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Ageing and radiation
American
Heart
Journal
October, 1961, Volume 62, Number
4
Editorial Ageing
and
radiation
G. J. Neary, Ph.D. Harwell, England
T
he starting point of my own reflections on the general problem of ageing is the commonly held view that whole-body irradiation of an animal can, in certain circumstances, speed up natural ageing. This generalization has only been checked experimentally to a limited degree. Certainly, irradiated animals normally have a reduced survival time; and after a single dose of irradiation or after lifetime lowlevel chronic irradiation the pathology at death is broadly the same as in unirradiated control animals. But even using only terminal data of this sort for CBA mice, it is possible to argue that there is an intrinsic process of ageing, enhanced by radiation, which operates from the start of life and is virtually complete by the time the changes of old age begin to appear; until then the process has little outward physiologic manifestation or effect on survival fitness. The argument is quite simple, but first it is necessary to clear a little ground and establish a common conceptual currency. Two basic questions may be posed: Why does an animal die? Why is there a variation in the age at death of comparable individual animals? One type of answer emphasizes the element of randomness in mortality, and the individuals in a population are often tacitly assumed to be identical. The age-specific death rate, the so-called “force of mortality,” is often interpreted as the probability that any survivor will die in a unit interval of time From the Medical Research Council Radiobiological Received for publication Feb. 16, 1961.
433
at that age. The observed progressive increase of the force of mortality, after a certain age, is attributed to a progressive decline in the physiologic state or vitality of the population and the individuals thereof. The logarithm of the mortality rate, the Gompertz function, increases approximately linearly with age, and so it has been an attractive idea to regard this quantity as an intrinsic indes of physiologic age. A quite different type of answer to the two basic questions concentrates attention on the individual; his life span in any given environment is predetermined by his initial genetic endowment. Merely to recognize the existence of this theoretical possibility is of considerable importance, because it then has to be admitted that the progressive increase with age in the age-specific death rate may result merely from the form of the distribution of individual life spans in the population. The concept of a “force of mortality” would then be out of place and there need be no relation between the Gompertz function and the physiologic state either of individuals or of the surviving population as a whole. In most quantitative deterministic theories, ageing is regarded as some process of change within cells, probably in their genetic apparatus. It is clear, however, that the fate of the individual cannot be considered solely in terms of the fate of a component cell. Even though changes within cells may be the root cause of ageing, it would be inResearch
Unit,
Harwell.
Didcot.
Berkshire,
England.
434
Neary
sufficient to consider only the primary process, without reference to the whole sequence of events in the complex of interacting physiologic systems. In practice, both random and deterministic factors undoubtedly play some part. For the human white female population of the United States at present the difference in age at death of identical twins is much less than the standard deviation over the whole population. On the other hand, there has been a significant reduction in mortality during the past hundred or so years in most economically developed countries. The reduction is chiefly in the acute causes of death and has been most marked in early and middle life; the chronic degenerative causes have shown a much smaller change. Hardin B. Jones has argued from such facts that there is a causal relation between disease experience and subsequent susceptibility to disease, but, so far, animal experiments have provided no definite confirmation of this theory. My own view is that even if all adverse external influences could be removed, an intrinsic process of ageing would remain, which is fundamental, inevitable, and irreversible. The process proceeds in two successive stages, induction and development, which together occupy the whole lifetime. During induction, changes occur within individual cells; these naturally occurring changes can also be produced by radiation. Because of homeostatic regulation, the production of the changed cells, which may or may not be viable, produces little physiologic impairment until a certain level of inductive change has been reached. Then homeostasis breaks down rather rapidly and the second stage, development, sets in. It involves a different level of organization and consists in physiologic interactions which proceed autonomously and autocatalytically, entailing rapid physiologic impairment culminating in death ; development thus corresponds to senescence. Once it has been triggered, further inductive change is superfluous, so that further irradiation at this stage is ineffective, provided that it is not sufficiently intense to have direct physiologic effects. The primary process of induction is genetically determinate and little influenced by random factors; the second process of
Am. Heart I. October, 1961
