‘Getting older is no problem. You just have to live long enough’
Research into the nature of ageing has helped us to understand its mechanisms first in terms of evolution, and then cell behaviour. We are essentially a society of cells and all our functions are determined by the activities of our cells. Evolution plays a key role, since it has selected cells to behave in a way that gives organisms reproductive success—a fundamental feature of Darwinian evolution. Evolution is not interested in health but only in reproductive success. Almost all the features of an organism, including of course humans, have been selected on this basis. The fertilised egg gives rise by division to all the cells that make up our body, as well as those of all other animals. Genes are turned on and off during the development of the embryo and this determines when and where particular proteins are made in cells and so also their behaviour. The details of this process have been selected for during evolution to give rise to adults that will reproduce.
Has ageing also been selected, and is it adaptive in that it helps reproduction? There have been suggestions that ageing was selected in order to reduce the number of adults so they did not compete with each other and so reduce reproduction in the group, but there is evidence to show that this is wrong.
It is essential to distinguish changes with time as an organism develops, and later grows, from the process of ageing. Ageing is not similar to the other biological changes that we go through with time as we develop in the embryo, and then grow older and mature after birth. An embryo gets older from the time it is fertilised, and the most obvious change with age after birth is growth itself, which is part of our genetically controlled developmental programme. We continue to grow for some 16 years. Puberty begins around 11 years and is the period of transition from childhood to adolescence, marked by the development of secondary sexual characteristics, accelerated growth, behavioural changes, and eventual attainment of reproductive capacity. Puberty changes occur as a consequence of the activation of a complex system that leads to an increase in frequency and amplitude of the hormones which stimulate the growth of sexual organs. This system is active in the early infancy periods, but becomes relatively quiescent during childhood, and puberty is marked by its reactivation leading to sexual maturity.
A remarkable case of failure to grow is Brooke Greenberg, a girl from Maryland who at 17 years old remained physically and cognitively similar to a toddler, despite her increasing age. She was about 30 inches tall, weighed about 16 pounds and had an estimated mental age of 9 months to 1 year. Brooke’s doctors termed her condition Syndrome X.
Another major change with age is that each of us will have two successive sets of teeth. The baby teeth begin to erupt at the age of around six months. Usually by 2 years old most of a child’s baby teeth will be in place. Some children get their teeth early, others later. Then typically by the age of 12, all of a child’s baby teeth will have fallen out and been sequentially replaced by a second set of teeth.
All these changes with age are quite different from ageing with its negative effects, and have been selected in evolution as part of our development programme to help with reproduction. So why do we have the negative effects of ageing? Was ageing selected and programmed into our development?
The blame must fall heavily on evolution. To repeat, evolution is only interested in reproduction and not in health once we have reproduced. Ageing, as we shall see, is due to the accumulation of damage in our cells with time. Ageing is not part of our developmental programme and there are no normal genes that promote ageing, though as we shall see there are changes in genes which can cause premature ageing. On the contrary, evolution has sensibly selected cell activities that prevent the damage in cells due to ageing, but which are usually only active until reproduction is greatly reduced. No animals die of old age, but they die because of predators and illnesses, including those which are age-related. The effect of evolution can be seen by comparing two-year-old mice with baby elephants at the same age. The mice are already old. Evolution has selected mechanisms to prevent the elephant ageing before it has offspring, and for some elephants old age is only evident from worn-out tusks. Evolution has generated great diversity in lifespan. For example, rats live for 7 years, and squirrels for 12.
As mentioned earlier, August Weismann, the great German theorist and experimental biologist of the nineteenth century, was one of the first biologists to use evolutionary arguments to explain ageing. His initial idea was that there exists a specific death-mechanism designed by natural selection to eliminate the old, and therefore worn-out, members of a population. The purpose of this programmed death of the old is to clean up the living space and to free up resources for younger generations: ‘… there is no reason to expect life to be prolonged beyond the reproductive period; so the end of this period is usually more or less coincident with death.’ Weismann probably came to this idea while reading the following notes of one of Darwin’s contemporaries and a co-discoverer of natural selection, Alfred Russel Wallace, which he later cited in his essay ‘The Duration of Life’:
…when one or more individuals have provided a sufficient number of successors they themselves, as consumers of nourishment in a constantly increasing degree, are an injury to those successors. Natural selection therefore weeds them out, and in many cases favours such races as die almost immediately after they have left successors.
But the theory is wrong, as almost all animals in the wild die before they get old. Death in the natural environment is not caused by ageing but is due to many other factors, particularly predators. Some animals like elephants do age in the wild, but such cases are rare. Wild mice die in the field at about 10 months, while in the laboratory they can live for several years. A number of animals have lifespans longer than might have been expected—for example flying birds live three times longer than land-living animals. Robins can live for 14 years but the albatross 50 years. This is because flying enabled them to escape predators and find new food sites, so early reproduction was no longer necessary. Why some reptiles like crocodiles and turtles have long lives is not clear.
