Antiaging Strategies D. L. KNOOK TNO Institute of Ageing and VascularResearch P.O. Box 430 2300 AK Leiden, The Netherlands LIFE EXPECTANCY VERSUS LIFE SPAN
Articles on some miraculous new antiaging device often appear in popular newspapers and magazines. Unfortunately, its always either a swindle or a sensational distortion of some minor truths. The topic of this section is the question, what kind of scientific attempt can be made to retard the aging process as well as its consequences. According to an old saying, the secret of prolonging life can be found in the art of knowing how not to shorten it. This in fact is also the starting point of many scientific approaches to developing antiaging strategies. If we accept a finite human life span with genetically, and consequently individually, determined limitations of maximum survival, the ultimate goal will be to live this life span. Life extension possibilities should therefore be read as possibilities to extend the life expectancy, not to extend the maximum life span. COMPRESSION OR DECOMPRESSION OF MORBIDITY An important issue in this context is whether, indeed, vital life expectancy will increase. Will the extra years added to life as a consequence of antiaging strategies be spent in good health or will these strategies merely prolong the terminal phase of the disease? In the latter case there will be decompression or expansion of morbidity, because life expectancy as such will continue but will be accompanied by rising morbidity. Therefore, antiaging strategies should aim not only at increasing life expectation per se, but also at diminishing or postponing the disease load in older persons. In the latter case, the result will be at least an equal increase in total life expectancy and vital life expectation. Hopefully, if vital life expectancy increases even faster, there will be a compression of morbidity. For this to be implemented, an analysis of the prevailing chronic disabling diseases of old age and of their relationship to aging processes is required. Disease of old age can be considered as specific manifestations of aging processes at the individual level, the outcome of which is the result of the long-term interplay of a genetically based constitution, life style, and environmental factors.
ANTIAGING STRATEGIES AT VARIOUS LEVELS OF BIOLOGICAL ORGANIZATION
Biological aging is characterized by a series of endogenous, interrelated mechanisms at the molecular, cellular, tissular, and organismic levels and by numerous exogenous factors resulting from the complex interaction of the organism with the 372
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environment. During the lifetime of an organism, numerous changes take place at various levels of biological organization. At each level, antiaging strategies can be developed, and some examples are mentioned in TABLE 1. At the molecular and cellular level are many intrinsic defense systems such as DNA repair systems, the immune system, free radical scavenger systems, and the cytochrome P-450 system. Considering the finite life span and the increased risk for diseases at old age, our endogenous defense systems are not perfect. Antiaging strategies might aim at enforcement of these natural antiaging defense systems. Aging of the reproductive system, with its numerous hormone-related physiological consequences, forms a specific issue. It is a major example of a clearly agerelated decline in organ function, and its relation to aging of the organism is still poorly understood. Age-related changes in a regulatory mechanism such as the ovarian hormone balance are well known. The involvement of hormones and of neuronal signals in many complex interactions of organs, tissues, and cells makes it evident that strategies aimed at the prevention of failures in these regulation processes will influence the aging process in a positive way. TABLE1. Some Antiaging Strategies at Various Biological Levels Molecular/cellular level Endogenous defense systems Cell transplantations Tissue/organ function level Drugs, hormones Organ transplantation Level of organism Decreased body temperature Dietary restriction
The life span of a particular individual can be shortened by dysfunction of any of a number of vital organs (heart, brain, kidney, liver, pancreas) or by more generalized physiological degeneration. Transplantation of a new vital organ or of cells (e.g., beta cells from the pancreas) can be considered an effective antiaging strategy.
ANTIAGING AT AN ORGANISMIC LEVEL
As an example of antiaging strategies at the level of the organism, the extensive research on Drosophila can be mentioned. Many environmental conditions have been demonstrated to affect in a positive way the life span in Drosophila. These conditions include a.0. low temperature and food concentration as well as specific conditions for light intensity, humidity, and larval density. These effects, however, were obtained with poikilothermic organisms and may offer only a partial clue to higher animals.
