliberately not transmitted to the next generation. Is this the origin of the soma and of senescence? It certainly is, according to Clark:
“it is in the programmed death of the macronuclei of early eukaryotes like Paramecium that our own corporeal deaths are foreshadowed.” Whether
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or not this statement is strictly true (Clark associates the programmed demise of the macronucleus with what he sees as our own programmed demise), it is certainly true in a general sense. The body is a useful but ultimately redundant subsidiary to the germ line — not only mortal, but designed from the very beginning to be thrown away. The advantages are obvious: a body enables the specialization of individual cells — a specialized team has every advantage over the individual amateur — and physical protection for the germ cells. But there is no need for the body to outlast its usefulness. As the old saying goes, a chicken is just an egg’s way of making another egg; and a man is just an egg cell’s way of making sure that the next egg cell is not riddled with errors.
The throwaway body is central to the evolution of ageing — why we age —
though it says little about the actual mechanism of ageing. The idea is known as the disposable soma theory of ageing, and was formulated by Tom Kirkwood in the late 1970s, and later developed by Kirkwood and the eminent geneticist Robin Holliday. Today, the theory is seen by most researchers as the best framework for understanding ageing.
The theory draws on the distinction between the immortal germ line and the mortal soma, or body, first postulated by the great German biologist August Weismann in the 1880s. Kirkwood and Holliday considered the dichotomy between the germ line and the soma as the outcome of a trade-off between survival and reproduction. In essence, to be of any use, the body must survive at least to reproductive age. Survival costs. A substantial portion of an organism’s energy is needed to maintain life — to keep body and soul together for long enough for the germ line to be propagated. Most of the food we eat is burnt up to keep the body working —
the heart beating, the brain thinking, the kidneys filtering, the lungs breathing. The same is true at a cellular level. The high rate of DNA damage and mutations that we noted in Chapters 6 and 10 must be corrected through the synthesis and incorporation of new building blocks. Molecular proofreading mechanisms are needed to ensure that repaired DNA reads correctly. Damaged proteins and lipids must be broken down and replaced. The importance of protein turnover is illustrated by our dietary requirement for nitrogen, in the form of amino acids, and by the continual excretion of nitrogen in the urine as urea. Urea excretion reflects the destruction and elimination of damaged proteins. The disposable
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soma theory infers that the energy required to keep these various metabolic systems going detracts from the energy available for reproduction.
The validity of the disposable soma theory hangs on the veracity of its predictions. If survival and reproduction both require energy or resources that are in limited supply, then there should be an optimal balance, in which bodily maintenance is set against reproductive success.
This optimal balance would be expected to vary between species, according to their environment, competitors, reproductive capacity, and so on.
If so, there ought to be a general relationship between the lifespan of species and their fecundity (the potential number of offspring produced during the reproductive period). Moreover, factors that tend to increase lifespan should decrease fecundity, and vice versa. Are such relationships detectable in nature?
Notwithstanding difficulties in specifying the maximum lifespan and reproductive potential of animals in the wild, or even in zoos, the answer is an unequivocal yes. With a few exceptions, usually explicable by particular circumstances, there is indeed a strong inverse relationship between fecundity and maximum lifespan. Mice, for example, start breeding at about six weeks old, produce many litters a year, and live for about three years. Domestic cats start breeding at about one year, produce two or three litters annually, and live for about 15 to 20 years. Herbivores usually have one offspring a year and live for 30 or 40 years. The implication is that high fecundity has a cost in terms of survival, and conversely, that investing in long-term survival reduces fecundity.
Do factors that increase lifespan decrease fecundity? There are a number of indications that they do. Calorie restriction, for example, in which animals are fed a balanced low-calorie diet, usually increases maximum lifespan by 30 to 50 per cent, and lowers fecundity during the period of dietary restriction. We shall see in Chapter 13 that the molecular basis of this relationship is only now being worked out, even though the original discovery was made in the 1930s. Nonetheless, the rationale in the wild seems clear enough: if food is scarce, unrestrained
breeding would threaten the lives of parents as well as offspring. Calorie restriction simulates mild starvation and increases stress-resistance in general. Animals that survive the famine are restored to normal fecundity in times of plenty. But then, if the evolved response to famine is to put life on hold until times of plenty, we would expect to find an inverse relationship between fecundity and survival. Are there any other, less stressful, examples?
