DHEA Begins New Series Anti-Aging Nutrient Review and Update Ward Dean, MD A question I‟m often asked, is “What are the best anti-aging/life extension drugs and nutrients?” In this and the following series of articles I‟ll attempt to address this question by reviewing what I consider to be the most effective potential life-extending substances currently available. There is, of course, no “silver bullet” for the aging process. There is no single substance that has been proved to retard the human aging process. The studies have just not been done. Nevertheless, I don‟t recommend doing nothing while waiting for someone to perform the studies to provide the definitive answers. I‟ve selected the substances to be discussed based on several criteria: First, I considered the mechanism by which the substance is believed to act. Most substances that will be discussed in this series act by multiple mechanisms. I place special importance on the mechanisms which are involved in one or more theories of aging (i.e., antioxidants/free radical theory; cross linkage inhibitors/cross linkage theory; hormone receptor sensitizers/neuroendocrine theory, etc). Second, I considered the health-enhancing effect of the substance. Third, of great importance, was whether the substance has shown the capability to reverse or restore a biomarker to a more youthful state. And fourth, and most important, has the substance demonstrated the ability to extend the maximum lifespan of one or more experimental organisms? I include practical considerations, as well. Among these are an individual‟s “pill capacity”—how many capsules/ tablets is a person willing to take? Also, we must consider the cost and availability—for example, some substances are beyond the reach of many people due to high cost or other impediments (i.e., legal issues, availability, requirement for a prescription, etc). With these caveats in mind, this series will present what I consider to be the most effective anti- aging/life extending substances readily available today. The substances to be featured in this series of articles are presented in no particular order. This month, we begin with DHEA. DHEA DHEA (dehydroepiandrosterone) is the most abundant steroid hormone in the body, and has been described as “the mother steroid,” due to its key position in the steroid hormone cascade1 (Fig. 1). DHEA reaches its highest levels in the blood at age 20-24, and drops progressively with age thereafter. This decline is so significant (the level of DHEA in 70-year-olds is only about 20 percent that of young adults) that it has been referred to as the “DHEA Deficiency Syndrome—A new term for old age.”2 Dr. William Regelson stated that DHEA is “the most significant endocrine biomarker”3 (Fig. 2). Ironically, for many years, scientists believed that DHEA was merely an interwww.e metabolite, with no physiological effects of its own. However, continuing research repeatedly confirms that this is not the case. Anti-Aging/Health-Promoting Effects of DHEA In 1986 Elizabeth Barrett-Connor, an epidemiologist at the University of California, San Diego, reported on findings involving 242 middle-aged and elderly men who were monitored for 12 years. Those men with the lowest DHEA levels subsequently turned out to have the highest death rates from all causes.4 Low levels of DHEA have also been found to predict cardiovascular mortality in a 10-year follow-up study of heart attack survivors,5 and are found in a number of other diseases, including breast cancer,6 Alzheimer‟s disease, HIV,7 and coronary artery disease.8 Scientists at the Washington University School of Medicine in St. Louis conducted a trial of DHEA involving 10 women and eight men, whose mean age was 73, to determine the effects of DHEA on bone-mineral density and body composition. After receiving 50 mg of DHEA daily for six months, bone-mineral density of the lumbar spine increased 2.5 percent, and IGF-1 (an indicator of growth hormone levels) increased from 108 to 143 mcg/l. The scientists concluded that “DHEA replacement …can partially reverse age-related changes in fat mass, fat-free mass and bone mineral density.”9 A much larger study of 280 healthy men and women, ranging in age from 60-79, was conducted by scientists at the National Medical Research Institute, Le Kremlin-Bicetre, France.10 The aim was to determine the effects of DHEA supplementation on a number of age-related conditions. In this study, women experienced improved bone turnover, increased libido, and “improvement of skin status,” in terms of hydration, epidermal thickness and normalization of pigmentation. The scientists concluded that “a number of biological indices confirmed the lack of harm of this 50 mg/day DHEA administration over one year—also indicating that this replacement therapy normalized some effects of aging, but does not create „supermen/women.