AGING AND FOOD RESTRICTION
Restriction of caloric intake is the only proven antiaging strategy in mammals. This unique position of caloric restriction among the possible strategies for interven-
374
ANNALS NEW YORK ACADEMY OF SCIENCES
tion in aging processes is reflected by its broad spectrum of effectiveness, at least in experimental animals kept under ideal laboratory conditions. These animal experiments show a clear-cut relation between daily caloric intake and the age of onset and incidence of age-related diseases. The magnitude of the effect is proportional to the total period of restricted feeding. Several hypotheses have been proposed, and are under study, to identify the basic mechanisms that translate dietary restriction into retardation of the rate of aging and postponement of age-related pathology. APPLICATION OF CALORIC RESTRICTION TO THE HUMAN SITUATION
Caloric restriction may provide an important tool for improvement in the quality of life in the elderly individual by the delay of onset of age-related diseases and the extension of vital life expectancy. There is little direct support for the effectiveness in humans, but strong circumstantial evidence exists that energy intake above requirements affects survival and age-related pathology also in the human population. However, several uncertainties preclude accurate estimations of the desirable caloric intake with optimal long-term effects for individual humans. These uncertainties include the question of the minimal, and thereby optimal, daily energy requirement in relation to actual energy intake in the general population. Present knowledge indicates that for a majority of populations in the Western world, a significant reduction in daily caloric intake should be possible without a serious risk of malnutrition. It is, however, completely unclear if the effect of caloric restriction will be the same or far less pronounced under less ideal conditions. Until now, all animal experiments were performed under optimal laboratory conditions. The situation in humans is much more complex than that in barrier-maintained, inbred, experimental animals because of genetic heterogeneity, exposure to a very complex and variable environment, and life-style factors. Recently, studies were performed to investigate the consequences of environmental and life-style factors on the long-term effects of caloric restriction in the These factors include chronic exposure to low levels of environmental and dietary toxins (e.g., alcohol) as well as acute exposure to microbiological (e.g., endotoxin) or physical challenges. Calorie-restricted (CR) and ad libitum fed (AL) BN/BiRij rats began to receive 25% (v/v) ethanol in their drinking water at the age of 3 months. The 50% survival time for AL rats was only 13 months compared to 27 months for CR rats. These results suggest that caloric restriction, including alcohol intake, can delay the aging pr0cess.I As an example of an acute microbiological challenge, the susceptibility to endotoxin-induced shock was tested. Long-term caloric restriction apparently did not increase the sensitivity of rats to an endotoxin challenge. These rats produced hypothermia that was milder than that observed in short-term calorie-restricted rats and ad libitum fed rats. The results also suggest that long-term calorie-restricted rats more efficiently metabolize glucose during an endotoxin challenge.2 Because of metabolic differences between rats and humans, extrapolation of these experimental data to the human situation should be done with great care. TECHNOLOGICAL APPROACH
We can broaden the scope of antiaging strategies by including all kinds of technological adaptations that will have a positive influence on the quality of life of
KNOOK ANTIAGING STRATEGIES
315
the elderly. Aging will result in a decline in functions and a need for care. Both aspects might be compensated to a certain extent by the application of new technologies. Development of the right technology may allow older persons to live independently for a longer period and to reduce dependency needs, thereby enhancing living standards.3 REFERENCES 1. BROUWER, A., W. F. SEIFERT, A. BOSMA, E. W. VAN LEEUWEN, H. F. J. HENDRIKS & D. L. KNOOK. 1992. In Modification of the Rate of Aging. A. Ruiz-Torres & G. Hofecker,
eds.: 197-205. Facultas-Universitatsverlag.Wien. D. L., H. F. J. HENDRIKS & A. BROUWER. 1991. Geriatria y Gerontologia 26(suppl. 2. KNOOK, 1): 45. D. L. 1992. In Studies in Health Technology and Informatics, vol. 3: Gerontechnol3. KNOOK, ogy. H. Bouma & V. Graafmans, eds.: 169-176. 1 0 s Press. Amsterdam.
