Applying Hormesis in Aging Research and Therapy: A Sensible Hope?
Éric Le Bourg, Ph.D.
Laboratoire d'Éthologie et de Cognition Animale
F.R.E. C.N.R.S. n° 2382
Université Paul-Sabatier, 118 route de Narbonne
F-31062 Toulouse cedex 4
Tel: 33 5 61 55 65 67
Fax: 33 5 61 55 61 54
The idea that mild stresses could have positive effects on longevity and aging is not new1 but it has received considerable attention only rather recently2. It is a usual thing in science that, after first positive results, debates occur about them: it is now the time of debates about hormesis and aging. This is a privileged period when new, and maybe provocative, ideas are needed.
As emphasized by Suresh Rattan, hormesis could be of some help for modulating aging and longevity but several issues remain to be resolved. Seven points are listed by Rattan but, while I agree with them, I feel that other hot questions have to be considered.
1. What is an Efficient Mild Stress in Aging Research?
Mild stresses can slightly increase longevity (e.g. in flies3,4). Yet, a positive effect on aging, as deduced from a delayed behavioral aging, is not always observed. For instance, exposure to hypergravity delays the age-related decline of climbing activity in Drosophila melanogaster3, but mild heat shock does not4. We cannot consider an increased longevity as a sufficient proof of the positive effect of mild stresses on aging, because the question is not only to increase longevity but also healthy life span. Nobody wants to live his/her 100th birthday as a bedridden invalid. The search for efficient mild stresses could be somewhat despairing, because some of them could have some effect on longevity but no one on aging. Therefore, it is not only needed to establish "biochemical and molecular criteria for determining the hormetic level for different stresses", but also criteria for the progression of aging. The study of behavioral age-related changes seems useful to reach this goal, because observing behavior is the only means to assess quality of life in animals.
Mild stresses are known to increase resistance to strong stresses (acclimation effect, see ref. 5 for a review), but what about the effects of mild stresses on resistance to other mild or moderate stresses? In everyday life, we are scarcely submitted to strong stresses, e.g. spending one hour in a deep freeze, and this is even truer for elderly who usually avoid dangerous ways of life. By contrast, people, and particularly elderly, are at risk to meet various moderate stresses, such as a sudden temperature drop during the winter. Elderly have a lower resistance to these stresses than young people, and these stresses are thus of a high value for aging research. It would be useful to study not only the resistance to strong stresses, but also to moderate stresses. Suppose that, in fruit flies for instance, a moderate stress kills only 10% of animals and slightly increases the speed of behavioral aging. If a mild stress applied before that moderate stress would lower that rate to, say, 1% with also beneficial effects on aging, it would become a good candidate for the prevention of aging. Such a mild stress could also have positive effects on resistance to strong stresses. However, that does not mean that mild stresses with positive effects on resistance to strong stresses have also an effect on resistance to moderate stresses. Studying resistance to moderate stresses seems thus of importance.
2. The use of Mild Stresses to prevent Aging and Age-related Pathologies
Let us suppose that various mild stresses have positive effects on longevity, aging, and resistance to moderate and strong stresses. The hot question would then to know whether they prevent age-related pathologies and delay aging in humans.
I am rather pessimistic about the latter issue, because I fail to see today how a mild stress could be used in practice. To do that, this mild stress would have to be easy to use, inexpensive and not time-consuming, in other words, easy like taking a pill. Clearly, people would be reluctant spending one hour a day sustaining a mild stress, and this for the rest of their life. The gurus of anti-aging medicine explain people they have to take daily dozens of pills if they want to live long and healthy. We must not give the false hope that mild stress is a miraculous recipe that could spare people from the burdens of age68, because we are today unable to tell whether it will be possible.
By contrast, the use of mild stresses to prevent age-related pathologies or to prepare elderly for surgical interventions has perhaps to be carefully considered. Repeated mild heat shocks delay morphological alterations observed during proliferative life span in cultured human skin fibroblasts9. In D. melanogaster, heat shocks confer a neuroprotection10 that is probably explained by the induction of the 70-kDa heat-shock protein (hsp70). In rats, electric foot shock induces hsp70 expression in the aorta11 and learning a two-way active avoidance task induces hsp70 in the cerebellum12. It has been suggested that hsp70 induction could protect the heart against the ischaemia-reperfusion injury13. We could imagine stressing elderly before to be subjected to a severe surgical operation, in order to induce hsp70 and facilitate recovery. Moreover, some drugs (e.g. aspirin13) could act in synergy with mild stresses. Concerning age-related pathologies, we could imagine that a mild stress applied once could protect elderly from some pathologies for some weeks. Suppose we apply this mild stress from time to time, and we could avoid or delay various diseases in elderly.
