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New Analog Ready For Clinical Trials Part 3 Of Our Exclusive, In-Depth Report On The New York Academy Of Science's Conference On DHEA
June 18-19, 1995, Washington D.C.
By Gregory M. Fahy, PhD. In an introduction to his presentation at the DHEA Conference last June, Dr. Arthur Schwartz of Temple University Medical School in Philadelphia referred to the contents of a paper in preparation that appears to be more interesting than his main message at the meeting.
Dr. Schwartz reported that, years ago, he carried out a lifespan study with DHEA and found that DHEA was able to block hair greying and extend lifespan in C57B1/6J mice, a naturally long-lived strain of mice. However, these effects were only observed when the dose of DHEA was high enough to produce unwanted side effects, such as increased production of testosterone and estrogen and peroxisome proliferation.
For this reason, Schwartz began to search for an analog of DHEA that would not produce these side effects. He now believes he has found what he was looking for, a fluorinated derivative of DHEA. Not only does it lack the side effects of DHEA, but it is also more potent as an anti-cancer agent, an anti-diabetic agent (in mice), and as a blocker of autoimmunity. According to Schwartz, it is poised to go into clinical trials shortly. DHEA (But not DHEA-Sulfate) Fights Cancer The main point of Schwartz's talk was to explain cancer inhibition by DHEA. He probed this question by setting up a simple test system in which skin tumors were induced to grow on the backs of lab mice in response to chemical inducers and promoters of cancer. He then administered DHEA (or the new analog) either orally or directly to the skin to avoid the systemic effects of DHEA such as weight loss. Because DHEA and calorie restriction both induce weight loss, he included a calorie restriction group as a further control and as an interesting point of comparison.
Both oral and topical DHEA dramatically inhibited cancer growth when given one hour before the cancer promoter. A single application of DHEA effectively inhibited both cancer initiation and cancer promotion!
The new DHEA analog also inhibited cancer initiation and promotion at half the dose required for DHEA itself. Calorie restriction, too, blocked tumor promotion. DHEA-sulfate, however, had NO anti-cancer effect. Blocking DHEA's Anticancer Effect In the past, it has been noted that DHEA blocks an enzyme called GGPD and thereby blocks the synthesis of the nucleic acids required for cell division. It was felt that the resulting shortage of nucleic acids might account for the inability of cancer cells to grow. In agreement with this theory, DHEA-sulfate, which did not block cancer growth, also did not block GGPD.
Schwartz then tested the ability of nucleic acids, supplied in the drinking water, to overcome the anti-cancer effects of DHEA. The results agreed with his expectation: the drastic anti-cancer effects of DHEA or its analog were blocked by the nucleic acids.
Furthermore, the anti-cancer effects of calorie restriction were also partially blocked by nucleic acids. A Different Explanation for DHEA's Anti-cancer Effect There is a problem with the nucleic acid depletion theory, however: the fact that the division of NORMAL cells, such as white blood cells in the immune system and rapidly-dividing cells in the gastrointestinal tract, were not inhibited by DHEA, despite a presumed depletion of nucleic acids in these cells as well. So depletion of nucleic acids or inhibition of cell division is probably not the mechanism of DHEA's effect.
To explain this discrepancy, Schwartz noted that G6PD can also lead to the production of free radicals that may contribute to the cancer process in combination with his cancer-inducing chemicals. By blocking G6PD, DHEA would prevent cells from becoming cancerous in the first place, while having little effect on cell division. The suppression of DHEA's effect by nucleic acids would then be due to their ability to prevent DHEA from inhibiting GGPD.
To test this idea, Schwartz turned to a different hormone, one that blocks free radical production without changing GGPD activity. This hormone should mimic DHEA's anti-cancer activity but be immune to blockade by nucleic acids. Mechanism of Cancer Prevention by Calorie Restriction The hormone Schwartz tested is another of the adrenal hormones, corticosterone. As he suspected, the administration of corticosterone drastically blocked tumor growth, and its effects were not blocked by nucleic acids.
Schwartz then made a crucial connection. He (and others) had found that calorie restriction blocks cancer development in his test system.