‟” Another year-long study of 16 “age-advanced” men and women (50 to 65 years old) evaluated the effects of 50 mg of DHEA daily on a number of age-related parameters.11 The men (but not the women) averaged decreased body fat mass (1.0 kg, or 6.1 percent), and increased knee and lumbar back muscle strength (15 percent). IGF-1 levels increased 16 percent in men, and 31 percent in women (Fig. 3). DHEA/cortisol ratios were restored to more youthful levels in both men and women. In an earlier study, these scientists also observed a remarkable increase in perceived physical and psychological wellbeing for both men (67 percent) and women (84 percent) (Fig. 4).12 DHEA and the Neuroendocrine Theory of Aging Long-time readers of Vitamin Research News are familiar with Prof. Vladimir Dilman‟s neuroendocrine theory of aging. The neuroendocrine theory holds that a major cause of aging and age-related diseases is a loss of hypothalamic and peripheral hormone receptor sensitivity. DHEA plays a key role in the neuroendocrine approach to anti-aging in several ways. First, DHEA is not only a major biomarker, but it is a biomarker that can be readily normalized (i.e., returned to youthful levels) by supplementation. In addition, DHEA is also a hormone receptor sensitizer (agonist). This means it actually helps hormones work better. For example, DHEA increases the number of NMDA receptors in the brain,13 increases IGF-1 and receptors for growth hormone,12 and reverses the age-related decline of some hypothalamic-pituitary functions.14 Dilman recognized hyperinsulinemia as a central finding in what he called the metabolic pattern of aging. As we get older, we are all shifting in a “diabetic direction” (Fig. 5). Hyperinsulinemia is not only an element in “Syndrome X” (hyperinsulinemia, hypertension, and coronary artery disease), but is also routinely found in obesity, cancer, diabetes and other age-related diseases. Dr. John Nestler of the Medical College of Virginia proposed that DHEA is the “missing link” between hyperinsulinemia and atherosclerosis.15 Nestler proposed that hyperinsulinemia is a cause of the decreased blood levels of DHEA, and that low levels of DHEA are a contributing factor to the development of atherosclerosis. He proposed that supplementation with DHEA may afford protection against the development of atherosclerosis in disease states characterized by hyperinsulinemia. DHEA has been shown to have the following effects: Anti-cancer 6 Anti-diabetic Anti-atherosclerotic 16 Anti-hypertensive Anti-fatigue 17 Anti-depressant 18 Anti-obesity Cognitive enhancing 19 Immune enhancing 20 Cholesterol-lowering 21 Increases bone mineral density 9 Alleviates MS, 3,17,22 Chronic Fatigue 17 and Systemic Lupus Erythematosis (SLE). 23 DHEA and Lifespan Considering the wide-ranging, well-documented beneficial effects of DHEA, and its highly touted anti- aging effects, there are surprisingly (at least, to me) no data to indicate that it will have any effect on maximum lifespan of any species. For example, scientists at the University of Wisconsin conducted an interesting study to determine the comparative effects of DHEA and caloric restriction on cancer incidence and lifespan of mice.24 In this study, four groups of 12 month-old mice were used. Two groups were fed a standard laboratory diet, and two were fed a calorically restricted diet. Caloric restriction is the best-tested means known to extend the maximum lifespan of experimental animals. To see if DHEA would perhaps add to this life- extending effect, DHEA was administered in the drinking water of one group on the laboratory diet, and to one group on the calorically restricted diet. To the disappointment of DHEA fans, and to the surprise of the scientists, DHEA appeared to have absolutely no effect on either cancer rates or longevity. Caloric restriction, however, resulted in an increased maximum lifespan of 15 percent. On the other hand, a Chinese study was more positive—but it was conducted on fruit flies.25 Scientists at the Fuian Epidemic Prevention Station found that DHEA increased the lifespan of female fruitflies, and increased blood levels of the potent antioxidant, superoxide dismutase, in rats. Mechanisms of Action One mechanism by which DHEA is believed to act is by its being a potent, uncompetitive inhibitor of glucose 6 phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose-phosphate cycle. The pentose phosphate