Applying Hormesis in Aging Research and Therapy:
Nadège Minois, Ph.D.
Max Planck Institute for Demographic Research
Laboratory on Survival and Longevity
Doberaner Strasse 114
Tel: 49 (0) 381 2081 128
Fax: 49 (0) 381 2081 428
In his very interesting review, Dr Rattan began by emphasizing the complexity of the aging process. On one hand, a single mutation is able to dramatically increase life span1, and on the other hand, the genes involved are completely different in different species and the aging process apparently takes various pathways in different organisms2, 3.
Apart from genetic manipulation, environmental changes are also known to modulate life span. The most reliable technique is calorie restriction, which largely increases life span in a broad range of species, and reduces or delays age-related pathologies and probably the aging process4.
The other environmental manipulation, which is the topic of Dr Rattan's review, is the exposure to mild stress. It is known for a long time that exposure to different mild stresses might have beneficial effects. The first studies focused mostly on their effects on growth parameters5. It is only recently that have been emphasized their beneficial effects on life span and aging6. As with almost all discoveries about aging, the use of mild stress has been tried to be readily applicable to mammals in general and humans in particular. For instance, some experiments have shown that whole-body hyperthermia in rats and rabbits improved the recovery of isolated hearts from ischemia/reperfusion7, 8. In humans, researchers are more interested in delaying age-related pathologies by using "hormesis-like stress response"9, 10.
However, before thinking of applying mild stress to delay aging in humans, some questions, not addressed in Dr Rattan's review, have to be raised.
The first one is about the biological relevance of hormesis in humans. Can human beings have a use for hormetic factors, or are they already benefiting from their effects? By living in a not totally protected environment, even if humans greatly reduced the impact of environmental changes, do humans encounter in their everydaylife enough stressors to be considered already in a situation mimicking mild stress exposure? In a laboratory, organisms are kept in an as constant environment as possible. When subjected to a mild stress, they react and the involved mechanisms might lead them to live longer. In other words, those organisms are not supposed to encounter any other stress during their life. On the contrary, wild organisms such as humans constantly face environmental changes. They probably already use, or have initiated the same mechanisms, or at least part of them, in their everydaylife. Exposing them to other mild stresses might thus not bring the same benefit on life span and aging as in laboratory-kept organisms, because they are already subjected on a daily basis to mild stress. The beneficial effects of mild stress might be already at work in wild organisms.
The second and last question I would like to discuss here is, if the biological relevance of mild stress in wild organisms is real, what would be the best way to apply hormesis to such organisms? It is obvious that the same mild stress exposure protocols as in the lab experiments cannot be used with wild animals, especially humans. Just on a practical point of view, it would be too time-consuming and compatible with nobody's life. The studies conducted so far in mammals and on human cell cultures have tried to mimic the responses induced by mild stress exposure by modulating the concentrations of some molecules that might be part of the mechanisms of action of mild stress. Even if we cannot deny some promising results brought by such studies, like the protection from oxidative damage of cell cultures overexpressing hsp7011, I see points to be cleared for such studies to bring the maximum knowledge.
An important fact is that we do not know yet a lot about the mechanisms of action of mild stress. Two main hypotheses have been advanced to explain their beneficial effects: a metabolic regulation and the induction of a stress response.
For instance, it has been shown that species more resistant to stress or living in stressful conditions have lower metabolic rates and, on the contrary, organisms more resistant to cold have higher metabolic rates12. However, to my knowledge, it has not been shown at the intra-specific level. Furthermore, calorie restriction does not lead to a lower metabolic rate in calorically restricted animals4. Finally, it seems difficult on a practical point of view to modify the basal metabolic rate of an organism.
Among others, those reasons are why researchers privilege the second hypothesis: the induction of stress response, and especially of heat shock proteins (hsp). It is known that hsp are responsible for the thermotolerance phenomenone.g., 12. Concerning their potential use for therapeutic needs, the only conclusive studies to date are their protective effect from oxidative damage: cell cultures or isolated hearts expressing higher levels of hsp are less susceptible to damages induced by ischemia/reperfusione.g., 13. Concerning the effects of hsp on aging and life span, the results are mitigated. For instance, Hsp104 is required for heat-induced life span extension in Saccharomyces cerevisiae14. On the contrary, Hsp70 overexpression in transgenic Drosophila melanogaster does not increase life span and does not delay behavioral aging15.
To conclude, I would say that mild stresses are a new promising tool for the study of biogerontology, and that it is urgent to unravel their mechanisms of action, to investigate what they can bring and what are their limitations. It is important to keep the discussion open and to see whether this is the beginning of a path leading to a new kind of palliative and therapeutic approach against aging, or a dead end.
1. Lithgow GJ, White TM, Melov S, Johnson TE. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proceedings of the National Academy of Sciences of the USA 1995; 92: 7540-7544.
2. Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science 1999; 285: 1390-1393.
3. Zou S, Meadows S, Sharp L, Jan LY, Jan YN. Genome-wide study of aging and oxidative stress response in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the USA 2000; 97: 13726-13731.
4. Masoro EJ. Caloric restriction and aging: an update. Experimental Gerontology 2000; 35: 299-305.
5. Sacher GA. Life table modification and life prolongation. In: Handbook of the biology of aging (Finch, C.E., Hayflick, L., Eds). Van Nostrand Reinhold Company, New York, 1977; pp582-638.
6. Minois N. Longevity and aging: beneficial effects of exposure to mild stress. Biogerontology 2000; 1: 15-29.
7. Currie RW, Karmazyn M, Kloc M, Mailer K. Heat-shock response is associated with enhanced post-ischemic ventricular recovery. Circulation Research 1988; 63: 543-549.
8. Currie RW, Tanguay RM, Kingma JG. Heat-shock response and limitation of tissue necrosis during occlusion in rabbit hearts. Circulation 1993; 87: 963-971.
9. Leppä S, Sistonen L. Heat shock response-Pathophysiological implications. Annals of Medicine 1997; 29: 73-78.
10. Benjamin IJ, McMillan DR. Stress (heat shock) proteins molecular chaperones in cardiovascular biology and disease. Circulation Research 1998; 83: 117-132.
11. Chong KY, Lai CC, Lille S, Chang C, Su CY. Stable overexpression of the constitutive form of heat shock protein 70 confers oxidative protection. Journal of Molecular and Cellular Cardiology 1998; 30: 599-608.
12. Hoffmann AA, Parsons PA. Evolutionary genetics and environmental stress. Oxford University Press, Oxford, 1991.
13. Su CY, Chong KY, Owen OE, Dillmann WH, Chang C, Lai CC. Constitutive and inducible hsp70s are involved in oxidative resistance evoked by heat shock or ethanol. Journal of Molecular and Cellular Cardiology 1998; 30: 587-598.
14. Shama S, Lai CY, Antoniazzi JM, Jiang JC, Jazwinski SM. Heat stress-induced life span extension in yeast. Experimental Cell Research 1998; 245: 379-388.
16. Minois N, Khazaeli AA, Curtsinger JW. Locomotor activity as a function of age and life span in Drosophila melanogaster overexpressing hsp70. Experimental Gerontology In press.