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.
It is an amazing fact that our skin cells are replaced about every 5 weeks, so by the time you are 20 years old you would have replaced your skin cells about 200 times. Do the cells that give rise to skin—skin stem cells—not age? Stem cells are cells that divide and then one daughter cell remains a stem cell to divide again, whereas the other can become specialised cell such as a skin cell. Using mouse skin cells as a model system, researchers compared several properties of young and old adult skin stem cells. They found that, over an average mouse’s lifetime, there was no measurable loss in their functional capacity. It seems that skin stem cells resist cellular ageing. There is no evidence that the lifespan of any species is determined by a limited supply or limited functionality of its stem-cell populations. An analysis of changes in gene activity as a mouse ages found that some tissues displayed large differences: in old mice, for example, there were genes in the brain which were more active, while other genes were less so, compared to a younger mouse.
Just less than one third of the variation in human lifespan is due to genetic differences that are important for survival after 60. Research on Danish twins born since 1870 found no evidence for an innate maximum lifespan shared by identical twins. Only about 25 per cent of the variation in adult lifespans could be attributed to genetic variation among individuals. The search for the genes that positively affect human ageing has been intense, but it has been very difficult. One example is the Peter Pan gene that extends human lifespan and acts via the insulin pathway which is so central in animal studies. Most of the long-lived men—those who eventually reached an average age of 98 years—had the same version of a gene which regulates the insulin pathway.
There are several illnesses related to old age which have a clear genetic basis and result in premature ageing. A genetic disease that causes premature ageing is Werner syndrome, which is a mutation in a gene that codes for a protein that unwinds DNA. Those with the illness typically grow and develop normally until they reach puberty, but usually do not have a growth spurt, resulting in short stature. The characteristic aged appearance of individuals with Werner syndrome typically begins to develop when they are in their 20s and includes greying and loss of hair; a hoarse voice; and thin, hardened skin. Affected individuals may then develop disorders such as cataracts, skin ulcers, type 2 diabetes, diminished fertility, severe hardening of the arteries, thinning of the bones and some types of cancer. People with Werner syndrome usually live into their late 40s or early 50s. The most common causes of death are cancer and atherosclerosis.
Premature ageing is known as progeria. Hutchinson-Gilford Progeria Syndrome—a very rare, genetic disease: only about 50 cases are currently identified worldwide—is due to a mutation in the LMNA gene that codes for a protein involved in the structure of the cell nucleus. Children with this mutation have small, fragile bodies, like those of elderly people, and typically live only about 13 years, and die from atherosclerosis and cardiovascular problems, although some have been known to live into their late teens and early 20s. The condition almost always occurs in people with no history of the disorder in their family. Whether the illness is similar to normal ageing is not known. Other genes are involved in age-related illnesses like Alzheimer’s.
All these results suggest that no life strategy is immune to the effects of ageing, and therefore immortality may be either too costly or mechanistically impossible in natural organisms. Yet there are exceptions. Germ cells are immortal and a few primitive organisms, including hydra, a primitive simple animal in the form of a tube with tentacles, exhibit very slow or negligible ageing. Individual hydra were observed over a period of four years and yet showed no age-related deterioration, either in terms of survival or reproduction rates. The reason is not clear, but may be related to the fact that hydra can reproduce by forming buds which will develop into mature hydra without sexual involvement, and are also capable of undergoing complete regeneration from almost any part of their body. Most of their body cells can contribute to regeneration, so if some age, they may die or be lost during growth or budding.
Amongst the environmental factors that are linked to ageing, nutrition plays a prominent role. The great increase of non-insulin-dependent diabetes—type 2—in industrialised nations as a consequence of eating too much is an expression of this environmental challenge that also affects ageing processes. The most consistent effects of the environmental factors that slow down ageing—from simple organisms to rodents and primates—have been observed for calorie restriction. In yeast, the fruit fly and the nematode, sirtuins have been observed to mediate as ‘molecular sensors’ in the effects of calorie restriction on ageing processes. Sirtuins are activated when cell energy status is low.
Exposure to a variety of mild stressors such as calorie restriction and heat can induce an adaptive response that increases lifespan. For example, long-lived nematode insulin-signalling mutants are more resistant to thermal and oxidative stress. The term hormesis describes such effects, which are beneficial at a low level but harmful at a higher level. If induction of stress resistance increases lifespan and hormesis induces stress resistance, can hormesis result in increased lifespan? Here the answer is definitively yes. For example, in nematodes, brief thermal stress sufficient to induce tolerance to heat also causes small but statistically significant increases in lifespan. One possibility raised by studies of hormesis is that the increase in lifespan in animals due to dietary restriction, or to insulin signalling mutants, results from hormesis.
Increased longevity can thus be associated with greater resistance to a range of stressors. This may result from the increased expression of genes contributing to cellular maintenance processes, thereby protecting against the molecular damage that causes ageing. Similarly, the physiological stress of exercise has an optimal point for developing muscle strength and improving cardiovascular health, beyond which detrimental effects can be experienced such as attrition of cartilage in joints, leading to arthritis. Another possible example here is alcohol consumption: relative to abstainers, moderate drinkers have reduced mortality risk, especially from coronary heart disease. However, it is not known whether this effect involves stress-response hormesis. The study of stress- response hormesis and the induction by stressors of biochemical processes that protect against stress is providing new insights into the mechanisms that protect against a range of pathological processes, including ageing.
There is a great deal of research into the cellular basis of ageing and the progress is impressive, but there is still a long way to go before we fully understand how cells get damaged with time and, more important, how they repair that damage. One area that may illuminate the repair mechanisms will be by understanding how germ cells are prevented from ageing.
Professor Tom Kirwood is a leading scientist in ageing who gave the Reith Lectures in 2001. I asked him how much do we understand about ageing?
We have a pretty good general understanding as to why ageing happens and a broad thrust of the
