STRESS MEDICINE, VOL. 3: 3 4 (1987)

ANNOTATIONS

THE PROCESS OF AGEING-BREAKDOWN OF BODY MAINTENANCE?

It is evident to everyone that ageing is an inevitable process, and we have no difficulty whatsoever in distinguishing young, middle-aged or old people. It is therefore a surprise that when physicians or scientists study the process of ageing, in animals or in humans, controversy usually arises. For example, it has been said that there is no such thing as human ageing per se, but there are many age-related diseases. This view is implicitly accepted by the medical profession, since a death certificate can never list ‘natural ageing’ as a cause of death: it must always be due to a specific failure of one or another organ system. If ageing is merely a cluster of specific age-related diseases, where does the process of ageing actually operate?

Attempts by scientists to answer this question are also controversial. It is obvious that different mammalian species have very different maximum lifespans, therefore ageing is genetically controlled. This leads to the assumption that ageing is genetically programmed, and that there are specific genes which in some way measure our lifespan. It is then easy to jump to the conclusion that there is a specific pacemaker or clock located somewhere in the body. This in turn convinces some scientists, who should know better, that the clock could be changed or bypassed, and that in the future this could lead to much increased longevity. These arguments are now far removed from the fact that ageing is genetically determined and bear little relation to a proper scientific understanding of the fundamental problem of ageing.

Another argument is that we age because we are highly evolved complex organisms. It depends on the supposition that the various parts of the body function and interact like the parts of a complex machine, and all machines have finite lifespan. The fallacy in this is that machines are put together piece by piece, whereas complex organisms have an intrinsic process of development from a fertilized egg. This led the evolutionary biologist G . C. Williams to raise the following crucial question. If organisins have evolved the seemingly miraculous feat of development from one cell to a highly complex adult structure, then why is it that they have not also solved the much lesser problem of continual maintenance of the adult body? The point is reinforced by the fact that ageing is not

0748-8386/87/010003-02$05 .OO 0 1987 by John Wiley & Sons, Ltd.

intrinsic to all biological systems. The germ cells which carry all the information for the specification of adult structures continue from generation to generation and are potentially immortal. Many plants with complex structures can be propagated indefinitely by grafting, or by other means independent of sexual reproduction.

To udderstand the process of ageing one must therefore understand why many organisms fail to maintain themselves indefinitely. Maintenance of cells, tissues and organs comprises a collection of complex processes some of which have been studied in great detail. These include: (1) a variety of elaborate enyzme mechanisms to repair damage in DNA; (2) special mechanisms to ensure that important macromolecules (especially DNA and proteins) are synthesized accurately; (3) the continual removal of altered or defective proteins by proteolytic degradation; (4) the elimination of damaging free radicals produced by respiration and other metabolic processes by enzymes or naturally occurring antioxidants; (5) continual replacement of short-lived or defective cells and the healing of tissue damage; and (6) a complex immune system to get rid of infectious agents. Although these and other processes can maintain the human adult for several decades, it is obvious that they cannot do so indefinitely. Therefore, it is a very reasonable hypothesis that ageing is due to the failure or breakdown of body maintenance mechanisms, and this failure gradually affects all organ systems. Ageing in man is associated with cardiovascular disease, a decline in brain function including sense organs, loss of hormonal controls, kidney failure, decrease in muscular strength and resilience of skin, weakening of bone structure, uncontrolled growth of tumours, and so on. It is striking that many of these changes occur with a degree of synchrony; this inevitably leads to complexity and expense in health care for the elderly. The alleviation or the cure of one age-related pathological symptom will soon be followed by another age-related disease. Medical maintenance can, for a while, make good the deficiency of body maintenance, but in the end both will fail.