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In some circumstances, longevity can be selected for in the wild. One study, carried out in the early 1990s by Steven Austad, a zoologist then working at Harvard, examined mortality, senescence and fecundity in the Virginia opossum, the only North American marsupial. Opossums are claimed to be one of the most stupid animals in the world, with a ratio of brain size to body size well below that of most mammals. They fall easy victim to predators. Their favourite ploy is to ‘play possum’, or feign death, with sadly predictable consequences. In the mountains of Virginia, few opossums survive beyond 18 months (more than half are eaten by predators) and those that are not eaten age rapidly. The main reason opossums survive at all, and indeed proliferate, is their tremendous fecundity.
An average female produces two litters, of eight to ten offspring each, in a single reproductive season.
Austad wondered what would happen to the lifespan and fecundity of opossums living in an environment free from predators. One place that fitted the bill was Sapelo Island, off the coast of Georgia, where opossums have probably lived without much predation for 4000 to 5000 years. The conditions provide a test case for the disposable soma theory. According to evolutionary theory, we would expect individuals freed from predation to age more slowly. This is because long-lived animals can have more offspring, and look after their offspring for longer, and so should be selected at the expense of short-lived animals. However, there are two possible outcomes, which give us an indication of the mechanism of ageing. If ageing results from a simple accumulation of damage, then slowing down the rate of damage should increase lifespan but have no effect on fertility earlier in life. Conversely, if the cost of repair is decreased fecundity, then we should see a different picture: longer lives should be gained at the expense of reproductive vigour earlier in life.
In the case of the Virginia opossum, this latter was exactly the case.
Austad tagged about 70 opossums in the Virginia mountains and on Sapelo Island, and monitored their progress through life. On the mainland, he confirmed that the surviving opossums aged rapidly beyond 18
months, which effectively limited their reproduction to a single season.
Only 8 per cent survived into a second reproductive season, and none into a third. Litters averaged about eight offspring. In contrast, ageing was much slower on the island. Here, half the female opossums survived into a second reproductive season, and 9 per cent into a third. Biochemical estimates of the rate of ageing (measurements of collagen cross-linking in the tail — the same changes that bring about the wrinkling of our own
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skin) suggested that island opossums age at virtually half the rate of their mainland cousins. Critically, litter size was reduced from eight to five or six. This litter size was sustained through the second reproductive season, implying that the total number of offspring was not reduced, rather the distribution of fertility was spread over a longer lifetime.
Similar patterns have been reported for other animals living in less insular circumstances. For example, the lifespan and fecundity of guppies (a South American freshwater fish, named after the Trinidad clergyman R. J. L. Guppy, who sent the first specimen to the Natural History Museum in London) is influenced by the rate of predation in different streams.
Heavy predation and high mortality is linked with rapid ageing and the compression of breeding into a short lifespan. Fecundity is reduced, or rather spread out, in longer-lived fish. The same is true of some birds. Lars Gustafsson has reported an inverse relationship between clutch size and lifespan in collared flycatchers in Gotland, Sweden. Again, there is a cost to early reproductive effort — females with larger brood sizes early in life laid smaller clutches later in life, compared with those that had smaller early broods.
But wouldn’t we expect animals to breed faster if faced with a threat to their survival? These findings may be no more than an ecological equivalent of the faster rate of bacterial replication in response to irradiation, or our own urge to find a sexual partner in the last few minutes after a nuclear warning. Certainly the evidence is supportive of the disposable soma theory, but it is far from proof. Can the relationship be emulated in the laboratory, with minimal exposure to predators or other life-shortening factors?