development may, because of its greater complexity-, be subject to such factors. One of the essential features which distinguishes this picture of ageing is the approximate constancy of physiologic competence for survival during induction, which in mice occupies about 80 per cent of the lifetime; physiologic ageing is mainly a phenomenon of senescence. The opposite assumption which has usually been made that all of the injury produced by the simple passage of time or by whole-body irradiation is necessarily expressed as proportional physiologic injury has, in my opinion, hindered the understanding of the problem, especially the analysis into reparable and irreparable injury. As Shock has pointed out, some indices of physiologic capacity are more or less constant throughout life; others appear to show a decline, but such data are usually obtained from different groups of individuals at different ages: “What we do not know, of course, is what happens to a single individual as he progresses through his life cycle.” The range of variation between individuals of the same age is almost large enough to admit the possibility that there is little change in the individual before senescence. In any case, some of these indices refer to maximum physiologic capacity, which may have relevance only to survival from the more extreme “accidents” in the presenescent period. The important question is whether there is a marked increase in the rate of loss of physiologic capacity during senescence. The experimental data which suggested to me the foregoing scheme were obtained in survival studies of chronically irradiated CBA mice under carefully kept conditions so that external disturbing factors were minimized. It is generally found that the mean life shortening of a group of mice or rats is roughly proportional to the mean accumulated radiation dose. It is reasonable to expect, therefore, that the life shortening for one individual will be roughly proportional to his individual accumulated dose. If esposed to a given dose rate throughout life, the naturally longer lived animals would receive a larger accumulated dose, and their absolute life shortening would exceed the average, but the proportional life shortening would be
Ageing and radiation
the same for all. The cumulative mortality curve against time for an irradiated group would thus correspond to that of a control group, but with the time axis contracted. The standard deviation of survival time ~voultl be decreased by radiation in the same proportion as the mean survival time itself. Conversely, the slope of the Gompertz plot would be increased. In fact, however, these features were not found with CBA mice. Up to about 15 rems per day, there was no reduction in dispersion of survival times even though the mean survival time was nearly halved ; the cumulative mortality curves were merely displaced from each other, not contracted ; the Gompertz plots were roughly of equal slope. These results would be explicable if the induction time and radiosensitivity were nearly the same for every member of a group of these genetically homogeneous mice. The effective accumulated dose during induction and the shortening of induction time relative to controls would then be the same for all. The duration of development was unaffected b,T radiation and was statistically the same for irradiated and control ailimals; a value of about 180 days was deduced. The Gompertz plots were very steep and roughly linear during the period of development; before that, in the induction period, the slope was much less. Further analytical details may be found in the original paper. An understanding of the basic process of cellular change during induction would not only be of great theoretical interest but also of practical importance in providing, perhaps, a basis for extrapolation of life-shortening data on animals to man. So far, however, little sure evidence is available from the radiobiologic data. The dose response is linear, which is clearly consistent with a cumulative injury due to irreversible changes in cells. The linearity argues against the primary process being one of chromosome structural damage and would suggest rather somatic gene mutation. The fact that short single doses of X or gamma radiation are some three times as efficient as the same doses delivered chronically at low rates indicates a dose rate factor which is not expected for gene mutation. Moreover, the large
435
size of the “doubling dose” (some thousands of rems) is surprising for a gene mutation unless cell selection for the radiation mutants is much more severe than for the natural mutants. Perhaps the site of the change is not in the chromosomes at all; in some organisms, ageing seems to be a cytoplasmic phenomenon. It is not known whether the cell change responsible for ageing causes the death of irreplaceable cells, or reduces the competence of cells for certain functions, or whether it results in autoimmune reactions between changed and normal cells or between changed cells themselves. It is also not known whether all the cells of the body are subject to the particular form of change or whether only special systems of cells are important-these latter might constitute the homeostatic systems supposed necessary to keep spontaneous autoimmunity suppressed. The question obviously arises as to whether the primary process is the same in different organisms, even as closely similar, say, as mice and men. If this assumption is made for the latter particular pair, we may note that, according to the simplest theory, the life shortening per rem is numerically equal to the ratio of the rate of cell change produced by unit dose rate to the spontaneous rate. There is no obvious reason why this ratio should be very different for a mouse and a man, and so the life shortening per rem in man may be only 0.08 days, the figure found for mice. It has frequently been assumed that the life shortening per rem in man would be greater than in a mouse in the ratio of the natural life spans, but the logic of this is not apparent. It is also interesting to speculate how the development period of 6 months in the mouse would be extrapolated to man. I leave it to physicians to decide whether a figure of 6 months or some 25 times this, i.e., about 12 years, is a better estimate of the period of senescence in man. REFERENCES 1. Jones, H. R.: A special consideration of the ageing process, disease, and life expectancy, Advances Riol. Med. Phys. 4~281, 1956. 2. Neary, G. J.: Ageing and radiation, Nature 187:10, 1960. 3. Shock, N. W.: Age changes in some physiologic processes, Geriatrics 12:40, 1957.
