Practical limitations of Prescribing Stress as an Anti-aging Treatment
Valery E. Forbes, Ph.D.
Department of Life Sciences and Chemistry
Tel: +45 46 74 27 23
Fax: +45 46 74 30 11
In his 'white paper' Suresh Rattan entertains the intriguing possibility that exposure to mild stress may have anti-aging and life-lengthening effects which could be applied to understand and prevent age-related impairments and diseases. It is clear that studying responses to stress at various levels of biological organization may provide important insights into the study of disease and aging, but the variability that occurs at all these different levels is likely to prevent the application of stress-induced hormesis from ever being used as a practical treatment to prevent aging and promote longevity in human populations. Below I give four examples of the way that variability in the phenomenon of hormesis will act as a complicating factor in its application.
The complexity of the aging process itself In his opening paragraph Rattan highlights the variability in the phenomenon of aging - within different parts of an organism, between different individuals and among species. Given the complexity and stochasticity of the aging process, it is difficult to envision how a stress or set of stresses could be applied that would simultaneously attenuate the aging process in all relevant body parts and processes. A stress that stimulates one process (e.g. DNA repair) may retard another (e.g., antioxidant enzyme activity). Prescribing a stress regime that reduces the likelihood of developing one age-related disease may thus increase the likelihood of developing another. In order to determine an effective longevity treatment programme, an individual's risk of developing various age-related symptoms would have to be estimated. There is evidence from a variety of species that stresses that stimulate growth or longevity may have correspondingly negative effects on reproduction.1 Such a reproductive tradeoff might not be relevant in the treatment of aging humans, but could be if aging preventive treatments were begun during early- or mid-adulthood.
Difficulty of predicting precisely the conditions under which hormesis will or will not occur As several reviews have documented2-5 there can be little doubt that hormesis has been demonstrated to occur in representatives from a broad range of taxonomic groups (i.e., from bacteria to mammals), for a number of traits (e.g., growth, longevity, reproduction) in response to a variety of harmful agents (e.g., ionizing radiation, heavy metals, organic toxicants). However, these reviews also indicate that general rules-of-thumb for predicting which traits will be stimulated and under what exposure conditions are not apparent. For example, Winner and Farrell6 studied the responses of four species of the water flea, Daphnia, to copper exposure. In two of the species examined, none of the measured traits indicated stimulation, in one species longevity, number of offspring produced and brood size were all stimulated, and in the fourth species only brood size appeared to be stimulated. Winner et al.7 found that whether or not reproductive stimulation of Daphnia magna in response to Cu exposure was observed depended on the animals' diet. In Daphnia pulex exposed to Cu, whether or not stimulation was observed depended on whether the Cu was applied continuously or in pulses8. In this same study, animals exposed to Cd showed no evidence for stimulation in any of the measured traits, in either pulsed or continuous exposures. Forbes1 reviewed a total of 98 cases from the invertebrate literature for evidence of hormesis, focusing on traits closely related to fitness (i.e., survival and reproductive traits). In 50 of these 98 cases, none of the measured traits showed evidence for hormesis, and in only 10 was there any indication that longevity was increased in response to the stress. In perhaps the most extensive review to date, Calabrese and Baldwin9 determined that hormesis curves exhibit considerable range and diversity with respect to patterns of the stimulatory dose, magnitude of the stimulatory response, and the relationship of the maximum stimulatory response to the no observed adverse effect level. Thus, whereas their review adds much strength to the existence of hormesis as a phenomenon, it also calls into question the extent to which the degree of stimulation and the exposure range over which it may occur is likely to be predictable a priori. Such predictability is essential if the phenomenon is to have practical applications in improving human health.
Variability among individuals that increases with age Rattan10 noted that there exists an age-related increase in variability among individuals, in terms of any physiological, cellular, or biochemical parameter that has been studied. If the variability among individuals in aging-relevant processes is itself age dependent, this will make it extremely difficult to set appropriate stress exposure levels for populations. It would seem that, to be effective, stress exposure scenarios would have to be determined on an individual basis and would need to be adjusted as an individual aged.
Evidence that long-term exposure to mild stress may decrease hormesis Colonies of hydroids that showed hormesis (measured by colony growth) following short-term pre-exposure to low concentrations of copper became impaired (i.e., had reduced growth rates) compared to control colonies when the pre-exposure period was lengthened11. The implication of this result is that initial stimulatory effects of exposure to mild stress might be associated with negative consequences if the stress exposure were continued over a long time period. Testing whether this complication applies to human aging and longevity could be a time-consuming process but would be necessary before stress-induced hormesis could find a practical application in the context of human health.
All of the above complications would make it difficult, if not impossible, to design general stress-exposure protocols for the treatment or prevention of aging and its associated impairments. One of the implications of the above is that the definition of 'mild stress' (i.e., that level of exposure needed to cause stimulation of anti-aging processes) would need to increase with age. Given that the negative consequences of excess stress on life expectancy and disease are known to be potentially severe, the risks of overshooting the hormetic exposure range would be of considerable concern. It has to be expected that background levels of stress exposure are likely to vary considerably within- and among individuals, and this would further complicate the prescription of additional mild stress treatments for disease prevention. I agree with Rattan that 'the range and diversity encountered in the progression of aging phenotype shows that aging is: (1) different in different species; (2) different in different individuals within a species; (3) different in different organs, systems and tissues within an individual; (4) different in different cells within an organ; (5) different in different organelles within a cell; and (6) different in different macromolecules.' But I believe that these observations will continue to challenge biogerontologists in developing efficient ways to prevent aging.
1. Forbes, V.E. (2000) Is hormesis an evolutionary expectation? Functional Ecology 14: 12-24.
2. Stebbing, A.R.D. (1982) Hormesis the stimulation of growth by low levels of inhibitors. Science of the Total Environment 22: 213-234.
3. Parsons, P.A. (1990) Radiation hormesis: an evolutionary expectation and the evidence. Applied Radiation Isotopes 41: 857-860.
4. Calabrese, E.J. & Baldwin, L.A. (1998) Hormesis as a biological hypothesis. Environmental Health Perspectives 106 (Suppl. 1): 357-362.
5. Parsons, P.A. (2000) Hormesis: an adaptive fitness response and an evolutionary expectation in stressed free-living populations, with particular reference to ionizing radiation. Journal of Applied Toxicology 20: 103-112.
6. Winner, R.W. & Farrell, M.P. (1976) Acute and chronic toxicity of copper to four species of Daphnia. Journal of the Fisheries Research Board Canada 33: 1685-1691.
7. Winner, R.W., Keeling, T., Yeager, R. & Farrell, M.P. (1977) Effect of food type on the acute and chronic toxicity of copper to Daphnia magna. Freshwater Biology 7: 343-349.
8. Meyer, J.S., Ingersol, C.G. & McDonald, L.L. (1987) Sensitivity analysis of population growth rates estimated from cladoceran chronic toxicity tests. Environmental Toxicology and Chemistry 6: 115-126.
9. Calabrese, E.J. & Baldwin, L.A. (2000) Reevaluation of the fundamental dose-response relationship. BioScience 49: 725-732.
10. Rattan, S.I. (1998) The nature of gerontogenes and vitagenes. Antiaging effects of repeated heat shock on human fibroblasts. Annals of the New York Academy of Sciences 854: 54-60.
11. Stebbing, A.R.D. (2000) Hormesis: interpreting the
b-curve using control theory. Journal of Applied
Toxicology 20: 93-101.