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The Alex Comfort Lecture, 1995

There is increasing evidence that many of the common intractable diseases of western society, vascular disease, rheumatic disorders, insulin-resistant diabetes, dementia, and cancer for example, result from complex interactions between our genetic make-up and our new environment combined with the ill-understood effects of ageing. In sorting out the different players in this complex pathology current research into the biology of ageing is becoming of increasing importance. As pointed out many years ago by Alex Comfort, the clinician whose name is associated with the lecture on which this editorial is based, one of the major difficulties in the field of the biology of ageing is the plethora of theories which attempt to explain the ageing process. However, although this is still the case most workers in this field subscribe to one or other version of what Kirkwood calls 'the disposable soma' theory. In simple terms this says that we are built like the products of the motor car industry, that is to function well but not for too long. It is important that we survive long enough to replace ourselves and hence, in evolutionary terms, most of our biochemistry is geared up to helping us to reproduce our kind and nurture it; what happens after that is of no great importance. Studies of the behaviour of cultured cells have shown us that the ageing process must be under some kind of genetic programming. Fortunately, there are now a number of good experimental models to study the biology of ageing. For example, in Drosophila, yeast, and C. elegans genes have been identified that, when mutated, appear to prolong or shorten life. Although their products are still being identified it appears that at least some of them are involved in the protection of tissues and DNA from oxidant damage. Work in several systems has provided some fascinating insights into the amount of damage mediated to our DNA through the action of noxious oxidants. Ames has estimated that in animals like the rat, with a high metabolic rate, there may be up to 100 000 insults to DNA per day; in humans the figure may be in the range of 10000. To counteract the resulting damage to our DNA we have evolved a complex series of DNA repair systems. There is increasing evidence that our ability to protect our DNA declines with age and that mutations of at least some of the genes involved in these repair systems greatly increase our likelihood of developing various cancers. Furthermore, oxidant damage may have importance for other targets than DNA and may well be involved in the pathogenesis of atheroma, cataract, and dementia. There are also some fascinating insights into the way our proteins change with ageing. In effect, as we get older we become over-cooked. In other words, ageing is associated with profound changes in the structure of our proteins, at least some of which involve complex chemical interactions with sugars. From the work of Cerami and others it is clear that the accumulation of the advanced glycosylation end products (f) may have important effects on tissue structure and may be involved directly in the vascular changes, those that occur in diseases like diabetes for example. Another fascinating observation that has important implications for both ageing and the generation of cancer is that our chromosomes tend to shorten as we age. This has been ascribed to the lack of telomerase, an enzyme which is necessary for building up the ends of our chromosomes. Recently it has been found that this enzyme, though it is never found in normal cells, appears to be present in many cancer cells. Here, again, is a fascinating link between the generation of malignant disease and the ageing process itself. Although these are early days it is now clear that the basic biology of ageing is going to be an extremely exciting field in the future. While it is clear that some pharmacological companies already have it in mind that it may be possible to reverse at least part of the ageing process, the most immediate and important aspect of this research is the information that it promises to yield about the cause of the basic pathological processes which underlie so many of our intractable killers. Thus while these studies may not help future populations to live to the age of 200 there is the real potential that they will have a profound effect on how we prevent and manage some of our chronic illnesses, and hence making living to 100 a much more pleasurable experience.