pathway is a major source of ribose-5 phosphate (R-5P), and extra- mitochondrial NADPH. Among other functions, NADPH and R-5P are required for RNA and DNA synthesis. It is believed that the DHEA-induced reduced pentose-phosphate cycle activity results in the observed two-pronged anti-cancer properties of DHEA—a reduction in tumor activation and tumor promotion.26 Another proposed mechanism is DHEA‟s ability to enhance the cell signaler, cyclic guanidine monophosphate (cGMP).27 A third mechanism is that it acts by mimicking the well-tested, life- prolonging mechanism of caloric restriction, and a fourth hypothesis suggests that DHEA acts as a cortisol-blocking agent.28 DHEA Dosage and Timing Although dosages of up to 1,500 mg per day have been safely used in a number of studies for periods up to six months, these dosages are now considered “heroic” or excessive. Most human studies in the last 15 years have used dosages for men and women ranging from 50 to 100 mg per day.10,11,29,30 I usually recommend starting doses of 25 mg for women and 50 mg for men. Although these are adequate for most people, even 25 mg may be excessive for some women who very efficiently convert DHEA to testosterone, and who may benefit by an even lower dose. Women with Lupus or MS, on the other hand, can usually tolerate higher doses without suffering the androgenic side effects of facial hair and voice deepening. I think that the timing of DHEA supplementation may also be as important as the dosage. Just as it is important to take melatonin at an appropriate time (about an hour before bedtime), I think it is important to take DHEA when levels are normally at their highest. In this regard, physicians at the University of Parma in Italy conducted a study to determine the appropriate time to take DHEA. They found that 50 mg of DHEA administered at 7 a.m. each day completely restored the circadian rhythmicity of DHEA and completely restored the cortisol/DHEA ratio in older subjects to that of much younger subjects.31 Dr. Etienne-Emile Baulieu of the College de France in Cedex, France, recommends that a dosage should be used that restores youthful levels of DHEA in the blood, without causing elevations of testosterone, DHT (dihydrotestosterone), or estrogen concentrations higher than those of a typical 30- to-40-year-old. She agrees that for most people, this is a dosage in the range of 25 to 50 mg once daily.32 Dr. Samuel Yen, of the University of California at San Diego, one of the most prolific scientists studying DHEA, recently described DHEA succinctly as a “multifunctional hormone with immunoenhancing, antidiabetic, antiobesity, anticancer, neurotropic, memory-enhancing, and anti- aging effects.”33 Although the life extending effects of DHEA have yet to be demonstrated, its wide-ranging beneficial effects on many age-related conditions, and demonstrated relationship to reduced mortality from all causes, make it a top choice for inclusion in a life-extension anti-aging supplement regimen. References 1. Regelson, W., Loria. R., and Kalami, M. Dehydroepiandrosterone (DHEA)—the “Mother Steroid.” I. Immunologic action. Ann NY Acad Sci 719, 1994, pp. 405-445. 2. Hinson, J.P., and Raven, P.W. DHEA deficiency syndrome: A new term for old age? J Endocrinol 1999, 163: 1-5. 3. Regelson, W., Kalimi, M., and Loria, R. Deheydroepiandrosterone (DHEA): The precursor steroid, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 4. Barrett-Connor, E., Khaw, K-T., and Yen, S.S.C. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. New Eng J Med 1986, 315: 1519. 5. Jansson, J.H., Nilsson, T.K., and Johnson, O. Von Willebrand factor, tissue plasminogen activator and dehydroepiandrosterone sulphate predict cardiovascular death in a 10 year follow-up of survivors of acute myocardial infarction. Heart 1998, 80: 334-337. 6. Schwartz, A.G. Inhibition of spontaneous breast cancer formation in female mice by long term treatment with dehydroepiandrosterone, Cancer Res 1979, 39: 1129-1132. 7. Merril, C.R., Harrington, M.G., and Sunderland, T. Reduced plasma dehydroepiandrosterone concentrations in HIV infection and alzheimer‟s disease, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 8. Feldman, H.A., Johannes, C.B., McInlay, J.B., and Longcope, C. Low dehydroepiandrosterone sulfate and heart disease in middle-aged men: cross-sectional results from the Massachusetts male aging study. Annals of Epidemiology 1998, 8: 217-228. 9. Villareal, D.T., Holloszy, J.O., Kohrt, W.M. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxford) 2000, 53(5): 561-568. 10. Baulieu, E.