Process of Aging: Part IX-DHEA
(3/18/07)- Ever since writing the article below this addendum, we have been watching the research literature for further clarification of DHEA and the sulfated version DHEAS. Today, we report on one of those studies.
The Oct. 19, 2006 issue of New England Journal of Medicine printed a research study by K. S. Nair and colleagues. The 2-year placebo-controlled, randomized, double-blind trial involved 87 elderly men with low levels of DHEAS and bioavailable testosterone and 57 elderly women with low levels of DHEAS. The dose of DHEAS was 75 mg per day in men and 50 mg per day in women. The researchers wanted to determine the effects of DHEA on body composition, physical performance, and insular sensitivity.
It is well known that estrogen and testosterone levels drop with age and that an association is made with this drop and aging... These associations do not prove causality, hence a study that looks at the role of enhancing levels of sex steroids in humans would add to the armamentarium of those seeking the proverbial fountain of youth.
The Nair study concluded: In all, we found little if any beneficial effect of restoration of DHEA levels in elderly men and women to those of healthy young people of the same sex. Although DHEA replacement has no detectable effect on body composition, physical performance, insulin action or quality of life, it resulted in a minimal and inconsistent effect on BMD, the magnitude of which was far smaller than that of established therapies for osteoporosis?Taken together, our data provide no evidence that either DHEA or low dose testosterone is an effective antiaging hormone supplement and argue strongly against the use of these agents for that purpose.? (p. 1658, Underlined for emphasis)
The result is another negative study about DHEA. This result will probably have little effect on the use of DHEA and proclaiming it as an antiaging product. What may prove a more useful approach is to solve the enigma of what is the role of this abundant steroid secreted from the adrenal cortex when compared with cortisol and aldosterone.
There may be a role for the therapeutic use of DHEA, as suggested by Arlt in a paper in Best Pract Res Clin Endocrinol Metab (2004; 18:363-380), in dealing with primary or secondary adrenal insufficiency.
What would happen if individuals started taking this supplement before middle age when the level of these endocrines drop off.? According to Arlt (see above), peak levels of sulfated DHEA occur between 25-35 years of age. It is not clear when the process of aging starts, even though we get older each year. Would we see different results in these individuals with an intake of DHEA?
The other interesting result one can take away from the studies of DHEA is that there appears to be no adverse effects of taking this supplement. This form of a negative conclusion could be used to encourage the taking of DHEA, because ?it doesn?t hurt you and may have unknown benefits, no yet discovered?. Of course, the opposite could also be true.
The dilemma continues for the consumer of this supplement. We await further research.
(8/18/01)- Dependable markers of biological age are few. Proposed markers include specific organ performance, voice analysis and steroid hormone profile. One such steroid suggested is the adrenal hormone dehydroepiandrosterone, common ly called DHEA. This steroid appears to decline with age to about 10-20% of the values in young adults by the eight or ninth decade of life. It appears to decrease more markedly with age than any other sex hormone, both in men and women. The general public has shown substantial attention to this dietary supplement as a replacement therapy for aging. No one to date has robustly shown this to be true. As far as we understand, the only intervention that extends life span in mammals is caloric restriction, invoving alteration in energy use. However, this has not been clearly demonstrated in humans.
It should be clear to all that aging is a complex biological process, genetically determined and environmentally modulated. It is one of those words difficult to define on any basis except operationally on a chronological continuum. This tells us nothing of the systemic or molecular basis of aging.
We do know that the endocrine system regulates body composition, fat deposition, skeletal mass, muscle strength, metabo lism, body weight and physical well being. Some of the physiological manifestations of aging are related to the effects of declining hormone levels. Thus we have a decrease in the gonadal production of estrogen in females (menopause) and testosterone in males (andropause), the adrenal production of dehydroepiandrosterone (DHEA) and DHEA sulfate, and a decrease in the activity of growth hormone (GH)/insulin-like growth factor (IGF) axis. This could account for some of the excitement accompanying hormone replacement therapy as a prevention of some of the consequences of aging.
Oral DHEA is readily available in over-the-counter preparations in pharmacies. A report from a conference on " DHEA and Aging" suggests that " although the concentration of the DHEAS in the circulation of adults is higher than any other steroid except cholesterol, and DHEA and DHEAS serve as precursors for sex steroids, a definitive biological function has yet to be established". In the five experimental studies usually cited of oral DHEA therapy in humans, only small numbers of selected subjects have been studied and the relatively brief trials conducted so far may be inadequate to unveil the spectrum of responses to DHEA therapy. Certain doses (50 mg/day) did result in a two-fold increase in serum androgen levels in women and slightly reduced high-density lipoprotein levels. Increased levels of circulating androgens have been associated with higher blood pressure and an atherogenic lipid profile in women. (Ref: Haffner SM, Newcomb PA, Marcus PM, Klein BEK, Klein R. Relation of sex hormones and dehydroepiandrosterone sulfate (DHEAS) to cardiovascular risk factors in postmenopausal women. Am J Epidemiology 1995; 142:925-954).
Results from the Massachusetts Male Aging Study indicate that serum DHEA levels have an inverse relationship to heart disease. (Ref: Feldman HA, Johannes CB, McKinlay JB, Longcope C. Low DHEAS and heart disease in middle-aged men: cross-sectional results from the Mass Male Aging Study. Ann Epidemiol; 8:217-228.)