The general relationship of body maintenance to the genetic control of ageing may be quite straightforward. It is very striking that the pathological or senile changes

4 AN NOTATIONS

seen in mice or rats after three years are very similar to those seen in man after 80 or 90 years. Although the chemistry of the cells, tissues and organs is basically the same, in short-lived species these age-related changes occur 30 times faster than in long-lived ones. This can be explained if the mechanisms for maintenance are more efficient and elaborate in long- lived than in short-lived species. Direct evidence has been obtained in one case, since Hart and Setlow showed that the ability of cells from different species to repair damage in their DNA was directly correlated with the longevity of the species in question.2 (A subsequent study questioned this result, but three others have confirmed it). Also, several types of cell, when grown in culture, have been shown to die out after a given number of cell divisions. The longevity of cells in culture correlates well with the maximum donor l i f e~pan .~

Cell and tissue maintenance depends on the investment of energy and metabolic resource^.^ Alternatively, these can be diverted into other channels, particularly more rapid growth to adulthood and reproduction. It is no coincidence that short-lived species mature and breed very quickly, whereas many long-lived ones, such as humans, whales or elephants, mature and breed slowly. Each species has evolved its own strategy for survival and one component of this is its maximum longevity.

The reason why no mammalian or other vertebrate has evolved the means to maintain its body, or soma, indefinitely was explained by P. B. Medawar many years ago.5 In a natural environment death occurs most commonly from disease, predators or starvation and aged individuals are rarely or never seen. So why should an organism invest resources to survive indefinitely when in all probability it will be killed by one or other of the intrinsic hazards of the environment? The investment would be counterproductive as it would inevitably decrease reproductive fitness6 In fact, the process of ageing can be said to be built into the very fabric of an organism’s structure. To achieve indefinite survival would probably require a totally different body organization, with much more potential for the replacement of defective parts, and especially those tissues, such as brain, which consist largely of postmitotic, non-dividing cells.

Although the scientific study of ageing may be controversial, the study of age-related disease is not, since a considerable body of medical literature is concerned with research on these diseases. The aim of this work is not only to devise better treatments, but also to understand the causes or origin of each age- related disease. It is paradoxical that the scientists and physicians involved in this work are not even aware

they are studying the process of ageing! On the other hand, the explicit scientific study of the process of ageing, known as gerontology, receives very little support and is often thought to be of peripheral biomedical interest. Huge sums are spent on the medical care of the elderly, and there is a large commitment to research on cancer, cardiovascular disease, Alzheimer’s disease, diabetes, and many of the other common age-related diseases. For the most part, the study of each these diseases is carried out independently of the studies of the others. A more logical strategy would be to pay much more attention to those basic cellular and molecular processes which are taking place in the body throughout adult life and which inevitably lead to the pathological changes of ageing.’ This would provide a scientific framework which would establish connections between the various fields of research and lead to an understanding of the origins of many of the debilitating diseases of old age, and therefore to the development of new procedures for their prevention or treatment.

ROBIN HOLLIDAY National Institute for Medical Research,

Mill Hill, London NW7 I A A , U K

REFERENCES 1. Williams, G. C. Pleiotrophy, natural selection and

the evolution of senescence. Evolution 1957; 11: 398-41 1.

2. Hart, R. W. and Setlow, R. B. Correlation between deoxyribonucleic acid excision repair and life span in a number of mammalian species. Proc. Nut. Acad. Sci. USA 1974; 71: 2169-2173.

3. Rohme, D. Evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc. Nut. Acad. Sci. USA 1981; 78: 5990-5013.

4. Kirkwood, T. B. L. and Holliday, R. The evolution of ageing and longevity. Proc. Roy. SOC. B. 1979;

5. Medawar, P. B. A n Unsolved Problem in Biology. H. K. Lewis, London, 1952. Reprinted in Medawar, P. B. The Uniqueness of the Individual. Dover, New York, 1981.

6. Kirkwood, T. B. L. and Holliday, R. Ageing as a consequence of natural selection. In: The Biology of Human Ageing. Bittles, A. H. and Collins, K. J. (Eds) Cambridge University Press, Cambridge,

7. Holliday, R. The ageing process is a key problem in biomedical research. Lancet 1984; ii: 1386-1387.

205: 531-546.

1986, pp. 1-16.

Received 28 November 1986