-E., Thomas, G., Legrain, S., et al, Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge study to a sociobiomedical issue. Proc Natl Acad Sci USA, 2000, 97(8), 4279-4284. 11. Morales, A.J., Haubricht, R.H., Hwang, J.Y., Asakura, H., and Yen, S.S.C. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clinical Endocrinology 1998, 49: 421-432. 12. Morales, A.J., Nolan, J.J., Nelson, J.C., Yen, S.S.C. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994, 78: 1360-1367. 13. Vincens, M. Use of dehydroepiandrosterone sulfate to increase the number of NMDA receptors in the brain, French Patent Appl 1998/14,669, 20 Nov 1998, Int Patent Appl WO 00 30,652 (Cl. A61K31/565), 2 June 2000, 19 pp. 14. Givalois, L., Li, S., and Pelletier, G. Effects of aging and dehydroepiandrosterone administration on pro-opiomelanocortin and mRNA expression in the anterior and interwww.e lobes of the rat pituitary. J Neuroendocrinology 1999, 11: 737-742. 15. Nestler, J.E, Clore, J.N., and Blackard, W.G. Dehydroepiandrosterone: the “missing link” between hyperinsulinemia and atherosclerosis? FASEB J 1992, 6: 3073-3075. 16. Barrett-Connor, E., and Khaw, K-T., The epidemiology of DHEAS with particular reference to cardiovascular disease: The Rancho Bernardo Study, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 17. Calabrese, V.P., Isaacs, E.R., Regelson, W., Dehydroepiandrosterone in multiple sclerosis: Positive effects on the fatigue syndrome in a non-randomized study, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 18. Barrett-Connor, E., Von Muhlen, D., Laughlin, G., Kripke, A. Endogenous levels of dehydroepindrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: The Rancho Bernardo Study. J Am Geriatr Soc 1999, 47(6), 685-691. 19. Bonnet, K.A., Brown, R.P. Cognitive effects of DHEA replacement therapy, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 20. Loria, R.M., Regelson, W., and Padgett, D.A. Immune response facilitation and resistance to virus and bacterial infections with dehydroepiandrosterone (DHEA), in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 21. MacEwen, E.G., Maki-Haffa, A.L., Kurzman, I.D. DHEA effects on cholesterol and lipoproteins, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 22. Roberts, E., Fauble, T.J. Oral dehydroepiandrosterone in multiple sclerosis, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 23. Van Vollenhoven, R.F., Morabito, L.M., Engleman, E.G., and McGuire, J.L. Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatology 1998, 25: 285-289. 24. Pugh, T.D., Oberley, T.D., Weindruch, R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res 1999, 59(7), 1642-1648. 25. Li, S., Huang, Z., Zheng, L., He, L., and Lium S. Anti-aging effect of dehydroepiandrosterone. Shanghai Shiyan Dongwu Kexue, 2000, 20(3), 151-153. 26. Schwartz, A.G., Fairman, D.K., and Pashko, L.L. The biological significance of dehydroepiandrosterone, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 27. Roberts, E. Deheydroepiandrosterone (DHEA) and its sulfate (DHEAS) as neural facilitators: Effects on brain tissue in culture and on memory in young and old mice. A cyclic GMP hypothesis of action of DHEA and DHEAS in nervous system and other tissues, in: The Biologic Role of Dehydroepiandrosterone (DHEA), by Regelson, W., Kalimi, M., and Loria, R. (eds.), Walter de Gruyter, Inc., Hawthorne, NY, 1990. 28. Williams, J.R. The effects of dehydroepiandrosterone on carcinogenesis, obesity, the immune system, and aging. Lipids 2000, 35: (3), 325-331. 29. Flynn, M.A., Weaver-Osterholtz, D., Sharpe-Timms, K.L, Allen, S, Krause, G. Dehydroepiandrosterone replacement in aging humans. J Clin Endocrinol Metab 1999, 84(5), 1527- 1533. 30. Wiebke, A., Haas, J., Callies, F. et al. Biotransforma-tion of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens. J Clin Endocrinol Metab 1999, 84(6): 2170-2176. 31. Ceresini, G., Morganti, S., Rebecchi, I., et al. Evaluation of the circadian profiles of serum dehydroepiandrosterone (DHEA), cortisol, and cortisol/DHEA molar ratio after a single oral administration of DHEA in elderly subjects. Metab, Clin, Exp., 2000, 49(4), 548-551. 32. Baulieu, E.-E., Dehydroepiandrosterone (DHEA): A fountain of youth? J Clin Endocrinol Metab 1996, 81: 9, 3147-3151. 33. Yen, S.C. Dehydroepiandrosterone sulfate and longevity: New clues for an old friend. Proc Natl Acad Sci U.S.A., 2001, 98(15), 8167-8169. 34. Finch, C.E., and Mobbs, C.V. Nonlethal measurements involving steroids and neurotransmitters as reflections of physiological aging, in: Biological Markers of Aging, by Reff, M.E., and Schneider, E.L. (eds) 1982, Baltimore, USDHHS, NIHPublication No., 82-2221, pp. 30-41.
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