But it also is known that calorie restriction causes overproduction of adrenal hormones, including corticosterone, which he had just found to be effective at suppressing cancer. Could it be that the protective effect of calorie restriction is caused entirely by adrenal hormone overproduction?
The answer appears to be positive. When Dr. Schwartz removed the adrenal glands from his animals, the anti-cancer effect of calorie restriction was eliminated! Further, removing the adrenal glands also led to more cancer in his non-calorie restricted animals!
It appears, therefore, that glucocorticoids (corticosterone in rodents, cortisol in humans) may be profoundly protective against cancer and may partly explain the effects of calorie restriction.
Although glucocorticoids are hazardous to use (far more hazardous than DHEA), Schwartz's observation puts us closer to an understanding of how to prevent the diseases of aging.
CYTOKINES, IMMUNITY, AND AGING Dr. Raymond A. Daynes (Dept. of Pathology, University of Utah School of Medicine, VA Medical Center, Salt Lake City, UT) chaired a session on "DHEA, Immunology, and Aging" and gave the introductory talk. His presentation was one of the highlights of the meeting. His focus was on aging of the immune system and, in particular, on the changes that occur with advancing age in the cellular hormones (cytokines and growth factors) that govern the immune response.
Cytokines are involved in host defense and healing and can affect almost every cell in the body. Cytokines can be regulatory factors, growth factors, or death factors. They form a very complex network that must remain in balance: too much or too little of various cytokines produces disease states or compromised responses to various challenges.
Aging results in major dysregulation of cytokines. For example, the ability to produce the cytokines CSF-GM, IL-2, and IL-3 in response to a stimulus falls profoundly, whereas IL-4, IL-5, IL-6, IL-10, and interferon gamma (IFG) are all overproduced, often dramatically. In fact, IL-6, IL-20, and IFG levels go up even without stimulation both in old animals and old humans, implying that all cells that can respond to these factors become constantly stimulated within the body.
Overproduction of IL-6 leads to abnormal immune responses, a fall in serum albumin, bone wasting, and an increased risk of breast cancer. Overproduction of IL-10 can inhibit cellular immunity needed to combat cancer. Overproduction of IFG (which rises by about 200-fold) suppresses many other essential cytokines, including TGF-beta, which helps cells stick to their extracellular caffolding and to other cells, and helps to stop tumor growth.
DHEA-S Restores Youthful Cytokine Levels in Aged Animals Daynes gave mice DHEA-sulfate (DHEA-S) in their drinking water at concentrations of 25, 50, and 100 micrograms/mi, resulting in doses of about 2-to-8 mg/kg/day. The result was that the cytokine derangements normally caused by aging were reversed or prevented. For example, IL-6, IL-10, and IFG were all restored to near normal levels. To see if this allowed more youthful immune system responses, Daynes immunized 24-month-old animals which had been on DHEA-S for 16 months and found that they responded like young animals! He also found that it was not necessary to be on DHEA-S chronically to obtain a positive result. For example, aging caused serum IL-6 to rise almost 9-fold, but within 24 hours of treatment with either DHEA-S or DHEA, IL-6 levels dropped to within 15% of youthful values!
Antibodies directed against self rose about 5-fold with aging, but after 2 weeks on DHEA-S, fell by over 50%! Restoring IFG also restored normal responses of other cytokines dependent on it, as expected. For example, integrins (molecules that govern the general abilit of cells to attach to extracellular structures) fell by more than 50% with aging, but were completely restored by DHEA-S.
Correction of IL-6, IL-20, and IFG was accomplished using a dose of DHEA-S 50 times lower than that reported to cause overproliferation of peroxisomes (intracellular organelles), a sometimes-feared side effect of DHEA.
In response to a question, Daynes pointed out that these changes were independent of the thymus (the master gland of immunity). There was no restoration of thymic function at all and no improvement in the age-related drop in T cells that reflects thymic involution, but this was not a limiting factor for a good immune response in these animals.
Is DHEA-S Better than Calorie Restriction? The physical appearance of Daynes' mice at 2 years of age was excellent, in stark contrast to the appearance of control mice.
To emphasize the importance of these improvements, Daynes closed his talk by showing preliminary results of a lifespan study now being conducted by Rick Weindruch at the University of Wisconsin in Madison, on behalf of a company called Paradigm Biosciences.
At the time of the meeting, the mice were 21 months old. Ninety-two percent of the control animals were still alive, and about 94% of the calorie restricted animals were alive. About 97% of the animals being given DHEA-S plus calorie restriction were still alive, whereas 99% of the mice being given DHEA-S alone were still alive.
Therefore, at this admittedly early stage of the experiment, DHEA-S by itself was doing better than either calorie restriction or calorie restriction plus DHEA-S. Stay tuned for further details.
DHEA-S Boosts Flu Vaccine's Effectiveness In the Aged Barbara Araneo (Dept. of Pathology, University of Utah, Salt Lake City, UT, and Paradigm Biosciences, Inc., Salt Lake City, UT), an associate of Dr. Daynes, discussed "proof of principle" experiments in mice showing complete protection from tetanus by oral DHEA-S due to the ability of DHEA-S to improve the antibody response to tetanus toxin. Unfortunately, the DHEA-S did not enhance the response to tetanus toxin in humans.
On the other hand, Araneo did show that a newly-licensed human influenza vaccine was significantly more effective at boosting antibody production in people between 65 and 85 years of age when combined with either oral DHEA-Sulfate or 7.5 mg of DHEA-S given as an intramuscular injection next to the vaccine injection site. This agrees with work reported by H.D. Danenberg and colleagues (Geriatric Unit and Dept. of Virology, Hadassah University Hospital, FinKarem, Jerusalem, Israel), who gave mice 10 mg of DHEA under the skin and found a complete reversal of the 30% aging-induced loss of antibody response to influenza vaccine as well as enhanced protection against live flu virus.
Araneo wanted to try prolonged administration of DHEA-S in human volunteers, which might have resulted in stronger responses to the flu vaccine as well as positive responses to the tetanus toxin, but this was precluded by the FDA because the FDA prefers acute administration studies.
DHEA-S Boosts Antibody Production through IgD Receptors Christina Swenson (Dept. of Pathology, New York University Medical Center, New York) reported a profound age-related loss of responsiveness to immunoglobulin D (IgD) in mice that was improved by DHEA-sulfate. DHEA-S (0.1 mg intraperitoneally 3 times a week, or via the drinking water at a concentration of 0.1 mg/ml) increased IgD receptors on the T cells of young and old mice as well as on the T cells of elderly humans, leading to improved antibody formation. Factors that Raise and Lower DHEA Alex Vermeulen (Dept. of Internal Medicine, University Hospital, Gent, Belgium) and Elizabeth Barrett-Connor (Dept. of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA) reported on factors that change DHEA levels. The only factor that (in the end) appeared to reduce DHEA-S blood concentrations was estrogen (including postmenopausal estrogen replacement).
Although cholesterol levels below 200 (only a slight effect in men), exercise (in men only), and obesity (in men) at first appeared to be associated with low DHEA-S levels, these effects were ultimately shown to be due to low alcohol intake. Factors that raise DHEA levels include: drinking alcohol (a very solid relationship), smoking (yes, smoking!), and possibly losing weight and exercising (slight effect in women only). Hypercholesterolemia and HDLs over 40 were associated with higher DHEA-S, but their effects could also be accounted for by ethanol intake. Neither growth hormone nor IGF-1 appear to influence DHEA levels, according to this study.
D. Jakubowia et al. (Hospital de Clinicas Caracas, Caracas, Venezuela) put 18 men and 29 women on a 1200-1400 kcal diet for 2 months and observed a 125% rise in serum DHEA-S in the men but no change in the women. Unfortunately, their data are suspect because at the beginning of the experiment their women had DHEA-S levels which were twice the men's levels, whereas, according to Barrett-Connor, women's levels are normally half of the male levels!
DHEA's Protection Against Cardiovascular
Disease May Be Weaker Than Thought The bad news is that the protection afforded by DHEA against cardiovascular diseases and overall mortality appears to be weaker than formerly reported. The good news is that early evidence for an increased risk for women with high DHEA-S levels appears to be incorrect.
Alex Vermeulen reviewed a recent study in which high DHEA-S was associated with a shorter lifespan in men (though not in women). Another recent study suggested that high DHEA-S is associated with a greater risk of blood clots lodging in the heart in men. A member of the audience stated that DHEA raises glucose levels in women, which may be a problem for women taking DHEA. The Definitive Study The definitive study, however, seems to be that of Elizabeth Barrett-Connor, whose original paper in the New England Journal of Medicine in 1986 showed that low DHEA-S levels are correlated with death from any cause. Barrett-Connor has now followed her study population for an additional 7 years and added new subjects to the group, thus increasing the statistical validity of her results.
The bottom line is that, except for showing no increased risk for women with high DHEA-S levels, she was able to confirm her old results while uncovering a number of confounding variables that were not taken into account in her original paper. Unfortunately, the protective effects of DHEA-S against cardiovascular disease seem to be weaker than first thought.
Barrett-Connor's original study showed a 60-70% lower death rate from coronary vascular disease and ischemic heart disease for men with high DHEA-S levels, but a 23-103% increase in risk for women.
These results, however, especially in the case of women, were based on small numbers of deaths. The Conclusions Of The Study Barrett-Connor concluded that, in men, DHEA-Sulfate is an independent protector against the risk of death from cardiovascular disease as well as death from all causes. In women, she essentially concluded that more data are required before the same statement can be made, but she clearly expects the final results to be similar for both men and women. She also alluded to the possibility that pharmacological use of DHEA-S could have far more powerful protective effects than these small differences from person to person under natural conditions.
Cancer Risk Barrett-Connor also examined the risk of death from all forms of cancer and found no protective effect for DHEA-S. However, she has done a separate analysis for breast cancer that was not presented at the conference. We await the results of that analysis with great anticipation.
Furthermore, data linking higher DHEA levels to protection from organic brain syndrome (J. American Geriatrics Society, Rudman et al., 1990) were not challenged by this new research. DHEA and Coronary Atherosclerosis In support of Barrett-Connor's findings, David Herrington (Section on Cardiology, Bowman Gray School of Medicine, Winston-Salem, North Carolina) studied the possibility that DHEA inhibits coronary atherosclerosis naturally in humans. He examined 101 men and 103 women who underwent elective coronary angiography and related the number of observed diseased vessels (vessels that were at least half-closed) and the extent of coronary atherosclerosis to circulating levels of DHEA and DHEA-S. He found a statistically significant trend for less and less coronary artery disease as DHEA-S or DHEA levels rose. His results were reported in the Journal of the American College of Cardiology in 1992.
Herrington followed up with a study showing that the development of atherosclerosis in 63 transplanted human hearts (1 and 5 years after transplantation) showed a significant (p=.05 or less) inverse correlation with free circulating DHEA. Total circulating DHEA showed a nearly-significant inverse correlation (p=.09). By comparison, the correlation with cholesterol was much lower (p=.23). Surprisingly, there was no correlation (p=0.89) with DHEA-S levels.
The most important data, however, were the survivorship data. Five years after getting a transplant, the high DHEA group had an 87% survival rate, whereas the low DHEA group had a 65% survival rate (p=.05). This very strong effect of naturally-existing levels of DHEA raises the question of whether transplant patients could be kept alive longer by giving them DHEA. This is of particular interest given the immune stimulating effects of DHEA/DHEA-S noted above.
Herrington concluded that the fall of DHEA with age may be one explanation for atherosclerosis and that even a small protective effect would be very significant given the size of the U.S. population and the high incidence of atherosclerosis.
DHEA Keeps the Blood Flowing Robert L. Jesse (Dept. of Cardiology, Medical College of Virginia in Richmond) noted that oxidants and lipid peroxides promote platelet aggregation (clot formation), which could lead to heart attacks or strokes. He gave DHEA to 10 healthy male volunteers aged 20-35, then collected their blood to check for platelet aggregating tendencies. DHEA significantly slowed and virtually prevented clotting in response to doses of the clot-promoting substance, arachidonic acid.