The illnesses associated with ageing have a significant negative impact on human mortality. Weissman later rejected his theory, and then wisely proposed that ageing was the result of resources being given to the germ line rather than the body. If deleterious ageing occurred in germ cells, eggs or sperm, the species would die out—how right he was.
Theories concerning the ageing process emerged which are not based on it being adaptive, and thus not due to pressures of natural selection. The first was the ‘mutation accumulation’ theory, first proposed by the great scientist Peter Medawar in 1952, and referred to earlier, which proposes that mutations in the DNA of genes which lead to detrimental age-related changes in cells could accumulate over successive generations, if their serious negative effects were only expressed well after the age of peak reproductive success. These mutations are chance events. Life tables for humans show that the lowest likelihood of death in human females comes at about the age of 14, which in primitive societies would likely be an age of peak reproduction. Evolution has ensured that the peak of reproduction is when animals are young. Women lose their eggs at a more or less constant rate until they are 35, when the rate increases twofold.
Deleterious mutations expressed later in life are relatively neutral to selection because their bearers have already reproduced, and so have transmitted their genes to the next generation. As few individuals would actually reach those ages, such mutations would escape negative selective pressure—evolution would neglect them. The theory also predicts that if there are fewer external hazards for an animal, ageing will be slowed down, as is the case for animals like the albatross. According to this theory, ageing is a non-adaptive trait because natural selection is negligent of events that occur in a few long-lived animals that provide little additional contribution to offspring numbers.
Genes can be beneficial in early life, and then damaging later on. In other words, genes showing favourable effects on fitness at young ages, and deleterious ones at old age, could explain the ageing process. Such genes will be maintained in the population due to their positive effect on reproduction at young ages despite their negative effects at older post-reproductive ages, and those effects in later life will look exactly like the ageing process.
Mutation accumulation theory thus suggests that from an evolutionary perspective, ageing is an inevitable result of the declining force of natural selection with age. For example, a mutant gene that kills young children will be strongly selected against and so will not be passed to the next generation, while a lethal mutation with effects confined to people over the age of 80 will experience no selection because it has no effect on reproduction, and people with this mutation will have already passed it to their offspring by that age. Over successive generations, late-acting deleterious mutations will accumulate, leading to an increase in mortality rates late in life, which is just what we see and experience.
According to this theory, persons loaded with a deleterious mutation have fewer chances to reproduce if the deleterious effect of this mutation is expressed earlier in life. For example, patients with progeria, a genetic disease with symptoms of premature ageing, live for only about 12 years and, therefore, cannot pass their mutant genes to subsequent generations. In such conditions, the progeria is only due to new mutations and is not from the genes of parents. By contrast, people expressing a mutation at older ages can reproduce before the illness occurs; such as is the case with familial Alzheimer’s disease. As an outcome, progeria is less frequent than late diseases such as Alzheimer’s because the mutant genes responsible for the Alzheimer’s disease are not removed from the gene pool as readily as progeria genes, and can thus accumulate in successive generations. In other words, the mutation accumulation theory correctly predicts that the frequency of genetic diseases should increase at older ages.
A second theory postulates that there might be genes whose expression is harmful in later life, but which are not silent earlier in life because they are actually beneficial to survival or reproductive fitness, and have some beneficial effects. Such mutations could thus have a selective advantage in early life and then a negative one later on. These genes will be maintained in the population due to their positive effect on reproduction at young ages despite their negative effects at old post-reproductive age, and their negative effects in later life will look exactly like the ageing process. Suppose, for example, that there is a gene increasing the fixation of calcium in bones. Such a gene may have positive effects early in life because the risk of bone fracture and subsequent death is decreased, but such a gene may have negative effects later in life because of increased risk of osteoarthritis due to excessive calcification. In the wild, such a gene has no actual negative effect because most animals die long before its negative effects can be observed. There is thus a trade-off between an actual positive effect at a young age, and a potential negative one at old age; this negative effect may become effective only if animals live in protected environments such as zoos or laboratories. Costly ornaments of male birds to attract females are essential for reproduction but a burden in later life—peacocks have limited mobility.
Although these concepts as to how mutations can cause ageing have guided attempts to merge evolutionary theory with empirical studies of the biology of ageing, there is little evidence of cumulative mutations that give rise to ageing, and only rare examples of genes that display the necessary early and late functions have been found. These theories do explain the universal occurrence of ageing. But they do not explain the actual process of ageing.
Ageing is best understood as the result of accumulation of random molecular damage in cells for a variety of causes—essentially errors due to wear and tear, and the mechanisms that cause this, and that involve damage to genes and proteins which the cells are unable to reliably repair, will be discussed next. These chance events occur in all body cells, and there are some mechanisms to repair the damage. An exception to such damage is in the germ cells that give rise to the next generation. Germ cells dare not suffer age-related damage, as if they did there would soon be no future healthy offspring. Evolution knows this and ensures that they do not age. By contrast, body cells do age, and evolution only cares to limit this so that reproduction can occur. Evolution selects those cellular activities that delay ageing until reproduction is completed.