Most of the circulating DHEA hormone is in the form of sulfate ester (DHEAS), but in vitro studies have shown DHEA rather than DHEAS is responsible for its physiological actions. Until recently, these androgens (form of enzymes), which are produced mainly in the zona reticularis of the adrenal cortex, have been considered of little importance. As topics on aging receive greater prominence, there has been an increasing interest in DHEA and DHEAS that either in native form, or as precursors of other steroids, exert a diversity of biological actions.
Interestingly, among subjects of the same age and apparently good health, there is a wide inter-individual variation in DHEAS concentration, but they remain stable over time in individuals. DHEAS are higher, by 10-30 % in men, but women have greater DHEA sulfates activity and much higher serum DHEA to DHEAS ratios than men. These gender differences are less marked in the individuals over 50 years of age. Serum DHEA & DHEAS levels also are influenced by smoking, alcohol consumption, obesity and chronic illness.
Low plasma DHEAS appears to be a secondary phenomenon rather than a specific indicator of common disease in old age. Tilvis et.al. did a five-year follow-up of random persons of three age groups (75, 80 and 85 years; N=571). Compared to healthy men, DHEAS levels were lower in men with history of, or those who manifest vascular diseases, dementia, diabetes mellitus, malignancies and musculoskeletal disorders but was similar in all disease groups. DHEAS did not predict increased risk of all-cause or cardiovascular mortality during the five-year follow-up. (See:Tilvis RS, Kahonen M, Harkonen. Dehydroepiandrosterone sulfate, disease and mortality in general ages population. Aging: clinical and Experimental Research 11 :30-34, 1999).
DHEAS is metabolized to the androgen testosterone and 5-alpha -dihydrotestosterone and also some weakly estrogenic products, by enzymes widely distributed throughout the body. Epidemiological evidence associating high levels of DHEAS with resistance to cancer, atherosclerosis, hypertension, diabetes mellitus, osteoporosis and disabilities of old age is tenuous at best.
DHEA appears to be a major modulator of stress reaction and an important regulator of metabolism, in partnership with other agen ts, such as melatonin. The low plasma concentrations, as seen in aging, might affect lipid and glucose metabolism. DHEA & DHEAS influence fatty acid metabolism and this may be in part a carnitine-dependent mechanism (L-carnitine is an essential co-factor for transport of long chain fatty acids across the inner mitochondrial membrane into the mitochondrial matrix, making them available for energy production by -oxidation.)
Administering DHEA can possibly protect against development of atherosclerosis, but no robust relationship has been demonstrated between plasma DHEAS and coronary artery disease or myocardial infarction or any other chronic disease associated with the aging process.
DHEA has been implicated in immunosenescence. As stated above, it is the most abundant adrenal steroid in young healthy individuals. After birth, the zona reticularis of the adrenals begin to produce DHEA. Production increases throughout puberty, until maximum serum concentrations are reached during the third decade of life. Then starts a slow but steady decline of approximately 2% per year in circulating blood levels, leaving a residual value of only 10-15% during the eight decade of life. The resulting decrease of DHEA may be partially responsible for the catabolic state that develops during aging-just the opposite that occurs during fetal development and puberty when DHEA levels are very high.
Decline is not the result of a change in the metabolism of DHEA, but instead appears to be effected by a diminished adrenal secretory rate. Adrenocorticotropic hormone challenge tests indicate that in the elderly subjects, the DHEA responses decreased, unlike that of cortisol secretion, which is maintained, if not prolonged. The resulting increase in the cortisol/DHEA ratio in the blood is thought to be partially responsible for the catabolic state that develops during aging.
Does supplementation with DHEA reverse the age-associated decline in response to vaccination? Some reports have attributed to DHEA an ability to reverse some aspects of immunosenescence. DHEA failed to improve responsiveness to commercially available killed trivalent vaccine in elderly human subjects. However the metabolite AED (androstenediol) may play a functional role in the maintenance of immune competent stage. This would indicate a need to prevent the steady age-associated decline in DHEA and AED. Prevention of the decline could delay or ameliorate the age dependent deterioration of immune function. This would improve the hosts response to vaccination and also aid in immune response to pathogens for which the host was not vaccinated. However, the decline is probably irreversible at some point. This may be the result of loss of receptors for DHEA and AED that arises with aging.
The full story of the role of DHEA is still not in. It may play some role in the aging process, but as of this date no robust research has indicated that it stops the endocrine aging process. Many questions remain to be answered by aging research. To what extent does DHEA insufficiency c ontribute to the aging process? What gender differences underlie the neuroendocrine changes that occur with aging? What are the implications, socially, economically etc., for society? We await further research results.
Go Back to Article I of Articles on Aging-Mortality risk factors
The Aging Process-Part II-Gender Difference
The Aging Process-Part III-Cellular Senescence
The Aging Process-Part IV-Biological Aging
Go to Article V of Articles on Aging-Arteriosclerosis
The Aging Process-Part VI-Aging in Males
Process of Aging in Women-Part VII-Muscular Strength and Bone Mass Density
The Aging Process-Part VIII-Infectious Disease
The Aging Process-Part X-Skin, Skeleton and Brain
The Aging Process:-Part XI-Apotosis and the Elderly
The Aging Process-Part XII-Biomarkers for Aging
The Aging Process- Part XIII- Body Odors
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Harold Rubin, MS, ABD, CRC, Guest Lecturer
August 18, 2001
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