Humans, though they have been able to explore the mysteries of the universe such as landing on the Moon and Mars, have limited knowledge of themselves. For instance, why do we degenerate when we get old? Thousands of scientists are devoting themselves to solve this puzzle and try to make people live longer. In fact, great progress has been made in this century because the mean life span of Americans has been greatly extended (Men from 46 to 76; and women from 48 to 78). However, we are still far away from the answers to this puzzle.

For the study described below, I use a very specific cell type the "human diploid fibroblast" (HDF) as a model of aging. Like cells in the body, these cells lose replicative capacity as a function of population doubling (PDL), providing a system for determining the mechanism of cell aging.

The equivalence between age of cells and age of human beings is as follows:

I would like to know what chemical agents change the degeneration HDF cells as they grow older. I have found that a number of environmental toxins increase degeneration of these cells. For example, chemicals that generate free radicals may be a major contributor to aging. This hypothesis has been tested by treating the HDF cells with oxidants or by treating the cells with antioxidants (that scavenge free radicals). We found that chemicals that increase free radicals accelerate HDF cell aging and antioxidants prolong the cell life. This suggests that humans should avoid chemicals that generate free radicals (like agents found in smog and tobacco smoke) and should avoid deficiencies of antioxidants (for example vitamins C and E ) that protect us from free radicals.

I am also interested in finding natural agents that extend the cell life. I have been studying a class of natural hormones: the glucocorticoids. glucocorticoids are hormones that are increased when we are under stress. Administration of glucocorticoids to humans could be deadly and I would never propose such an experiment or recomend this (in fact I would strongly caution against this!) We can do these experiments in cells to understand how aging is regulated by them. The information learned from cells may be used in the future to develop a specific drug that protects us from aging related degeneration. Glucocorticoids play an important role in regulating defense mechanisms. In addition, hyperadrenocorticism and food restriction (which induces increase in glucocorticoids) have been found to extend life span in rats and mice. However, glucocorticoids, have been shown to kill neurons of hippocampus in the brain.

We have carried out a study to investigate whether glucocorticoids retard or accelerate aging in HDF cells. We have found that cortisol, the major stress hormone in human, increased the PDL of HDF, and elevated the DNA synthesis, meaning it retards the aging process of HDF cells. Further study showed that cortisol inhibited the generation of reactive oxygen species in the senescent cells and prevented oxidants-induced oxidative damage. The aging retarding effect of cortisol can been seen in the morphological pictures of the young cells, senescent cells, and senescent cells plus cortisol treatment below.

The aging retarding effect of cortisol
	young cells
	senescent cells
	senscent cells plus cortisol

These results may suggest that stress hormones, though causing neuronal damage at high concentration, retard aging of HDF cells and protect HDF cells from oxidant challenge. With these results, we can explain several experimental facts: 1. Food restriction extends life span in rats and mice is due to the induction of increased glucocorticoids. 2. The reason that adrenalectomy causes oxidative damage in the brain of rats is due to the lack of production of glucocorticoids from the adrenal gland (8). 3. Stress hormones play an important role in the reduction of oxidative damage. Mechanistically, cortisol might protect cells from oxidative damage by inhibition of oxidant production via the inhibition of the synthesis of prostaglandins, an important source of oxidants. In addition, cortisol, because of its steroidal nature, can fluidize membranes, stabilizing them against oxidative attack (7). We conclude that keeping basal levels of glucocorticoids appears to be important as we age. It is hoped that this research demonstrates the importance of reducing exposure to pollution, maintaining a healthy diet with adequate levels of antioxidants and that scientist are coming closer to an understanding of biological basis of age related degeneration.

References

2. Chen, Q., A. Fischer, J. D. Reagan, L. J. Yan, and B. N. Ames. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A 92: 4337-41, 1995.

3. Han, E.-S., N. Levin, N. Bengani, J. L. Robert, Y. Suh, K. Karelus, and J. F. Nelson. Hyperadrenocorticism and food restriction-induced life extension in the rats. J. Gerontol. :Biol. Sci. 50A: B288-94, 1995.

4. Klebanov, S., S. Diais, W. B. Stavinoha, Y. Suh, and J. F. Nelson. Hyperadrenocorticism, attenuated inflammation, and life-prolong action of food restriction in mice. J. Gerontol.: Biol Sci. 50A: B78-82, 1995.

5. Landfield, P. W., and J. C. Eldridge. Evolving aspects of the glucocorticoid hypothesis of brain aging: hormonal modulation of neuronal calcium homeostasis. Neurobiol Aging 15: 579-88, 1994.

6. Landfield, P. W., and J. C. Eldridge. The glucocorticoid hypothesis of age-related hippocampal neurodegeneration: role of dysregulated intraneuronal calcium. Ann N Y Acad Sci 746: 308-21; discussion 321-6, 1994.

7. Liu, J., and A. Mori. Stress, aging, and brain oxidative damage. Neurochm. Res. 24: 1479-97, 1999.

8. Liu, J., I. Yokoi, S. Doniger, H. Kabuto, H. C. Yeo, A. Mori, and B. N. Ames. Adrenalectomy causes oxidative damage and monoamine increase in the brain of rats and enhances immobilization stress-induced oxidative damage and neurotransmitter changes. Int. J. Stress Manag. 5: 39-56, 1998.

9. Munck, A., P. Guyne, and N. Holbrook. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrine review 5: 25-44, 1984.

10. Munck, A., and A. Naray-Fejes-Toth. The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited. Mol Cell Endocrinol 90: C1-4, 1992.

11. Sapolsky, R. M., L. C. Krey, and B. S. McEwen. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev 7: 284-301, 1986.

12. Sapolsky, R. M., L. C. Krey, and B. S. McEwen. Prolonged glucocorticooid exposure reduces hippocampal neuron number: Implication for aging. J. Neurosci. 5: 1222-1227, 1985.

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