By David Jay Brown

William Regelson, M.D., a practicing oncologist and research scientist, is an expert on the therapeutic benefits of hormone replacement and has been a leading researcher in the field of aging for over twenty years. He is the co-author of the best-selling books, The Melatonin Miracle and The Super-Hormone Promise, which detail the latest research in hormone supplementation and which provide intelligent guidelines for taking steps to slow and, in some cases, even reverse the aging process.

Dr. Regelson is a professor of Medicine at the Medical College of Virginia Commonwealth University and is a specialist in medical oncology. He has joint appointments in microbiology and biomedical engineering.

I spoke with Dr. Regelson about his work with DHEA and other hormones with regard to the aging process. I found him to be a very warm and thoughtful man. At 73 years of age he sounds vibrant and his mind is very sharp -- a living and vital testament to his own research.

David: Why did you become interested in researching the therapeutic benefits of DHEA?

Dr. Regelson: It's a bio-marker for aging and it declines in a linear fashion with the progression of aging. If you're going to approach aging rationally, you have to bio-quantitate human aging. DHEA, as a bio-marker for aging, is one of the best indicators of how old you really are. It has been proven valuable in the prevention of cancer. So, I clinically studied it as an anti-tumor agent. I gave it to about 20 patients with a variety of cancers. We also used it to treat people with multiple sclerosis because it has anti-viral activity as well.

David: Was this study written up? What were the results?

Dr. Regelson: Yes, we wrote it up in The Biologic Role of Dehydroepiandrosterone (DHEA), which is a book that we published in 1990 by Walter de Gruyter. We mention it in the text. We didn't write it up as a definitive paper, because the results were negative. Well, they weren't completely negative. We had an MS paper that came out, which appeared in our book, along with a MS paper by Eugene Roberts (from the City of Hope in Duarte, California) using DHEA.

Roberts gave a gram a day, and we gave forty milligrams per kilogram per day. And patients with MS did feel stronger. They did lose heat intolerance, and showed improvement. But remember, both of us had only about twenty patients per study, and it wasn't a double-blinded study, so there was no way to develop comparison. One had to go on the basis of individual evaluation, and numbers where small. We couldn't stimulate anybody in the field to do it. I think DHEA is worth trying with multiple sclerosis.

As far as cancer is concerned, unfortunately the numbers were small. It was a pilot study, and, again, I couldn't stimulate interest. At the time that we did it, I ran into political trouble here at the medical school in regard to the director of the cancer center, and had to drop out of cancer research, so I couldn't pursue it. DHEA, I think, has anti-tumor activity, but it's best as a drug in combination with other anti-cancer treatment. You can say that, that's fine, but it's something that has to be looked at.

There are individual reports of it improving cancer. There's a pancreatic cancer case report I know of. There are reports of multiple myeloma, where DHEA blocks IL-6, and IL-6 is a cytokine which is involved in the stimulation of multiple myeloma. So it has a place. It just needs more work, and it needs good controlled studies, which have not been done, because it hasn't been picked up. It's also been looked at in breast cancer, where the results are indifferent, but again the study was not a good one.

Roger Loria and I showed that DHEA can inhibit Coxsackie-B-entero virus, which, we think, is the virus that causes diabetes in human beings. We found that it had tremendous protective effects in test animals against a variety of lethal infectious agents, particularly viral agents. So, as a result of DHEA having both anti-cancer and even cancer prevention activity, we were very interested in it.

Arthur Schwartz of Temple University School of Medicine, Philadelphia did most of the work when it comes to cancer prevention. He is really the patriarch of my interest because he's the one who pointed out to me that cancer has a linear increase with age. Meaning the older we get the less DHEA we have. So it became logical to see how DHEA would effect aging patterns if it were to be taken to replace what had been lost due to aging. After having given it to cancer patients at pharmacologic dosages of 40 milligrams per Kilograms per day for periods as long as two and a half years, and also for lesser periods of time to multiple sclerosis patients, I felt it was a very safe drug.

David: Why?

Dr. Regelson: It was totally benign. No toxicity, nothing. And this was using extraordinarily high dosages. Forty milligrams per killogram is anywhere from six to eight grams a day. So we saw no major toxicity, except in women, where at that high dose you'll get hair on their face. That's a pharmacologic dose, which is a very large dose.

So I started looking at using it for myself, for my wife and for administering it under different clinical settings. Unfortunately, there was no interest at that time, meaning about the 1980's at the National Institute on Aging. In those days, it was like, "So what!" There was no major interest. Now there's a lot of interest in DHEA. Now there are all sorts of RO-1's out for good DHEA studies. (An RO-1 is a contractual study with the National Institute of Health. They send out requests for proposals, and then assign the study to whoever comes out with the best request.)

David: Could you just talk about some of the general benefits that one could expect from using DHEA as a supplement?

Dr. Regelson: DHEA is, in a sense, a mother steroid. Pregnenolone is a grandmother steroid as it gives rise to not only DHEA but also to corticosteroids. DHEA doesn't effect the corticosteroid pathway but gives rise to the male and female hormones, which decline with progressive age. It's pretty evident to me, really to anybody, particularly in view of hormone replacement therapy for women during menopause, that hormone levels decline with age. Well, estrogen replacement is a valid approach.

We replace estrogen and progesterone, but what about DHEA? It certainly declines with age, so that when you're in your eighties, you're producing only ten to fifteen percent of what your body made in your twenties. The real decline is seen in your late forties, whether you're male or female. So the idea would be to take enough DHEA to bring your body, if you will, back to age twenty. What possibilities might this have on your life span and quality of life in middle and older age?

