Hormesis and Aging
Wayne A. Van Voorhies, Ph.D.
Molecular Biology Program
New Mexico State University
Las Cruces, N.M. 88003-8001
Rattan's article on the potential use of hormesis in aging research provides a well-reasoned and insightful overview of both the factors responsible for aging and the importance of stress responses in potentially modulating senescence. Rattan proceeds from the premise that the causal mechanisms responsible for aging are likely to vary not only between, and within species, but also even between different cell types of the same individual. As such aging may have different causal mechanisms between different species, and multiple causal mechanisms within species. As a direct consequence of this, it is unlikely that a single cause of aging will be common to all organisms.
This lack of a single mechanism of aging presents an important issue. In contrast to such well-coordinated and regulated biologic processes such as organismic development, aging more likely occurs from a series of stochastic, non-deterministic events. As such aging resulting from the inevitable breakdown of basic biologic function over time. From this perspective the most feasible approach towards increasing longevity will come via methods that either increase an individual's intrinsic rate of biologic repair or prevent such damage from occurring, rather than attempts to identify and control a master aging program. One method which has been proposed to potentially increase rate of biological repair, and hence reduce the rate of aging, is hormesis.
Hormesis is often defined as an agent or factor having beneficial biological effects at low levels but causing toxic effects at higher doses. In terms of its relevance to aging, hormesis has been characterized by a mild stress or series of stresses increasing the longevity of an organism. One example of an hormetic effect in aging comes from research that exposed Drosophila to high and low levels of ionizing radiation. While high radiation levels reduced fly longevity, low levels of radiation increased fly longevity compared to non-irradiated control animals1. Hormesis is commonly thought to function via low doses of a stressor enhancing biologic function by upregulating the general stress response and biologic repair pathways of an organism.
As Rattan points out relatively few studies have been conducted that explicitly test the importance of hormesis to aging. Similarly, it is also important to consider that while factors that upregulate stress pathways may extend longevity, increasing stress responses can have deleterious effects on other aspects of the organism's phenotype. Three examples, from Drosophila, the nematode worm Caenorhabditis elegans, and from the effects of caloric restriction on animals, illustrate this point. It is critical to quantify such deleterious side effects if hormesis is to be used as a method to extend longevity, particularly for use in humans.
Such deleterious side effects are seen in lines of Drosophila which over-express heat shock proteins. Heat shock proteins are stress-induced proteins which bind to abnormally folded proteins to either assist in correctly refolding these proteins or to degrade them. As such an increased production of heat shock proteins would appear to be beneficial to an organism as it would allow it to repair or contain greater levels of molecular damage. Consistent with this expectation are results showing that the increased production of heat shock proteins can decrease mortality rates and increase longevity in Drosophila lines genetically modified to over-express heat shock proteins2. This increased production of heat shock proteins, however, also has other deleterious phenotypic effects on the flies, and lines which have increased expression of heat shock proteins also have reduced growth rates and a longer period of development3.
This theme of "no free lunch" is a common among many of the methods which have been shown to extend longevity. C. elegans is popular model organism for studying aging. Much of this interest has been due to the identification of numerous genes in C. elegans that, when mutated, can significantly increase worm longevity. One factor proposed for why these mutants live longer is that these mutations increase stress response pathways that allow the animal to reduce or repair biologic damage4, 5. Consistent with this hypothesis, several studies have shown that long-lived C. elegans mutants are more resistant to some stresses than wild-type worms6, 7.
Other experiments, however, indicate that long-lived C. elegans mutants can also have alterations in other aspects of their phenotypes. At least some of the long-lived C. elegans mutants have reduced metabolic rates compared to wild-type worms8. As such, while these mutants may have a chronologically extended life span, their physiological life span9, 10, the number of physiological events carried out over their lifetime, is equivalent to that of wild-type animals. Additionally many of the long-lived strains of the nematode C. elegans have reduced fecundity and slower rates of development8. Additional support that mutations in C. elegans that extend longevity can have other deleterious effects comes from a study showing that while a population of long-lived C. elegans mutants grows as well as wild-type worms when food is abundant, under reduced food levels wild-type worms grow better11.
Caloric restriction has also received a great deal of attention as a near universal method of increasing longevity. Although it has been known for over sixty-five years that a careful reduction of total caloric intake can extend rodent life span12, 13, the underlying mechanism through which caloric restriction extends longevity is still uncertain. Most explanations for the beneficial effects of caloric restriction on longevity focus on the hypothesis that caloric restriction increases the ability of the organism to withstand stress. It is also important, however, to consider some of the detrimental side effects of caloric restriction that could limit its use in humans.
