Lewis Wolpert - You’re Looking Very Well

Model animal organisms have been invaluable in investigating what determines ageing and lifespan. These organisms include the nematode worm C. Elegans , which has about half our number of genes, a fixed small number of cells—959—and normally only lives for about 25 days; the fruit fly Drosophila , with an average lifespan of 30 days, which is a key model for genetic studies; and mice, which live for several years. The reason the nematode worm begins to die after a couple of weeks is due to the degeneration of its muscle after 15 days. Just why this occurs so soon is not understood, but the worm does not build its muscle nearly as robustly as mammalian muscle, and it contains no satellite cells that can replace damaged muscle cells.

Recent landmark molecular genetic studies have identified an evolutionarily conserved insulin-like growth-factor pathway that regulates lifespan in the nematode, fruit fly, rodents, and probably in humans. Reduction of the activity of this pathway appears to increase lifespan and enhance resistance to environmental stress. Genetic variation within the FOXO3A gene (the names given to genes can be quite weird), which can reduce this pathway’s activity, is strongly associated with human longevity.

A dramatic example of an increase in lifespan came from the nematode worm. If the worms are placed under conditions where there is a limited food supply and many other worms are present, then instead of developing into adult worms through a series of larval stages, they develop into an alternative larval form known as a dauer larva. These dauer larvae neither feed nor reproduce, but if conditions improve they moult into adulthood and can then reproduce. But the dauer larvae, with their very dull lives, can live for up to 60 days, more than twice as long as normal worms. This is due to interference with the insulin pathway. Insulin plays a major role in the ageing process. A major discovery was a mutation in a single gene that caused the worms to live twice as long and remain healthy. This gene codes for a receptor for an insulin-like growth factor. The mechanism by which this increases longevity is not clear, but involves many other proteins. When sirtuins are over-expressed there is an increase in lifespan, and they were shown to interact with proteins of the insulin signalling cascade.

Reduced signalling by chemicals similar to our insulin also extends the lifespan of the fly Drosophila . It has recently been shown that in mice, less insulin receptor signalling throughout the body, or just in the brain, extends lifespan up to 18 per cent. Taken collectively, these genetic models indicate that diminished insulin-like growth-factor signalling may play a central role in the determination of mammalian lifespan by conferring resistance to internal and external stressors. The effects of eating less—calorie restriction—which can increase lifespan, also operate via the insulin effect. Fasting does reduce insulin secretion, but one must be cautious in trying too hard to reduce insulin secretion, as this can lead to diabetes.

There are genes that can extend lifespan or reduce it. The AGE-1 gene, for example, encodes part of a cellular signalling pathway that regulates dauer formation in the nematode worm via insulin-like growth-factor signalling. Mutations in genes encoding constituents of this pathway can extend lifespan not only in the nematode, but also in the fruit fly and the mouse. Single-gene mutations that affect longevity act via their interaction with multiple target genes. The increased lifespan in age-1 and related mutants in the nematode is associated with reduced reproductive fitness. The age of first reproduction is sometimes delayed or even prevented by the inappropriate formation of a dauer larva.

Sirtuins are also involved in mammalian ageing. A protein in the cell nucleus of mammals, NF-kappaB, is not only the master regulator of immune system responses, but can also regulate ageing. Activation of NF-kappaB signalling has the capacity to induce ageing in cells. Several longevity genes, such as the sirtuins, can suppress NF-kappaB signalling, and in this way delay the ageing process and extend lifespan. The protein SIRT1—the mammalian equivalent of sirtuins—manages the packaging of DNA into chromosomes, and this role controls gene activity. When DNA damage occurs, SIRT1 abandons this critical task in favour of assisting with DNA repair. Mice that were bred for increased SIRT1 activity demonstrated an improved capacity to repair DNA and to help prevent undesirable changes in gene expression with ageing. It is involved in life extension that comes from calorie restriction.

There are other ways in which cells can age. A limit to the number of times some cells can divide in culture was discovered by Leonard Hayflick in 1965, when he demonstrated that normal human body cells in a cell culture divide about 52 times, but the number is less when the cells are taken from older individuals. There is no such limit for germ cells or cancer cells or embryonic stem cells. The explanation for the decline in cellular division of body cells in culture with age appears to be linked to the fact that the telomeres, from the Greek word for ‘end part’, which protect the ends of chromosomes, get progressively shorter as cells divide. This is due to the absence of the enzyme telomerase, which makes the telomere grow back to its normal length after each division. This enzyme is normally expressed only in germ cells, in the testis and ovary, and in certain adult stem cells such as those that replace cells in the skin and gut, as these cells have to be prevented from ageing. If the telomeres get very short, the cell is no longer able to divide and this means it cannot become a cancer cell. It may be that the telomeres can count how many divisions the cell has gone through, as they get a little shorter at each division. This could function to protect the cell against runaway cell divisions as happens in cancer, and ageing of the cells so that they have a limited number of divisions could be the price we have to pay for this protection.

Individuals can have their own telomere profile. In addition to the common profile, it is found that each person has specific characteristics, which are also conserved throughout life. Studies on both twins and families indicate that these individual characteristics are at least partly inherited. The length of individual telomeres might occasionally play a role in the heritability of lifespan. In diseases that result in premature ageing there is accelerated telomere shortening, and this may be partly responsible for the condition. There is new evidence that telomere shortening affects ageing in the general population, and is also likely to affect the way a person ages facially. A mutation in the so-called Peter Pan gene speeds up ageing due to telomere shortening. Up to 7 per cent of the population have two copies of this mutation, and they look up to eight years older than other people of the same age. About one third of the population has one copy, ageing them by three to four years. A fortunate, and fresh-faced, 55 per cent do not have the mutation and they remain youthful-looking for longer. Previous research has linked long telomeres with good health and shorter ones with age-related ills such as heart disease and some cancers. Shorter telomeres may thus be associated with shorter lives. One study found that among people older than 60, those with shorter telomeres were three times more likely to die from heart disease and eight times more likely to die from infectious disease. A study of centenarians, Ashkenazi Jews, found that their offspring have longer telomeres, and these are associated with protection from ageing diseases and better cognitive function, and can confer exceptional longevity.

There is increasing evidence that the nervous system may act as a central regulator of ageing by coordinating the physiology of body tissues. In worms, a number of different mutations that disrupt the function of sensory neurons extend lifespan. Furthermore, killing of specific neurons can increase lifespan in worms and flies. An intriguing question is whether functional disconnection in the brain leads to disruption of brain-systemic feedback loops involving crucial hormonal and autonomic systems. Such a loss of integrated function may contribute to age-related physiological changes, such as hypertension and insulin resistance, and predispose individuals to age-related pathological changes in the brain. It will be exciting to explore the extent of these functional connections in future studies.