You’re Looking Very Well

by Lewis Wolpert

  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.

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  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.

  7. Understanding

  ‘From age to age, nothing changes, and yet everything is completely different’

  — Aldous Huxley

  If ageing is not programmed by our genes, then why and how do we age? The answer lies in our cells. We are essentially a society of billions of cells. Cells, for their size, are the most complex structures in the universe. It is proteins that determine how cells behave; genes only provide the essential code for making proteins. A typical cell, like one in our skin, will contain thousands of different proteins, and millions of copies of some of them. Complex interactions between the proteins and the genes determine which proteins will be synthesised and so determine how the cell behaves.

  Proteins are long strings of quite small units, amino acids, whose sequence is coded for by the DNA of the genes, and this sequence determines how proteins will fold and then function. We age because of wear and tear, in a way not dissimilar to that of any machine, for example a car; death rates for cars follow a similar pattern to those for animals. There is no single ageing process. Ageing results from an accumulation of cellular damage and the limitations in the cells’ ability to repair the damage, particularly in our DNA and proteins, and so restore normal function to the cell. The maintenance of the integrity of DNA is a challenge to every cell, for such damage leads to the absence of key proteins, the synthesis of proteins in the wrong cells at the wrong time, and also to proteins with bad properties. Such damage accumulates randomly throughout life, from the time when body cells and tissue first begin to form. It is striking how organisms with the same genes, like identical twins, can age quite differently because of the random nature of the causes of the damage. Chance events are an integral part of ageing.

  Cells are very complex and there are at least 150 different proteins that are involved in repairing DNA when it is damaged. Other damage occurs in mitochondria that produce the energy for cellular activities, and in membranes that surround the cell and are also present internally. How long we, and other animals, can live is determined primarily through mechanisms that have evolved to regulate the levels of cellular damage in the body. As discussed earlier, it is only the germ cells which give rise to eggs and sperm for reproduction that do not age as the damage is repaired. Because our germ-line—the cells that give rise to eggs and sperm—gives rise to the next generation it must avoid any damage due to ageing. This requires elevated levels of maintenance and repair in germ cells, as compared with body cells. Some trees can live 5,000 years, the reason being that there is no clear difference between germ and body cells, so there are mechanisms to prevent ageing in all their cells.

  How do body-cell repair processes deal with the chemical diversity of the molecular damage that is central to ageing? The forms that damaged molecules in the cell and environmental toxins can take are almost limitless. It is another example of the brilliance of evolution that a set of genes has evolved to code for proteins that deal with the near-infinite structural diversity of molecular junk that accumulates with age. The most common molecular sign of ageing in cells is an accumulation of altered proteins derived from erroneous synthesis and wrong folding. There are a number of special proteins which help cells deal with proteins that have folded wrongly and other faulty proteins, and which can delay ageing and extend lifespan in some organisms. Protein turnover is essential to preserve cell function by removing proteins that are damaged or redundant. There is evidence that an accumulation of altered proteins contributes to a range of age-related disorders, such as Alzheimer’s and Parkinson’s disease. People with two copies of the longevity variant of the CETP gene involved in lipid metabolism have been shown to have slower memory decline and a lower risk for developing dementia and Alzheimer’s disease

  Cells can deal with the accumulation of damaged proteins and mitochondria due to ageing by eating bits of themselves—autophagy, the degradation of a cell’s own damaged components. Autophagy can destroy damaged cell structures like mitochondria, cell membranes and proteins, and the failure of autophagy is thought to be one of the main reasons for the accumulation of cell damage and ageing. During ageing, the efficiency of autophagy declines, and damaged cellular products accumulate. TOR (Target of Rapamycin) is a protein enzyme which controls metabolism and can stimulate cell growth but can also block autophagy. Inhibition of TOR by rapamycin can increase lifespan in model organisms. In the nematode worm there is clear evidence that lifespan is linked to the capacity to regulate autophagy. Results from the fly demonstrate that promoting expression of an autophagy gene in the nervous system extends lifespan by 50 per cent, thereby providing evidence that the autophagy pathway regulates the rate at which the tissues age. Recent studies have revealed that the same signalling factors regulate both ageing and autophagy, and this involves longevity factors like the sirtuins which were discovered in yeast.

  Although ageing is a multifactorial process with many mechanisms contributing, anything that damages the DNA and so leads to absence of proteins or faulty proteins can cause a malfunction of the cells. Some of the most important mechanisms causing ageing may involve damage to DNA. Damage to DNA can cause a mutation which alters the coding for a protein. There is also DNA in mitochondria that produce the energy for the cell. DNA may be the structure whose integrity cells have the most difficulty in maintaining over their lifetime. The DNA in every chromosome experiences thousands of chemical modifications every day and there is often repair—removal of damaged bases in the DNA is estimated to occur 20,000 times a day in each body cell. While DNA damage has not been shown to cause ageing directly, a number of rare human disorders, caused by mutations in DNA repair genes, include symptoms of premature ageing.

  Cells tend to respond to serious DNA damage by committing suicide—apoptosis—and this provides a way of preventing the damaged cell becoming cancerous. This occurs much more often in aged tissues in which the background accumulation of damage is greater, and the resulting loss of cells may itself accelerate ageing. Long-lived organisms probably invest in better DNA maintenance. The benefit of this is seen both in slower ageing and delayed incidence of cancer, since genome instability contributes to both these processes. Humans are less likely to get cancer than mice, as they have invested more in DNA repair. While long-lived organisms make greater investments in cellular maintenance and repair t
han short-lived organisms, with age the repair mechanisms fade.

  Nature and evolution seem to have a fine sense of irony when they made our lives so dependent on oxygen, which is essential for energy production but may also be a major cause of ageing and our eventual death. One possible cause of the damage to DNA and other molecules that leads to ageing places much of the blame on small modified oxygen molecules. Oxygen is required by the mitochondria in cells to produce energy from the molecules derived from food. The production of ATP, the key energy source in cells, by the mitochondria results in the production of these reactive oxygen molecules. Free radicals like reactive oxygen are formed due to loss of an electron which they steal from another molecule, and which makes them unstable and able to damage other molecules. Severe reduction of mitochondrial function in worms shortens lifespan significantly, and a prime candidate has been damage caused by reactive oxygen. Certain dwarf mice live almost twice as long and this is due to reduction in damage to the mitochondria in their brains. Many long-lived mutants are resistant to oxidative stress, and species of mammals that live longer tend to have cells that, when tested in culture, are more oxidative stress resistant. Large animals produce reactive oxygen at a slower rate.

  Even single-cell organisms like bacteria and yeast age. The critical requirement for ageing in unicellular organisms is that a parent cell, when it divides, provides a smaller, and essentially younger, offspring cell. This occurs in yeast and the simple bacterium E. coli, and they share having a visibly asymmetric division and an identifiable juvenile phase. E. coli divides down the middle, giving each daughter cell one newly regenerated tip. But the cell’s other tip is passed down from its mother, or grandmother, or some older ancestor. The cell that inherits the old tip exhibits a diminished growth rate, decreased offspring production, and an increased incidence of death. Thus the two apparently identical cells produced during cell division are in fact functionally asymmetric; the old cell should be considered an ageing parent repeatedly producing rejuvenated offspring. Asymmetric division may be a way for the cells to get rid of damage by dumping it into the older cell at division.