Articles on some miraculous new antiaging device often appear in popular newspapers and magazines. Unfortunately, its always either a swindle or a sensational distortion of some minor truths. The topic of this section is the question, what kind of scientific attempt can be made to retard the aging process as well as its consequences. According to an old saying, the secret of prolonging life can be found in the art of knowing how not to shorten it. This in fact is also the starting point of many scientific approaches to developing antiaging strategies. If we accept a finite human life span with genetically, and consequently individually, determined limitations of maximum survival, the ultimate goal will be to live this life span. Life extension possibilities should therefore be read as possibilities to extend the life expectancy, not to extend the maximum life span. COMPRESSION OR DECOMPRESSION OF MORBIDITY An important issue in this context is whether, indeed, vital life expectancy will increase. Will the extra years added to life as a consequence of antiaging strategies be spent in good health or will these strategies merely prolong the terminal phase of the disease? In the latter case there will be decompression or expansion of morbidity, because life expectancy as such will continue but will be accompanied by rising morbidity. Therefore, antiaging strategies should aim not only at increasing life expectation per se, but also at diminishing or postponing the disease load in older persons. In the latter case, the result will be at least an equal increase in total life expectancy and vital life expectation. Hopefully, if vital life expectancy increases even faster, there will be a compression of morbidity. For this to be implemented, an analysis of the prevailing chronic disabling diseases of old age and of their relationship to aging processes is required. Disease of old age can be considered as specific manifestations of aging processes at the individual level, the outcome of which is the result of the long-term interplay of a genetically based constitution, life style, and environmental factors.
ANTIAGING STRATEGIES AT VARIOUS LEVELS OF BIOLOGICAL ORGANIZATION
Biological aging is characterized by a series of endogenous, interrelated mechanisms at the molecular, cellular, tissular, and organismic levels and by numerous exogenous factors resulting from the complex interaction of the organism with the 372
KNOOK ANTIAGING STRATEGIES
313
environment. During the lifetime of an organism, numerous changes take place at various levels of biological organization. At each level, antiaging strategies can be developed, and some examples are mentioned in TABLE 1. At the molecular and cellular level are many intrinsic defense systems such as DNA repair systems, the immune system, free radical scavenger systems, and the cytochrome P-450 system. Considering the finite life span and the increased risk for diseases at old age, our endogenous defense systems are not perfect. Antiaging strategies might aim at enforcement of these natural antiaging defense systems. Aging of the reproductive system, with its numerous hormone-related physiological consequences, forms a specific issue. It is a major example of a clearly agerelated decline in organ function, and its relation to aging of the organism is still poorly understood. Age-related changes in a regulatory mechanism such as the ovarian hormone balance are well known. The involvement of hormones and of neuronal signals in many complex interactions of organs, tissues, and cells makes it evident that strategies aimed at the prevention of failures in these regulation processes will influence the aging process in a positive way. TABLE1. Some Antiaging Strategies at Various Biological Levels Molecular/cellular level Endogenous defense systems Cell transplantations Tissue/organ function level Drugs, hormones Organ transplantation Level of organism Decreased body temperature Dietary restriction
The life span of a particular individual can be shortened by dysfunction of any of a number of vital organs (heart, brain, kidney, liver, pancreas) or by more generalized physiological degeneration. Transplantation of a new vital organ or of cells (e.g., beta cells from the pancreas) can be considered an effective antiaging strategy.
ANTIAGING AT AN ORGANISMIC LEVEL
As an example of antiaging strategies at the level of the organism, the extensive research on Drosophila can be mentioned. Many environmental conditions have been demonstrated to affect in a positive way the life span in Drosophila. These conditions include a.0. low temperature and food concentration as well as specific conditions for light intensity, humidity, and larval density. These effects, however, were obtained with poikilothermic organisms and may offer only a partial clue to higher animals.
