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’
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
