The Relationship Between Hormesis and Caloric Restriction

Edward J. Masoro, Ph.D.

21 1/2 Legare Street, Charleston, SC, 29401

Tel: 843-853-3445, E-mail: masoro@aol.com



The "white paper" of Turturro, Hass, and Hart makes clear that the answer to the question of whether caloric restriction induces hormesis depends on how hormesis is defined. Based on the initial definition, which describes hormesis as the stimulation of growth by a low concentration of a substance that inhibits growth at high concentrations, they conclude that caloric restriction is not a hormetic agent but can be a co-hormetic agent. On the other hand, utilizing an often used broader concept, which defines hormesis as the non-monotonic dose-response behavior of a compound that at higher concentrations has adverse effects, they conclude that caloric restriction appears to be hormetic. However, I was surprised that this "white paper" did not discuss Neafsey's 1990 review paper1 in which she concluded that based on Gompertzian analyses, life-prolonging caloric restriction and longevity hormesis are different entities.

Since my interest in hormesis is not as a toxicologist but as a gerontologist, I would like to propose still another definition: Hormesis is the beneficial action(s) resulting from the response of an organism to a low intensity stressor. Based on this definition, I have concluded that the well characterized antiaging action of caloric restriction is an example of hormesis2.

The first issue that must be addressed is whether such caloric restriction is a low intensity stressor. The increase in life span, delay in age-associated physiological deterioration, and retardation of a spectrum of age-associated diseases resulting from such caloric restriction are not the usual characteristics of a stressor, but they are consistent with a low intensity stressor having a hormetic action. Moreover, as pointed out in the "white paper" of Turturro and colleagues, severe caloric restriction causes calorie-protein malnutrition, which has many detrimental characteristics consistent with the damaging effects of an intense stressor. Probably the strongest evidence that life-prolonging caloric restriction is a low intensity stressor is its effects on the glucocorticoid system; rats on such a dietary regimen show a modest but significant daily elevation of the afternoon peak concentration of plasma free corticosterone3.

Assuming that life-prolonging caloric restriction is a chronic, low intensity stressor, the question then arises as to how such a stressor retards the aging processes. Before attempting to answer this question, it is necessary to briefly present my view of the basic nature of aging. I believe that aging, in the sense of senescent deterioration, results from long-term organismic damage due to intrinsic factors (such as oxidative metabolism and glycation) and extrinsic factors (such as chronic infections and toxic contaminants in air, water, and food); i.e., aging results from damage that is not fully prevented by the organism's protective and repair processes. In my view, caloric restriction has its antiaging action (hormetic action if you will) by enhancing protective processes and, possibly repair processes as well.

Does caloric restriction protect animals from the harmful effects of damaging agents? Indeed, there is considerable evidence that it protects rodents from damage due to acute, intense damaging agents (stressors, if you like). For example, the acute loss of body weight in response to a surgical procedure is markedly less in rats of all ages maintained on caloric restriction3. In young mice, caloric restriction has also been found to attenuate the inflammatory response caused by the injection of carageenan into the foot pad4. Moreover, the ability of rats to survive a sudden, marked rise in environmental temperature has been found to be greatly enhanced by caloric restriction5. Indeed, studies in Turturro's laboratory6 have shown that caloric restriction protects rodents from the acute damaging action of toxic drugs.

Of course, these findings on acute, intense damage do not prove that caloric restriction also protects against the effects of long-term, low intensity damaging agents, which are an inevitable part of daily living, and which I postulate as the major cause underlying senescence. However, genetic manipulations of nematodes, yeast, and fruit flies have shown that those genetic alterations that increase the resistance of the organism to acute, intense stressors also retard aging processes, as evidenced by significant extension of life span7-11. Thus there is substantial evidence to indicate that caloric restriction has a hormetic action, which is manifested by increased resistance to acute, intense stressors and by the retardation of senescence.

Is there an adaptive evolutionary basis for these actions of caloric restriction? In considering this question, Steve Austad and I focused on the fact that in the wild, rats and mice, as well as many other species, encounter unpredictable periods of food shortage. Our hypothesis is that those members of a population whose genomes were sufficiently plastic to direct energy away from reproduction, and towards maintenance and repair, had an increased chance of surviving the period of food shortage and thus had selective advantage12. Such animals would have an increased resistance to stressors during relative short periods of food shortage in the wild and a decreased rate of aging during long-term, moderate-level food deprivation, such as used in the caloric restriction studies of biological gerontologists. Moreover, there is information on the possible physiological mechanisms underlying this hormetic action. Specifically, caloric restriction has been found to enhance the expression of one or more stress response genes5 and to promote the functioning of the adrenal cortical glucocorticoid system3.

In conclusion, based on my definition of hormesis, the evidence is strong that caloric restriction is a hormetic agent. It is suggested that this definition of hormesis may be of value not only for the field of biological gerontology but for other fields, such as toxicology, as well.

REFERENCES

1. Neafsey, P. J., Longevity hormesis. A review. Mechanisms of Ageing and Development 1990; 51: 1-31.

2. Masoro, E. J., Hormesis and the anti-aging action of caloric restriction. Experimental Gerontology 1998; 33: 61-66.

3. Sabatino, F., Masoro, E. J., McMahan, C. A., and Kuhn, R. W., An assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. Journal of Gerontology: Biological Sciences 1991; 46: B171-B179.

4. Klebanov et al, Hyperadrenocorticism, attenuated inflammation and the life-prolonging action of food restriction in mice. Journal of Gerontology: Biological Sciences 1995; 50A: B78-B82.

5. Heydari, A. R., Wu, B., Takahashi, R., and Richardson, A., The expression of heat shock protein 70 is altered by age and diet at the level of transcription. Molecular and Cellular Biology 1993; 13: 2909-2918.

6. Duffy, P. H. et al, The effect of dietary restriction and aging on the physiological response of rodents to drugs. In: Implications for the Design and Interpretation of Toxicity and Carcinogenicity Studies (Hart, R. W., Neuman, D. A. and Robertson, R. T., Eds.). ILSI Press: Washington, DC, 1995, pp. 125-140.

7. Service, P. M., Hutchinson, E. W., MacKinley, M. D., and Rose, M. R., Resistance to environmental stress in Drosophila melanogaster selected for postponed senescence. Physiological Zoology 1985; 147: 380-389.

8. Arking, R. et al, Elevated paraquat resistance can be used as a bioassay for longevity in a genetically based long-lived strain of Drosophila. Developmental Genetics 1991, 12: 362-370.

9. Kennedy, B. K., Austriaco, N. R. Jr., Zhang, J., and Guarente, L., Mutation in the silencing gene SIR4 can delay aging. Cell 1995; 80: 485-496.

10. Lithgow, G. J. and Kirkwood, T. G. L., Mechanisms of the evolution of aging. Science 1996; 273: 80.

11. Lin, Y, J., Seroude, L., and Benzer, S., Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 1998; 282: 943-946.

12. Masoro, E. J. and Austad, S. N., The evolution of the antiaging action of dietary restriction: A hypothesis. Journal of Gerontology: Biological Science 51A; 1996: B387-B391.