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 mechanisms, but in terms of what there is still to be learned and in terms of any intervention we are only at the beginning. The number of scientists working on ageing is tiny compared, for example, to those working on cancer. Extending life expectancy is one of humanity’s greatest successes, as we have doubled it over the last two hundred years, and for the first 150 of those years it was done by preventing people dying young by getting rid of infections and advances in general sanitation, vaccines and so on. Until about 25 years ago that was thought to be the end of the story. But it is a great surprise that the increase in life expectancy has not slowed one jot as people are getting old in better shape, and there is a decline in death rate in older people. After all this success, should we now be tampering with the ageing process itself?
This raises challenging questions. In my view it is perfectly OK to use science to increase lifespan provided the emphasis is on the quality of the years gained. Is immortality possible? At a theoretical level, yes. When I had, some years ago just finished my book on ageing, Time of Our Lives, I had an idea for a work of fiction, a short story, ‘Miranda’s Tale’, where science has managed to indefinitely postpone the ageing process. It has to be a possibility as the germ line does not age, they have better repair mechanisms, and there is also elimination of less good cells. It would not be by taking a drug, but would require changing our genetic constitution. There are animals like hydra which do not age. But I do not think it a practical objective. It is science fiction and should stay there.
What did he feel about his own ageing?
I think ageing is a challenging process—I am just coming up to 60 so not yet much affected. I enjoy being alive so I want to become older and I enjoy talking with older people. One has to accept reduction in mobility. Many young people do not want the problems of old age, but when they reach that age they may enjoy a very full and active life. Most people including scientists still think that we are programmed to age, although the evidence is totally against it—it is part of the need to see a purpose.
8. Extending
‘Every Man desires to live long; but no Man would be old’
How long can we, and should we, live? How to live for ever has been a compelling subject for a very long time. One of the earliest legends about immortality, and also one of the earliest written stories, is that of Gilgamesh, the Babylonian demigod, from around 2000 BC. When he aged and began to fear death, Gilgamesh was told that he could survive forever if only he could show that he could master sleep by not sleeping for seven days and nights. But try as he might, he failed to do this. The gods then told him that he could find a plant underwater that, if he ate it, would make him alone immortal. Gilgamesh found the plant, but was enjoying swimming so much that he left the plant on the shore while he continued swimming. A snake came along and ate the plant. The lesson to be learned was that ageing was unavoidable.
The legends of the Greeks are filled with the adventures of the immortal gods and humans who seek immortality through their deeds, or through the acts of the gods. But there was also a more realistic attitude. The Greek philosopher Democritus criticised people for yearning for a long life, and argued that if they developed the right attitude to ageing and death they could live more peacefully. The Roman Lucretius thought it absurd not to recognise that a long life was insignificant compared to how long one remains dead. He also argued that death was essential to keep the population down.
The ancients were all too aware of the dangers of immortality if the effects of ageing were ignored. This is illustrated by the story of Tithonus in Greek mythology, a story we should keep in mind when trying to extend life. Tithonus was the lover of the goddess of dawn, Aurora, and so good at what he did for her that she went to her father, the god of gods, Zeus, and asked if Tithonus could have eternal life. Zeus, being a doting father, immediately granted Tithonus immortality. The problem was that Aurora had failed to also ask for him to have eternal youth. With time the ageing process took its toll, and when Tithonus reached a hundred he had mild cognitive impairment and went around Aurora’s castle babbling incessantly: