~ DHEA - The DHEA Debate
A Critical Review of Clinical and Experimental Data
One of the most confusing issues in health care today is the role of DHEA in anti-aging. While some promoters claim that it is a magic bullet that will confer heath and longevity, others state emphatically that it has no value or is actually dangerous. Consumers are left in a quandary. Concluding that it is better to be safe than sorry, millions of Americans ignore what may be one of the most important anti-aging, health-sustaining substances available today.
Stephen Cherniske, MS, is a biochemist with more than 30 years of academic, clinical, and research experience. He was an adviser to members of the U.S. Olympic team, served on the faculty of the American College of Sports Medicine, and taught clinical nutrition at the university level for over a decade. His 1996 book, The DHEA Breakthrough (Random House), was an international best-seller that helped launch the anti-aging movement worldwide.
In 1998, he was chosen to direct the Bioregenics Project, an international research effort to explore the physiology of aging. In 2001, the project was completed with an independent, double-blind, placebo-controlled human clinical trial demonstrating that the underlying causes of aging can be modified by nutrition, diet, and lifestyle.
This remarkable three-year research project forms the basis for his latest book, The Metabolic Plan (Random House, 2003). Between 1996 and 2003, Cherniske conducted hundreds of interviews and presented more than 1,000 hours of lectures to professional and lay audiences. In these interviews and scientific conferences, he encountered tremendous resistance to the use of DHEA. At the same time, more than 3,000 scientific studies on DHEA were published, leading to a clear understanding of the chemistry, function, and clinical value of this important hormone.
The DHEA controversy continues to rage, fueled more by opinion than facts. The following interview of Stephen Cherniske by an imaginary "naysayer" was designed to explore all of the objections that have been raised to the prudent use of DHEA. Importantly, Cherniske provides meticulous documentation for his views, with more than 160 references to current biomedical literature. It is our fervent hope that this level of scientific support will clear up the DHEA controversy once and for all. Failing that, it should at least force the naysayers to back up their claims with reasonable evidence.
Naysayer: DHEA, once touted as the cure-all for aging, has been a bust. It does not enhance sports performance, eliminate wrinkles, restore energy levels, or confer any significant anti-aging benefit. In fact, since it is converted to testosterone and estrogen, DHEA can promote cancer.
Stephen Cherniske: In science, you only find what you're looking for. Naysayers invariably are looking for short-term benefits, when aging is a complex, lifelong process. It's like the farmer who plants an apple orchard and concludes that his efforts were wasted because after six months, he has no fruit. When DHEA supplementation does not produce remarkable results (for example, weight loss) in 28 days, naysayers conclude that "it doesn't work."1
In reality, DHEA is an effective tool in weight management, but you have to break out of the diet pills, instant-results mentality. In fact, you have to stop thinking about weight loss and remember that the goal is fat loss, in which case the long-term solution is one that improves insulin sensitivity and promotes muscle mass. In human clinical trials, DHEA has been shown to do both.2-5 Research shows that obese women have lower DHEA levels than lean controls.6
New research is also showing that declining DHEA levels are associated (in animals and humans) with a subsequent decline in carnitine-driven fatty acid oxidation. Thus, restoring optimal DHEA levels may have a profound effect on long-term weight management. Remember that fat burning produces energy but also requires energy to get started. Thus the accumulation of fat with advancing age may be related as much to decreased energy production as it is to a sedentary lifestyle. Researchers at the University of California, San Francisco, conclude that reduced carnitine availability correlates with the age-related decline of DHEA.7 Here is a quote from a study that investigated the role of DHEA and fat loss:
"Regarding the action of DHEA as a fat-reducing hormone, it is possible that this hormone reduces the peripheral requirement for insulin by increasing glucose disposal, and that lower insulin levels are associated with a higher plasma ratio between lipolytic hormones and insulin, and a higher efficiency of lipolysis and loss of body fat."8
Another area where the instant-results mentality causes confusion is in the area of mood and feelings of vitality or well being. We know that DHEA is positively associated with feelings of well being, and that low levels of DHEA are associated with depression.9-11
Naysayer: Wait a minute. There are good studies showing that DHEA does not enhance feelings of well-being.12,13
Stephen Cherniske: Both of those are two-week studies, which is a flawed design for the evaluation of changes in mood, memory, and cognition. What concerns me is that naysayers use this two-week (too weak) data, even when they are aware of longer studies (of up to one year) that demonstrate remarkable effects of DHEA on mood, libido, immunity, memory, and overall well-being.14-20
One study in particular shows a beneficial effect of DHEA on midlife dysthmia, otherwise known as the "blahs." I include the abstract from this study in the sidebar on the next page because it demonstrates improvements in "anhedonia (lack of joy/pleasure), fatigue, lack of motivation, emotional 'numbness,' sadness, inability to cope, and worry."21
Interestingly, these effects were experienced in as little as three weeks, but I maintain that the range of health and anti-aging benefits from DHEA unfold gradually over the course of years. Weight loss is gradual and requires regular exercise. The important difference is that DHEA can help restore the metabolic state in which exercise becomes easier, more enjoyable, and productive.
Naysayer: So you have demonstrated that DHEA supplementation can reverse certain psychological aspects of aging, but what about your claims that DHEA exerts anti-aging physical benefits?
Stephen Cherniske: One of the most consistent and devastating aspects of aging is the emergence of the metabolic syndrome, which is also termed Syndrome X. Decreased insulin sensitivity, free testosterone, and HDL, along with increased LDL, total cholesterol, and triglyceride levels, characterize the metabolic syndrome. The decline in DHEA secretion contributes to the metabolic syndrome and its related diseases such as heart attack, stroke, and type II diabetes.
DHEA-mediated reduction of cardiovascular risk is a gradual process, resulting from decreased platelet aggregation, reduction of serum lipids, and improvements in insulin sensitivity and endothelial function.3,22 A study on DHEA and heart disease uncovered the following:
"A 100 micrograms per deciliter increase in DHEA sulfate concentration corresponded with a 48% reduction in mortality due to cardiovascular disease and a 36% reduction in mortality for any reason. The natural level of DHEA sulfate was measured and those individuals with higher DHEA sulfate levels lived longer and had a much lower risk of heart disease."23
Seeking to explain these remarkable benefits, researchers found that DHEA sulfate levels are positively associated with HDL and negatively correlated with LDL and total cholesterol.24 A human study in the Journal of Epidemiology concluded:
"The mean Atherogenic index was significantly inversely correlated with the rise of tertiles in DHEAS levels, both before and after adjustment for age, total cholesterol HDL, and triglyceride. These results suggest that DHEAS may have an important role in the etiology and prevention of atherosclerosis."25
Recently, scientists found a strong correlation between low DHEA levels and hypothyroidism.26 But instead of looking at the long-term benefits of DHEA therapy, naysayers pointed to the failure of DHEA to restore thyroid function in short-term studies. They missed the point entirely.
Naysayer: And the point is?
Stephen Cherniske: That restoring DHEA levels is very likely to have a beneficial effect on the entire endocrine system, including the thyroid, but this effect will be gradual. In fact, most pathology is cumulative, but conventional medicine acts only when problems become acute.
In other words, a person does not become thyroid deficient overnight. In most cases, years of degeneration precede the metabolic disease state. Unfortunately, this degeneration goes unnoticed and a pharmaceutical "fix" known as thyroxine is used for the end-stage disease.
Naysayer: What's wrong with thyroxine?
Stephen Cherniske: Nothing. It is a useful drug to treat hypothyroidism; but there is something wrong with a health care system that does nothing to prevent a disease, and only springs to action when the problem becomes acute. The data strongly suggest that hypothyroidism develops in part due to declining levels of DHEA, and there is good evidence that people with optimal levels of DHEA are at decreased risk for thyroid disease.27-29 Moreover, hypothyroidism is often caused by an autoimmune reaction, and high levels of antithyroid antibodies have been correlated with low levels of DHEA.30
Bottom line, we think the problem is our thyroid, or our blood pressure, cholesterol, blood sugar, expanding waistline, or failing memory. But these are not the problem, they are the symptoms of one problem known as aging. Until we address the underlying cause of aging, we will simply be chasing after each of the symptoms as they inevitably arise.
Naysayer: But you said that aging was a complex process. Now you're saying that it has a simple underlying cause that can be easily altered.
Stephen Cherniske: No, declining production of DHEA is not the single cause of aging. The underlying cause of aging is the loss of regenerative capacity and the accumulation of cellular damage. The Metabolic Model of Aging describes this as a seesaw between damage and repair, and the model holds true on every level, from the sub-microscopic realm of DNA to the cell, organs, and the entire organism.
With this understanding, DHEA plays a critical role because it is the most comprehensive anabolic (repair) signal in the human body. It can therefore help to tip the see-saw in your favor by supporting repair functions throughout the body and brain. Moreover, DHEA has been shown to reduce cellular damage via its antioxidant and immune-stimulating activity.
Another long-term factor contributing to "the DHEA advantage" arises from a reduction in stress hormone-related catabolic damage. Elevated stress hormones and low DHEA are strongly associated with immune suppression, depression, brain degeneration, and even dementia.31,32 Conversely, DHEA supplementation has been shown to effectively reduce this type of degeneration.33
Naysayer: Still, the only intervention that has been proven to slow or reverse the aging process is calorie restriction.
Stephen Cherniske: You're right that calorie restriction can prevent disease, maintain health and youth in animals at advanced ages, and even extend maximal life span to the human equivalent of 140 years.
But one of the most remarkable observations seen in calorie-restricted animals, including primates, is that the treatment raises DHEA levels.34 In fact, some leading endocrinologists believe that the improvements in health and longevity from calorie restriction stem in great part from the life-long maintenance of DHEA.35-37 Again, these are long-term influences on immunity, glucose tolerance, body composition, and cardiovascular risk factors that would be missed in short-term studies.
DHEA AND WELL BEING: STUDY ABSTRACT
"This study evaluated the efficacy of the adrenal androgen, dehydroepiandrosterone, in the treatment of midlife-onset dysthymia. A double-blind, randomized crossover treatment study was performed as follows: 3 weeks on 90 mg dehydroepiandrosterone, 3 weeks on 450 mg dehydroepiandrosterone, and 6 weeks on placebo. Outcome measures consisted of the following. Cross-sectional self-ratings included the Beck Depression Inventory and visual analogue symptom scales. Cross-sectional objective ratings included the Hamilton Depression Rating Scale, the Cornell Dysthymia Scale and a cognitive test battery. Seventeen men and women aged 45 to 63 years with midlife-onset dysthymia participated in this study. Response to dehydroepiandrosterone or placebo was defined as a 50% reduction from baseline in either the Hamilton Depression Rating Scale or the Beck Depression Inventory.
RESULTS: In 15 patients who completed the study, a robust effect of dehydroepiandrosterone on mood was observed compared with placebo. Sixty percent of the patients responded to dehydroepiandrosterone at the end of the 6-week treatment period compared with 20% on placebo. A significant response was seen after 3 weeks of treatment on 90 mg per day. The symptoms that improved most significantly were anhedonia, loss of energy, lack of motivation, emotional "numbness," sadness, inability to cope, and worry.
CONCLUSIONS: This pilot study suggests that dehydroepiandrosterone is an effective treatment for midlife-onset dysthymia."21
21. Bloch M, Schmidt PJ, Danaceau MA, Adams LF, Rubinow DR. Dehydroepiandrosterone treatment of midlife dysthymia. Biological Psychiatry. 1999 Jun 15;45(12):1533-41
A Critical Review of Clinical and Experimental Data
Naysayer: That's just it. There doesn't seem to be any long-term studies to back up the anti-aging claims for DHEA.
Stephen Cherniske: You just haven't looked. When the National Institutes on Aging analyzed data from the Baltimore Longitudinal Study of Aging, they found a profound relationship between DHEA levels and survival.38
"Consistent with the beneficial effects of calorie restriction on aging and life span in other animals, men with lower temperature and insulin and those maintaining higher DHEA levels have greater survival than their respective counterparts."39
Likewise, studies of people aged 90 to 106 demonstrate that those who reach this remarkable milestone have higher-than-average DHEA levels. As you would expect, this was associated with a higher muscle-to-fat ratio and greater functional ability.40,41
The average adult replaces more than 300 billion cells each day. Anti-aging is accomplished in three ways: by providing optimal raw materials for this repair activity, reducing the damage that these cells are exposed to, and restoring and maintaining anabolic (repair) metabolism. As I mentioned, DHEA is the most comprehensive repair signal in human biochemistry, and it is time that we fully appreciate the influence it has on one's rate of aging. I am not the only scientist who believes that anti-aging is virtually impossible without paying careful attention to one's DHEA level. Here are the findings from a study on hormones and aging:
"The maintenance of a good physical functional ability and quality of life is related to serum testosterone, estrogen, and DHEA(S) concentrations."42
Naysayer: But isn't that the problem — that DHEA, because it is a cell proliferator, might accelerate nascent tumors?
Stephen Cherniske: Wrong! DHEA is a cell regulator. It induces apoptosis (cell death) in malignant and malfunctioning cells,43-45 and controls hyperplasia (abnormal cell growth) in the smooth muscle of the lungs.46 In numerous animal models, it has been shown to mimic the cell-regulating, anticancer benefits of calorie restriction.36,47
In thousands of animal studies, DHEA has been shown to prevent diabetes, obesity, infection, liver disease, and many types of cancer.48 In humans, DHEA levels predict mortality in a number of disease states, including AIDS, sepsis, cancer, and heart disease.49-52 And supplementation with DHEA has been shown—in controlled human studies—to increase muscle mass, improve bone density, combat stress and depression, enhance quality of life, restore immunity, protect the brain, improve memory, reduce the symptoms of systemic lupus erythematosus, and reduce risk for diabetes and cardiovascular disease.3,4,22,53-61
Continued . . .
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