One classic experiment suggests that it can. In the fruit fly Drosophila, the cost of extended life is lower fecundity, even in the laboratory. This conclusion comes from the selective breeding experiments carried out by Michael Rose, an evolutionary biologist at the University of California, Irvine, and others. Rose postulated that the flies reaching sexual maturity fastest would be the most fertile and therefore the shortest lived. Conversely, the slowest to mature would be the least fertile but the longest lived. To test this idea, he maintained two populations of flies over a number of generations. In the first population, the first-laid eggs were collected and used for breeding the next generation. The procedure was repeated for each successive generation. In the second population, only the very last eggs laid were selected for breeding the next generation. Rose found that the average lifespan of flies propagated from the last-laid eggs
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more than doubled over ten generations. The total number of eggs laid in a lifetime was similar in both lines, but in comparison with the short-lived population, the long-lived flies reproduced more slowly while young, and faster later in life. Thus, even in the absence of predation or other life-shortening factors, there is a trade-off between longevity and fecundity, in which the price of longevity is the suppression of fecundity earlier in life.
A trade-off between sex and death sounds, on the face of it, the worst possibility in the worst of all possible worlds. Is chastity the price of a long life? Does this confirm Aristotle’s gloomy dictum, that each act of sex has a direct life-shortening effect? Quite the contrary, in fact. The trade-off frees us from a tyrant: the belief that senescence is inevitable. Sex is not tied directly to lifespan, unless we have a heart condition. The two are linked because, as a species, the resources that our genes directed at reproduction, over evolutionary time, were subtracted from our investment in maintenance. After a million years of human evolution, we have found a stable balance; but this balance can, in principle, be shifted. The working assumption has always been that we must make the best of limited resources, invested over a probable lifespan in the wild. Neither of these conditions — limited resources or probable mortality in the wild from predation, starvation, infection and accident — is the same now as it was for our first human ancestors.
If the disposable soma theory is correct, we can make two predictions, both of which are supported by the findings outlined in this chapter. First, if lifespan is set to an optimum, then that optimum can be shifted by changing the parameters. The changes in lifespan that we have noted took place over generations. If we wish to extend our own lives within a single generation, we must find out the terms of the contract, in other words the genes or biochemistry in which it is written. Second, if we want to enjoy a life extension, we are not obliged to remain childless. The trick applied by nature is to defer sexual maturation.
In the next chapters, we will examine the terms of the contract, and whether there is anything we can do to rewrite them. First, however, it is worth thinking about ourselves for a moment. Is there any evidence in people that lifespan is an optimal trade-off between reproductive prowess and longevity? There are exceptions to every rule, especially in biology.
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Are we, perhaps, the exception to this one? The question is difficult to answer directly, as we live so long anyway. Any direct measurements would require many decades. Even so, there are two indications that the rule does indeed apply to us.
First, our lifespan is much longer than other primates. The fecundity of the great apes has barely changed over evolution. The chimpanzee, gorilla, orangutan and human female all have an inter-birth interval of two to three years, and a similar number of offspring per female. Despite this, humans live twice as long as a gorilla or a chimpanzee. The discrepancy is simply explained: in primates, longevity has been purchased by deferring sexual maturity, by slowing down the rate of growth to adulthood. Humans live twice as long as gorillas, but take a third longer to reach sexual maturity.
In Western societies, we may be assisting this trend. Women give birth to their first child later and later. According to the Population Reference Bureau, just 10 per cent of women in Europe now give birth to their first child before the age of 20. In comparison, in the developing world, some 33 per cent of mothers have their first child before the age of 20; in West Africa the figure is around 55 per cent. Of the 15 million young women aged 15 to 19 who give birth every year, 13 million live in less developed countries. It is too early to say whether we are actively selecting for longevity in Europe, but it is hard to see why we should not. I suspect that this trend will prove more powerful than any foreseeable medical breakthrough.
The second indication that our own lifespan is an optimal trade-off comes from a study of genealogical records by Tom Kirkwood and Rudi Westendorp, an epidemiologist at the University of Leiden in The Nether-lands. Kirkwood and Westendorp reasoned that the detailed records of births, deaths and marriages from the British aristocracy might provide buried evidence of a trade-off between human fertility and longevity.