Additional evidence was obtained by damaging the insides of rabbit blood vessels with a balloon and then watching how well platelets attached to the damaged blood vessel wall. DHEA greatly inhibited platelet attachment to and interaction with the vessel wall. Within the vessel wall itself, intimal hyperplasia (a key step in forming atherosclerotic plaques) was drastically inhibited by DHEA.
When balloons are used to open up clogged blood vessels in humans I (angioplasty), a nagging problem is reclosing (restenosis) of the opened blood vessel. When Jesse examined this question, he found that 68% of vessel wall segments showed restenosis without DHEA administration, but only 25-28% showed restenosis when either high or low doses of DHEA were administered.
Finally, Jesse transplanted rabbit hearts and found that dietary DHEA drastically reduced the rapid atherosclerosis that characteristically occurs in these transplants, regardless of whether or not cholesterol was added to the diet to exacerbate the problem. Papers At The Poster Sessions Not everyone had a chance to present results orally at the DHEA Conference. Much useful INFOrmation also came out of the poster sessions. Some examples follow.
In complete contradiction to John Nestler's careful studies, D. Jakubowicz and colleagues at the Hospital de Clinicas Caracas, Caracas, Venezuela reported giving 22 men, aged 55-59 years, 300 mg of DHEA nightly for 1 month. They observed a 27% fall in insulin levels. They also found an 89% increase in IGF-1 (which produces growth hormone-like effects), a 14% fall in body fat, and a 7.8% increase in lean body mass. The latter two effects were postulated to be due to the rise in IGF-1.
Bernard Lavellee and colleagues (MRC Group in Molecular Endocrinology, CHUL Research Center, Quebec, and Medical College of Virginia, Richmond) suggested that insulin lowers circulating levels of DHEA by causing DHEA to be linked to fatty acids and then taken up into tissues. The implications of such an effect, if it exists, are unknown.
X.-D. Lei and RA. Prough (Dept. Biochem., School of Medicine, Univ. of Louisville, Louisville, KY) found that only massive doses of DHEA cause peroxlsomal proliferation, and that doses much lower than those that produce this feared side effect were capable of "blunting methylnitrosourea-induced mammary cancer" in female rats.
J.R Porter and E Svec (Obesity Research Program, Depts. of Medicine and Physiology, LSU Med Center, New Orleans) fasted normal and fat female Zucker rats for 1 day, then gave them 25-200 mg/kg of DHEA by injection. Two hours later, they were allowed to chose cafeteria style from nearly pure selections of protein, carbohydrate, and fat. In comparison to similarly-treated rats who got no DHEA, both normal and fat rats ate about the same amount of carbohydrate, but both dropped their protein and particularly their fat intake. The problem with this study, however, is the high DHEA doses used.
Porter and Svec also gave either fenfluramine (an appetite suppressant), DHEA, or the combination of both compounds, to lean and fat Zucker rats by intraperitoneal injection for three days. They found that the combination of fenfluramine and DHEA had a spectacular effect on food intake: "the fat intake of the lean rat decreased to almost half and the obese rats nearly stopped eating." This effect did not wear off when the treatment was continued for 4 weeks. Doses as low as 6.25 mg/kg/day of DHEA and 0.312 mg/kg/day of fenfluramine were effective. This treatment resembles a new therapy for humans that is currently gaining in popularity in which fenfluramine is combined with serotonin reuptake inhibitors like Prozac, which are antidepressants that block compulsive behaviors such as overeating. DHEA could be more a attractive additive to fenfluramine than Prozac for many overweight individuals.
O.M. Wolkowitz ct al. (Dept. Psychiatry, UCSF, San Francisco, CA, and Dept. Neurobiochemistry, City of Hope, Duarte, CA) showed that DHEA is both an antidepressant and a memory enhancer in 51-72 year old men and women. A total of 6 patients with low DHEA and/or DHEA-S levels received 30-90 mg of DHEA per day by mouth for 4 weeks.