Heart
Journal
October, 1961, Volume 62, Number
4
Editorial Ageing
and
radiation
G. J. Neary, Ph.D. Harwell, England
T
he starting point of my own reflections on the general problem of ageing is the commonly held view that whole-body irradiation of an animal can, in certain circumstances, speed up natural ageing. This generalization has only been checked experimentally to a limited degree. Certainly, irradiated animals normally have a reduced survival time; and after a single dose of irradiation or after lifetime lowlevel chronic irradiation the pathology at death is broadly the same as in unirradiated control animals. But even using only terminal data of this sort for CBA mice, it is possible to argue that there is an intrinsic process of ageing, enhanced by radiation, which operates from the start of life and is virtually complete by the time the changes of old age begin to appear; until then the process has little outward physiologic manifestation or effect on survival fitness. The argument is quite simple, but first it is necessary to clear a little ground and establish a common conceptual currency. Two basic questions may be posed: Why does an animal die? Why is there a variation in the age at death of comparable individual animals? One type of answer emphasizes the element of randomness in mortality, and the individuals in a population are often tacitly assumed to be identical. The age-specific death rate, the so-called “force of mortality,” is often interpreted as the probability that any survivor will die in a unit interval of time From the Medical Research Council Radiobiological Received for publication Feb. 16, 1961.
433
at that age. The observed progressive increase of the force of mortality, after a certain age, is attributed to a progressive decline in the physiologic state or vitality of the population and the individuals thereof. The logarithm of the mortality rate, the Gompertz function, increases approximately linearly with age, and so it has been an attractive idea to regard this quantity as an intrinsic indes of physiologic age. A quite different type of answer to the two basic questions concentrates attention on the individual; his life span in any given environment is predetermined by his initial genetic endowment. Merely to recognize the existence of this theoretical possibility is of considerable importance, because it then has to be admitted that the progressive increase with age in the age-specific death rate may result merely from the form of the distribution of individual life spans in the population. The concept of a “force of mortality” would then be out of place and there need be no relation between the Gompertz function and the physiologic state either of individuals or of the surviving population as a whole. In most quantitative deterministic theories, ageing is regarded as some process of change within cells, probably in their genetic apparatus. It is clear, however, that the fate of the individual cannot be considered solely in terms of the fate of a component cell. Even though changes within cells may be the root cause of ageing, it would be inResearch
Unit,
Harwell.
Didcot.
Berkshire,
England.
434
Neary
sufficient to consider only the primary process, without reference to the whole sequence of events in the complex of interacting physiologic systems. In practice, both random and deterministic factors undoubtedly play some part. For the human white female population of the United States at present the difference in age at death of identical twins is much less than the standard deviation over the whole population. On the other hand, there has been a significant reduction in mortality during the past hundred or so years in most economically developed countries. The reduction is chiefly in the acute causes of death and has been most marked in early and middle life; the chronic degenerative causes have shown a much smaller change. Hardin B. Jones has argued from such facts that there is a causal relation between disease experience and subsequent susceptibility to disease, but, so far, animal experiments have provided no definite confirmation of this theory. My own view is that even if all adverse external influences could be removed, an intrinsic process of ageing would remain, which is fundamental, inevitable, and irreversible. The process proceeds in two successive stages, induction and development, which together occupy the whole lifetime. During induction, changes occur within individual cells; these naturally occurring changes can also be produced by radiation. Because of homeostatic regulation, the production of the changed cells, which may or may not be viable, produces little physiologic impairment until a certain level of inductive change has been reached. Then homeostasis breaks down rather rapidly and the second stage, development, sets in. It involves a different level of organization and consists in physiologic interactions which proceed autonomously and autocatalytically, entailing rapid physiologic impairment culminating in death ; development thus corresponds to senescence. Once it has been triggered, further inductive change is superfluous, so that further irradiation at this stage is ineffective, provided that it is not sufficiently intense to have direct physiologic effects. The primary process of induction is genetically determinate and little influenced by random factors; the second process of
Am. Heart I. October, 1961