AGING AND FOOD RESTRICTION
Restriction of caloric intake is the only proven antiaging strategy in mammals. This unique position of caloric restriction among the possible strategies for interven-
374
ANNALS NEW YORK ACADEMY OF SCIENCES
tion in aging processes is reflected by its broad spectrum of effectiveness, at least in experimental animals kept under ideal laboratory conditions. These animal experiments show a clear-cut relation between daily caloric intake and the age of onset and incidence of age-related diseases. The magnitude of the effect is proportional to the total period of restricted feeding. Several hypotheses have been proposed, and are under study, to identify the basic mechanisms that translate dietary restriction into retardation of the rate of aging and postponement of age-related pathology. APPLICATION OF CALORIC RESTRICTION TO THE HUMAN SITUATION
Caloric restriction may provide an important tool for improvement in the quality of life in the elderly individual by the delay of onset of age-related diseases and the extension of vital life expectancy. There is little direct support for the effectiveness in humans, but strong circumstantial evidence exists that energy intake above requirements affects survival and age-related pathology also in the human population. However, several uncertainties preclude accurate estimations of the desirable caloric intake with optimal long-term effects for individual humans. These uncertainties include the question of the minimal, and thereby optimal, daily energy requirement in relation to actual energy intake in the general population. Present knowledge indicates that for a majority of populations in the Western world, a significant reduction in daily caloric intake should be possible without a serious risk of malnutrition. It is, however, completely unclear if the effect of caloric restriction will be the same or far less pronounced under less ideal conditions. Until now, all animal experiments were performed under optimal laboratory conditions. The situation in humans is much more complex than that in barrier-maintained, inbred, experimental animals because of genetic heterogeneity, exposure to a very complex and variable environment, and life-style factors. Recently, studies were performed to investigate the consequences of environmental and life-style factors on the long-term effects of caloric restriction in the These factors include chronic exposure to low levels of environmental and dietary toxins (e.g., alcohol) as well as acute exposure to microbiological (e.g., endotoxin) or physical challenges. Calorie-restricted (CR) and ad libitum fed (AL) BN/BiRij rats began to receive 25% (v/v) ethanol in their drinking water at the age of 3 months. The 50% survival time for AL rats was only 13 months compared to 27 months for CR rats. These results suggest that caloric restriction, including alcohol intake, can delay the aging pr0cess.I As an example of an acute microbiological challenge, the susceptibility to endotoxin-induced shock was tested. Long-term caloric restriction apparently did not increase the sensitivity of rats to an endotoxin challenge. These rats produced hypothermia that was milder than that observed in short-term calorie-restricted rats and ad libitum fed rats. The results also suggest that long-term calorie-restricted rats more efficiently metabolize glucose during an endotoxin challenge.2 Because of metabolic differences between rats and humans, extrapolation of these experimental data to the human situation should be done with great care. TECHNOLOGICAL APPROACH
We can broaden the scope of antiaging strategies by including all kinds of technological adaptations that will have a positive influence on the quality of life of
KNOOK ANTIAGING STRATEGIES
315
the elderly. Aging will result in a decline in functions and a need for care. Both aspects might be compensated to a certain extent by the application of new technologies. Development of the right technology may allow older persons to live independently for a longer period and to reduce dependency needs, thereby enhancing living standards.3 REFERENCES 1. BROUWER, A., W. F. SEIFERT, A. BOSMA, E. W. VAN LEEUWEN, H. F. J. HENDRIKS & D. L. KNOOK. 1992. In Modification of the Rate of Aging. A. Ruiz-Torres & G. Hofecker,
eds.: 197-205. Facultas-Universitatsverlag.Wien. D. L., H. F. J. HENDRIKS & A. BROUWER. 1991. Geriatria y Gerontologia 26(suppl. 2. KNOOK, 1): 45. D. L. 1992. In Studies in Health Technology and Informatics, vol. 3: Gerontechnol3. KNOOK, ogy. H. Bouma & V. Graafmans, eds.: 169-176. 1 0 s Press. Amsterdam.