Future research will probably tell us whether these hypotheses are valuable.
3. Conclusions: Mild Stresses as Gerontological Research Tools
It is currently unknown whether mild stresses will help, some day, physicians treating elderly, but they are useful today to study the aging process. Rattan is right when writing that, "after decades of systematic collection of data describing age-related changes", gerontologists try to develop "efficient ways to prevent age-related impairments and diseases". Genetic tools are invaluable to do that, but mild stresses could allow us to modulate aging in wild animals, i.e. in animals living in the normal world and not only in well-protected environments. Human beings are wild animals, too, and it is one reason why it is of the highest importance to have at one's disposal environmental means to delay aging. Calorie restriction is another environmental means to increase longevity and delay aging, but ad-libitum feeding is sometimes considered as a pathological living condition (see ref.14, p.325 and issue 6, volume 19 of Human and Experimental Toxicology, june 2000). However, this procedure has to be applied daily throughout life to see positive effects. It is hard to see how it could be used in human beings to delay aging or prevent age-related pathologies. It has also to be suspected that people practicing food restriction would be more frail and at risk to suffer from infections and sterility. Therefore, mild stresses could challenge or complement food restriction in the prevention of age-related pathologies, and it could be needed to study the progression of age-related pathologies in model species, such as rodents, to confirm whether it is the case. While it is not sure that mild stresses will help preventing age-related pathologies, there is a sensible hope that they will help understanding the aging process. We may hope that, in ten years from now, we shall know whether mild stresses were indeed useful or, still again, a false hope for gerontology research.
This work was partly supported by a grant (Santé-Société 98N72/0048) from the French Centre National de la Recherche Scientifique (CNRS).
1 Sacher GA. Effects of X-rays on the survival of Drosophila imagoes. Physiological Zoology 1963; 36: 295-311.
2 Johnson TE, Lithgow GJ, Murakami S. Hypothesis: Interventions that increase the resistance to stress offer the potential for effective life prolongation and increased health. Journal of Gerontology: Biological Sciences 1996; 51A: B392-B395.
3 Le Bourg E, Minois N. Increased longevity and resistance to heat shock in Drosophila melanogaster flies exposed to hypergravity. Comptes Rendus de l'Académie des Sciences, Paris 1997; 320: 215-221.
4 Le Bourg E, Valenti P, Lucchetta P, Payre F. Effects of mild heat shocks at young age on aging and longevity in Drosophila melanogaster. Biogerontology 2001; in press.
5 Minois N. Longevity and aging: Beneficial effects of exposure to mild stress. Biogerontology 2000; 1: 15-29.
6 Le Bourg E. Gerontologists and the media in a time of gerontology expansion. Biogerontology 2000; 1: 89-92.
7 Le Bourg E. Gerontologists and the media: False hopes and fantasies can be hazardous for science. Biogerontology 2000; 1: 371-372.
8 De Grey ADNJ. Gerontologists and the media: The dangers of over-pessimism. Biogerontology 2000; 1: 369-370.
9 Rattan SIS. Repeated mild heat shock delays ageing in cultured human skin fibroblasts. Biochemistry and Molecular Biology
International 1998; 45: 753-759.
10 Karunanithi S, Barclay JW, Robertson RM, Brown IR, Atwood HL. Neuroprotection at Drosophila synapses conferred by prior heat shock. The Journal of Neuroscience 1999; 19: 4360-4369.
11 Isosaki M, Nakashima T. Psychological stress induces heat shock protein 70 expression in rat aorta. Japanese Journal of Pharmacology 1998; 76: 305-308.
12 Ambrosini MV, Mariucci G, Tantucci M, Bruschelli G, Giuditta A. Induction of cerebellar hsp70 in rats learning a two-way active avoidance task. Molecular Brain Research 1999; 70: 164-166.
13 Leppä S, Sistonen L. Heat shock reeponse Pathophysiological implications. Annals of Medicine 1997; 29: 73-78.
14 Arking R. Biology of aging. Second edition. Sinauer associates, Sunderland, 1998.