Commentary on "Applying Hormesis in Aging Research and Therapy"

S. Michal Jazwinski, Ph.D.

Department of Biochemistry and Molecular Biology

Louisiana State University Health Sciences Center

1901 Perdido St., Box P7-2

New Orleans, LA 70112

Tel/Fax: 504 568 4725


The article by Dr. Rattan emphasizes the diverse manifestations of aging on the one hand and the common element of repair and maintenance as major determinants of longevity on the other. I have no quarrel with this specifically. However, the bewilderment with the varied nature of the biochemical functions defined by longevity genes and spilling over into the definition of "private genes" is less helpful. Four broad physiological principles underlying the aging process in species ranging from yeast to human were discerned some time ago1. They include metabolic control, resistance to stress, gene dysregulation, and genetic stability; they can readily be lumped into the general categories of repair and maintenance. The seemingly heterogeneous array of longevity genes highlights the biochemical richness of the pathways and processes that determine longevity. However, it does not diminish the recurrent character of the four principles listed above. This recurrent character has been consistently re-affirmed. If this were not the case, any consideration of hormesis as a route to the understanding and "treatment" of aging would be fruitless, because the principle would be lost in the detail.

The classification into "public" and "private" longevity genes2 has considerable value when ecological and evolutionary perspectives are taken into account. However, the parallel categorization into "major" and "minor" longevity genes, and associated aspects of aging, provides a stronger rationalization for the comparative biology of aging3. In the continuum of major to minor genes, it is easy to accommodate multiple, simultaneously limiting factors for longevity, no matter how dissimilar their function. Even in a genetically homogeneous population maintained under constant conditions many different aspects limit life span. This feature of aging is related to the variation in life spans among the individuals in such a population, and it has been proposed to be the result of the epigenetic stratification of the population due to random change acting at the level of individuals4. Interestingly, this phenomenon is under genetic control5. It is important to keep this stratification in mind when contemplating the effects of hormetic interventions on specific individuals.

Hormesis may be naturally at work in an aging population. Dr. Rattan has alluded to this in the beginning of his section on homeodynamics. The compensatory response to mitochondrial dysfunction in yeast, known as the retrograde response, is a clearcut example4. The induced adjustments in cell physiology that it entails result in an extension of life span6. With this documented example, it is not too far fetched to expect that artificially imposed hormesis works. And it does, at least for mild heat stress in yeast7, nematodes8, and fruit flies9.

A cautionary note is required at this point. The "mild repeated stress" indicated by Dr. Rattan can only be repeated a limited number of times. Chronic bouts of mild stress can shorten life span10. In fact, there appears to be a rather precise number of such episodes of stress that the organism can tolerate. Importantly, rapid recovery from the stress is at least as important as the mounting of the response to begin with. It is sobering to note that the course of aging in mouse skeletal muscle is associated with an increase in stress responses11. Extension of life span by caloric restriction attenuates this age-related effect. The fine-tuning of hormetic interventions will definitely be called for.


1. JAZWINSKI, S. M., 1996 Longevity, genes, and aging. Science 273: 54-9.

2. MARTIN, G. M., S. N. AUSTAD and T. E. JOHNSON, 1996 Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 13: 25-34.

3. JAZWINSKI, S. M., 1993 The genetics of aging in the yeast Saccharomyces cerevisiae. Genetica 91: 35-51.

4. JAZWINSKI, S. M., 2000 Metabolic control and ageing. Trends Genet 16: 506-11.

5. DE HAAN, G., R. GELMAN, A. WATSON, E. YUNIS and G. VAN ZANT, 1998 A putative gene causes variability in lifespan among genotypically identical mice. Nat Genet 19: 114-6.

6. KIRCHMAN, P. A., S. KIM, C.-Y. LAI and S. M. JAZWINSKI, 1999 Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 152: 179-90.

7. SHAMA, S., C.-Y. LAI, J. M. ANTONIAZZI, J. C. JIANG and S. M. JAZWINSKI, 1998 Heat stress-induced life span extension in yeast. Exp Cell Res 245: 379-88.

8. LITHGOW, G. J., T. M. WHITE, S. MELOV and T. E. JOHNSON, 1995 Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A 92: 7540-4.

9. KHAZAELI, A. A., M. TATAR, S. D. PLETCHER and J. W. CURTSINGER, 1997 Heat-induced longevity extension in Drosophila. I. Heat treatment, mortality, and thermotolerance. J Gerontol A Biol Sci Med Sci 52: B48-52.

10. SHAMA, S., P. A. KIRCHMAN, J. C. JIANG and S. M. JAZWINSKI, 1998 Role of RAS2 in recovery from chronic stress: effect on yeast life span. Exp Cell Res 245: 368-78.

11. LEE, C.-K., R. G. KLOPP, R. WEINDRUCH and T. A. PROLLA, 1999 Gene expression profile of aging and its retardation by caloric restriction. Science 285: 1390-3.