Four different measurement scales for depression showed strong statistically significant improvement, and both automatic and semantic memory measures showed statistically significant improvements.
GENERAL DISCUSSION The last event of the meeting was a general consideration of where we are with DHEA research and what needs to be done in the future. The session chairmen were each allowed to voice their thoughts on these matters, and comments were permitted from the floor. Some of the more interesting topics discussed were the following: Cortisol Vs. DHEA The stress hormone cortisol may have important (though incompletely understood) antagonistic relationships with DHEA, and the cortisol/DHEA ratio may be important measure of health status. With aging, the cortisol to DHEA ratio goes up by a factor of 5. In end stage renal failure, too, cortisol levels are high and DHEA levels are low. DHEA or DHEAS can block some of the acute effects of cortisol. Asthmatics are helped by cortisol but made worse by DHEA. The administration of steroids changes DHEA-S levels, which take 6 weeks to recover after discontinuing the steroids. Is There A New Form Of DHEA? It was suggested that 50% of the DHEA in circulation may be chemically bonded to fatty acids in the high and low density lipoprotein fractions of the blood. This would be a new form of circulating DHEA about which little is currently known. Should DHEA Be Used Now? The tension between the clinicians who want to use DHEA now and those who insist on further studies before using it continued during this wrap-up session. Dr. John Broder asked the physicians whether they would replace DHEA in their patients today. Nestler said no, because "'no strong confirmed benefit of DHEA has been shown in humans" and there is always the possibility of unwanted side effects. For example, Nestler said, growth hormone is now known to have a number of harmful side effects. But, Broder pressed, isn't it logical to assume, as a working hypothesis, that there will be no side effects if all we are doing is restoring DHEA levels to what they were in youth? The answer given was that this would be the expectation, but one has to remember that natural DHEA levels are not attained by ingesting DHEA, and that building up DHEA levels in this way could produce problems in some unknown way. DHEA advocate Dr. Jorge Flechas stated, from the audience, that there is such a thing as a DHEA deficiency state or syndrome, which involves hair loss, fingernail changes, increased oiliness, and fatigue, and that many people suffer from this syndrome.
Nestler objected that Flechas' experience is anecdotal and could be contradicted by other anecdotal evidence, but Flechas replied that you can't get funded for a large study without preliminary results such as his own and reiterated that everyone over 40 has an indication for DHEA replacement. He further stated that most people who take DHEA do not lose weight but do feel better and more vital, and that LDL cholesterol and total cholesterol fall in men who take DHEA. (These lipids may go up or down in women, perhaps depending on their estrogen levels.) Is DHEA Good Or Bad For Breasts? DHEA is concentrated ten-fold to 500-fold over blood concentrations of the hormone in breast cyst fluid and also accumulates in breast secretions. A long-term Italian study linked DHEA-S accumulation in breast cysts to increased risk of breast cancer. Caution was advised in giving DHEA to postmenopausal women. But another doctor responded that DHEA prevents breast cancer, even human breast cancer transplanted into mice. Are DHEA/DHEA-S Blood Levels Meaningless? Another point that was mentioned on and off during the conference is the difference between circulating levels of DHEA/DHEA-S in the blood and tissue levels of these hormones. DHEA concentrations are highest in liver and brain, with significant concentrations also in the mesenteric lymph nodes, spleen, and thymus. When DHEA is added to the diet for 14 days, huge quantities appear in all the organs of the body. As a result, some doctors felt that measuring serum levels may be "a waste of time," though this was far from agreed upon. The Worst Side Effects Of DHEA When asked what was the most frightening possible side effects of DHEA, Dr. Yen answered that it was masculine hair growth, acne, and a receding hairline in women, or increased estrogen production in men. He explained that DHEA has a high affinity for (and stimulation of) hair follicles and sebaceous glands, and that the New England Journal of Medicine carried an article linking teenage acne to the rise in DHEA that takes place near puberty. Clearly, much remains to be learned about this exciting anti-aging hormone, which more and more physicians are giving to their middle-aged and older patients.
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