While animals subjected to caloric restriction do live longer, caloric restricted animals take longer to reach sexual maturity, have a reduced adult body size, and can show large fluctuations in body temperature compared to ad libitum fed animals14, 15. Equally important for the use of caloric restriction to increase longevity are studies showing that while caloric restriction did increase rodent longevity it did not protect the rats against age-related declines in memory or sensorimotor performance16. Few individuals would probably choose to extend their life spans if they were faced with the prospect of spending the extended portion of their life with declining mental function.
These examples are consistent with the point made by Rattan that studies of aging should proceed from the premise of understanding why an organism lives as long as it does, rather than attempting to determine the specific causes of aging in that organism. Over the course of an organism's history, evolution has favored individuals that were able to produce the largest number of progeny which were then capable of producing offspring themselves. Viewed from this perspective the longevity of an organism is secondary to maximizing reproductive output, and mutations which favor longevity at the expense of fertility will be selected against17. Humans are currently in the unique evolutionary position of being able to potentially choose for increased longevity even if it reduces our fertility.
The purpose of this commentary is not to rule out any possibility that we will be able to extend longevity. Rather it is to point out that it is critical to carefully consider all effects of any method, be it hormesis, gene mutations, or environmental manipulations, that extends longevity. Aging is an inherently complicated biological process that reflects the sum of an organism's genotype and the interaction of these genes with the environment. Understanding the mechanisms responsible for senescence will require broad-based approaches that study more than a single aspect of the aging phenotype and an appreciation that no single factor will likely be responsible for aging in all organisms or even within a single organism.
1. Minois, N. Longevity and aging: beneficial effects of exposure to mild stress. Biogerontology 2000; 1, 15-29.
2. Tatar, M., Khazaeli, A.A., Curtsinger, J.W. Chaperoning extended life. Nature 1997; 390, 30.
3. Feder, M.E., Hofmann, G.E. Heat-shock proteins, molecular chaperones, and the stress response: evolutionary and ecological physiology. Annual Review Physiology 1999; 61, 243-82.
4. Lithgow, G.J., Kirkwood, T.B.L. Mechanisms and evolution of aging. Science 1996; 273, 80.
5. Martin, G.M., Austad, S.N., Johnson, T.E. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genetics 1996; 13, 25-34.
6. Lithgow, G.J., White, T.M., Melov, S., Johnson, T.E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proceeding National Academy Sciences USA 1995; 92, 7540-7544.
7. Murakami, S. & Johnson, T. Life extension and stress resistance in Caenorhabditis elegans modulated by the tkr-1 gene. Current Biology 1998; 8, 1091-1094.
8. Van Voorhies, W.A., Ward, S. Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate. Proceeding National Academy Sciences USA 1999; 96, 11399-11403.
9. Strauss, R.E. Brain-tissue accumulation of fluorescent age pigments in four poeciliid fishes (cyprinodontiformes) and the estimation of "biological age". Growth Development and Aging 1999; 63, 151-70.
10. Lindstedt, S.L., Calder, W.A. Body size, physiological time and longevity of homeothermic mammals. Quarterly Review of Biology 1981; 56, 1-16.
11. Walker, D.W., McColl, G., Jenkins, N.L., Harris, J., Lithgow, G.J. Evolution of lifespan in C. elegans. Nature 2000; 405, 296-7.
12. Sohal, R.S., Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 1996; 273, 59-63.
13. Masoro, E.J. Caloric restriction and aging: an update. Experimental Gerontology 2000; 35, 299-305.
14. Roth, G.S., Ingram, D.K., Lane, M.A. Calorie restriction in primates: will it work and how will we know? Journal of American Geriatric Society 1999; 47, 896-903.
15. Lane, M.A., Baer, D.J., Rumpler, W.V., Weindruch, R., Ingram, D.K., Tilmont, E.M., Cutler, R.G., Roth, G.S. Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents. Proceeding National Academy Sciences USA 1996; 93, 4159-64.
16. Markowska, A.L. Life-long diet restriction failed to retard cognitive aging in Fischer- 344 rats. Neurobiology of Aging 1999; 20, 177-89.
17. Kirkwood, T.B. & Austad, S.N. Why do we age? Nature 2000; 408, 233-8.