development may, because of its greater complexity-, be subject to such factors. One of the essential features which distinguishes this picture of ageing is the approximate constancy of physiologic competence for survival during induction, which in mice occupies about 80 per cent of the lifetime; physiologic ageing is mainly a phenomenon of senescence. The opposite assumption which has usually been made that all of the injury produced by the simple passage of time or by whole-body irradiation is necessarily expressed as proportional physiologic injury has, in my opinion, hindered the understanding of the problem, especially the analysis into reparable and irreparable injury. As Shock has pointed out, some indices of physiologic capacity are more or less constant throughout life; others appear to show a decline, but such data are usually obtained from different groups of individuals at different ages: “What we do not know, of course, is what happens to a single individual as he progresses through his life cycle.” The range of variation between individuals of the same age is almost large enough to admit the possibility that there is little change in the individual before senescence. In any case, some of these indices refer to maximum physiologic capacity, which may have relevance only to survival from the more extreme “accidents” in the presenescent period. The important question is whether there is a marked increase in the rate of loss of physiologic capacity during senescence. The experimental data which suggested to me the foregoing scheme were obtained in survival studies of chronically irradiated CBA mice under carefully kept conditions so that external disturbing factors were minimized. It is generally found that the mean life shortening of a group of mice or rats is roughly proportional to the mean accumulated radiation dose. It is reasonable to expect, therefore, that the life shortening for one individual will be roughly proportional to his individual accumulated dose. If esposed to a given dose rate throughout life, the naturally longer lived animals would receive a larger accumulated dose, and their absolute life shortening would exceed the average, but the proportional life shortening would be
Ageing and radiation
the same for all. The cumulative mortality curve against time for an irradiated group would thus correspond to that of a control group, but with the time axis contracted. The standard deviation of survival time ~voultl be decreased by radiation in the same proportion as the mean survival time itself. Conversely, the slope of the Gompertz plot would be increased. In fact, however, these features were not found with CBA mice. Up to about 15 rems per day, there was no reduction in dispersion of survival times even though the mean survival time was nearly halved ; the cumulative mortality curves were merely displaced from each other, not contracted ; the Gompertz plots were roughly of equal slope. These results would be explicable if the induction time and radiosensitivity were nearly the same for every member of a group of these genetically homogeneous mice. The effective accumulated dose during induction and the shortening of induction time relative to controls would then be the same for all. The duration of development was unaffected b,T radiation and was statistically the same for irradiated and control ailimals; a value of about 180 days was deduced. The Gompertz plots were very steep and roughly linear during the period of development; before that, in the induction period, the slope was much less. Further analytical details may be found in the original paper. An understanding of the basic process of cellular change during induction would not only be of great theoretical interest but also of practical importance in providing, perhaps, a basis for extrapolation of life-shortening data on animals to man. So far, however, little sure evidence is available from the radiobiologic data. The dose response is linear, which is clearly consistent with a cumulative injury due to irreversible changes in cells. The linearity argues against the primary process being one of chromosome structural damage and would suggest rather somatic gene mutation. The fact that short single doses of X or gamma radiation are some three times as efficient as the same doses delivered chronically at low rates indicates a dose rate factor which is not expected for gene mutation. Moreover, the large
435
size of the “doubling dose” (some thousands of rems) is surprising for a gene mutation unless cell selection for the radiation mutants is much more severe than for the natural mutants. Perhaps the site of the change is not in the chromosomes at all; in some organisms, ageing seems to be a cytoplasmic phenomenon. It is not known whether the cell change responsible for ageing causes the death of irreplaceable cells, or reduces the competence of cells for certain functions, or whether it results in autoimmune reactions between changed and normal cells or between changed cells themselves. It is also not known whether all the cells of the body are subject to the particular form of change or whether only special systems of cells are important-these latter might constitute the homeostatic systems supposed necessary to keep spontaneous autoimmunity suppressed. The question obviously arises as to whether the primary process is the same in different organisms, even as closely similar, say, as mice and men. If this assumption is made for the latter particular pair, we may note that, according to the simplest theory, the life shortening per rem is numerically equal to the ratio of the rate of cell change produced by unit dose rate to the spontaneous rate. There is no obvious reason why this ratio should be very different for a mouse and a man, and so the life shortening per rem in man may be only 0.08 days, the figure found for mice. It has frequently been assumed that the life shortening per rem in man would be greater than in a mouse in the ratio of the natural life spans, but the logic of this is not apparent. It is also interesting to speculate how the development period of 6 months in the mouse would be extrapolated to man. I leave it to physicians to decide whether a figure of 6 months or some 25 times this, i.e., about 12 years, is a better estimate of the period of senescence in man. REFERENCES 1. Jones, H. R.: A special consideration of the ageing process, disease, and life expectancy, Advances Riol. Med. Phys. 4~281, 1956. 2. Neary, G. J.: Ageing and radiation, Nature 187:10, 1960. 3. Shock, N. W.: Age changes in some physiologic processes, Geriatrics 12:40, 1957.