Explaining ageing in these terms is partly based on an idea of Weismann, who dropped his theory that ageing was adaptive, and then suggested that ageing evolved because organisms separate in their body those organs involved in reproduction, particularly those that give rise to germ cells—eggs and sperm—from the rest of the body. They invest heavily in those organs involved in reproduction, and this neglect of the body results in ageing. Support for this is found in model organisms, where fertility and lifespan are closely linked. In the nematode C. elegans, cutting out of germline precursor cells of the gonad abolishes reproduction but extends lifespan, as do mutations that reduce germline proliferation. In the fruit-fly D. melanogaster, a reduction in reproduction extends lifespan in females, and certain long-lived mutant females exhibit reduced egg laying, with some being almost sterile. Certain mice that have mutations causing dwarfism are long-lived and sterile.
Researchers have also found that ageing and lifespan do evolve in subsequent generations of biological species in a theoretically predicted direction, depending on particular living conditions. For example, selection for later reproduction—artificial selection of late-born progeny for further breeding—produced, as expected, longer-lived fruit flies, while placing animals in a more dangerous environment with high extrinsic mortality redirected evolution, as predicted, to a shorter lifespan in subsequent generations. Selection of eggs from older flies progressively led to much older flies which lived twice as long.
This all fits with Thomas Kirkwood’s disposable soma theory, where soma refers to the body. The power of selection fades with age. The disposable soma theory argued that ‘it may be selectively advantageous for higher organisms to adopt an energy saving strategy of reduced accuracy in somatic cells to accelerate development and reproduction, but the consequence will be eventual deterioration and death’. Given finite resources, the more the body spends on maintenance of the body, the less it can spend on reproduction. Molecular proofreading is reduced and so are other accuracy-promoting devices in body cells. Energy must be devoted to germ cell reliability but damage can accumulate in body cells—there are so few germ cells by comparison. From the point of view of evolution, the prevention of ageing is only necessary until the animals have reproduced and cared for the young sufficiently well; nature has therefore provided repair measures to delay the process until that is done. According to this theory, we and other animals are disposable once reproduction and the rearing of children have been completed.
Pacific salmon of both sexes do not care for the young and they die a few weeks after spawning. The male marsupial mouse dies after intense spawning from immune system collapse, but not the female. There are also animals that live well past their reproductive period—including whales and human females. In both cases this is due to their looking after and nursing the young, their own as well as those of others in the case of whales.
There is overwhelming evidence that there are strong genetic influences on the rate of ageing. Perhaps the most compelling evidence is that the differences of rates of ageing within individuals of a species are negligible compared with the vast differences across species. Honeybee workers live only a few weeks compared to the queen, who lives for years because she was fed honey when a larva. A mayfly moults, reproduces and dies within a single day, in some cases with a functional lifespan measured in hours; by contrast, giant tortoises can live for over 150 years, helped probably by their protective armour. The powerful influence of genetics is further reflected by the ever increasing number of single-gene mutations that can influence the lifespan of organisms ranging from yeast to mice.
An important example is that of female reproduction changing with getting older. This, due to menopause, is unlike ageing, and is programmed by our genes. Women can reproduce over long periods. The oldest mother is from India—she had twins at 70 with IVF. In the UK the oldest is 66. It is argued that 63 should be the maximum age, as the child needs a mother for some 20 years, which takes her to 83. A girl became the UK’s youngest mother at the age of 12.
This raises the question of why there is a menopause in women and thus an end to reproduction. The average age in Britain for the menopause to occur is 51 years old. Why do women forgo years of their reproductive lives? What selection pressures could result in this unique human adaptation? Menopause may be explained by the ‘good mother’ theory—energy should be devoted to looking after children rather than having more. It may have been that, since childbirth is risky in humans, menopause allowed older women to survive longer and better raise their existing children. Another possibility is commonly known as the ‘grandmother’ hypothesis, and argues that women who stopped ovulating in their golden years were freed from the costs of reproduction and were better able to invest in their existing children and grandchildren, thus helping to ensure that more individuals with their menopause-inducing genes thrived and had children themselves.
A remarkably complete and instructive data set from Gambia offers a window into a world without the benefits of modern health care. What the data reveals is that children were significantly more likely to survive to adulthood if they had a grandmother’s assistance. Grandmothers from Gambia are crucial to infant survival. In other studies data revealed that a child was over 10 times less likely to survive if its mother died before it was two years old, but that children between one and two had twice the chance of surviving if their maternal grandmother was still alive. No other relatives had any effect. But while menopause may result in less cancer, it increases the risk of heart disease and osteoporosis.