Now here again, you can only operate on the basis of inference because human studies have not really been done. You cannot fully extrapolate from a mouse to a human being. Mice do not metabolize DHEA. Except for hamsters, rodents do not utilize DHEA. But if you give mice DHEA, it has profound effects on resistance to infection, and it improves memory performance. However, at the same time, if it isn't a normal metabolite of a mouse, you can't expect it to be implicated in mouse survival. A mouse does not make DHEA, although it is helped by it. So it teaches us about some of the mechanisms for DHEA action. But if you're going to do an aging study in a mouse, and a mouse doesn't normally use DHEA, it's not really the ideal animal.

There's a study now being done by Lane's group at the National Institute on Aging regarding caloric restriction in primates. They're doing this in rhesus monkeys at the University of Wisconsin and the University of Maryland. The studies have shown that if you calorically restrict monkeys, their DHEA values remain youthful. We've known for a long time that if you calorically restrict rodents, it delays the aging process. Now, this work is being extended to monkeys, which are primates, so they make DHEA the way that we do, which declines with age. These monkeys live about thirty or forty years, so there's a more rapid decline relevant to their age.

So DHEA values stay up. Now, what does that mean? I mean, what is the exact significance of it? As a bio-marker it's very meaningful, but why? What is DHEA doing? Is it helping the animal in some way to be healthier, and will it live longer? That's the critical issue, particularly in primates that make DHEA. You can learn from an animal that makes it. So if we really want to do DHEA studies, we should look at hamsters, because they make it, but rats and mice do not. So if you're going to study DHEA, and if it will delay aging, you want to do it in the right animal.

So that's why we should be looking at DHEA in hamsters, although I don't know anybody who's done the appropriate studies. But certainly DHEA declines in human beings, so I believe that people should take it. It up-regulates immunity, and it down-regulates auto-immunity (immune reactions against the self).

Van Vollenhoven's group at Stanford has shown that DHEA can reverse the symptoms of lupus, an autoimmune disease that attacks blood vessels. There is a company called Gene Labs, out of Redwood City, California, that has conducted a major study ? which they're to be complimented for ? following up on van Vollenhoven's work. This study is supposed to show whether or not DHEA has value in lupus. They haven't reported the results yet, but the rumor is that the results are very promising, confirming what the Stanford group has shown.

So here you have a hormone that somehow or other puts a damper on auto-immunity. We know that if you're chronically ill with rheumatoid arthritis, your DHEA values are very low. Infection also puts a stress on DHEA levels. Hans Selye, the father of the concept of stress as a factor in survival and behavior, found that DHEA was the most potent hormone for protecting his animal models against stress-related injury. So the idea, then, is not to take a pharmacologic dose of DHEA that will suppress your endogenous (produced from within a cell or organ) production dramatically, but to take a dose to replace what will bring you back to age twenty. In other words, the physiological amount that was present at the most youthful, reproductive phase of your life, which is age twenty.

David: Is there evidence that taking DHEA as a supplement suppresses endogenous production?

Dr. Regelson: Well, I don't know. But the assumption might be that it would. So. I think you need to be aware of this caution.

David: What guidelines would you offer to someone interested in trying DHEA as a therapeutic agent?

Dr. Regelson: I think it would be good to have a baseline level of your own DHEA done. It's always good if you have a doctor who's supportive of you ? although most doctors are not cooperative (because it's not FDA

approved) and they don't read, and they don't pay any attention. So, you need to find a good doctor, who's interested in it, and supports you taking it as a replacement. I take it every other day rather than every day to avoid getting major storage in my body fat, or to avoid suppressing my own endogenous production. So I pulse it (emulating the body's natural pulsatile release of DHEA). I don't know whether this is valid or not because the studies have not been done.

David: What's been your personal subjective experience with it?

Dr. Regelson: I can't judge that, as I've been on it for seventeen years. My wife's been on it for about twenty-one years now, and she does not suffer from osteoporosis.

Labrie's group from Montreal has found that DHEA can be substituted for estrogen and progesterone in post-menopausal women. It's been available in Europe as Prasterone® for at least twenty years as a post-menopausal hormone replacement therapy. So it's not that we have to worry about its toxicology. It's a very benign hormone. If you take too much, women will get a little extra hair on their face or maybe some acne. If you cut the dose, it goes away.

David: Are those the only side effects?

Dr. Regelson: As far as we can tell.

David: If DHEA is the precursor to all these other steroid hormones, why would somebody want to take other steroid hormones with DHEA?

Dr. Regelson: Why should one take others simultaneously? I don't know. It would depend on whether DHEA can act to fully maintain the other hormone levels. I don't know that there's enough information to give us absolute answers on that. But if you read Labrie, the suggestion is that it can do that.

David: Is there any evidence that the body loses some of it's ability to break DHEA down into the other steroid hormones, such as testosterone andestrogen?

Dr. Regelson: Not to my knowledge. But there may be variations in ability among different individuals. According to Labrie it's certainly an excellent anti-menopausal hormone for maintenance of bone integrity. There are claims that DHEA can improve mood and energy performance in aging individuals . Although, some people are raising questions about the work being done at the University of California, La Jolla, who are making these positive claims. Some people claim that the data isn't strong enough. However, there is very good data that DHEA is a very good antidepressant, that it can improve mood. So does testosterone. It may very well work by increasing the endogenous level of male hormone, which makes you feel good.

There are also reports that DHEA and pregnenolone (the precursor to DHEA) can relieve depression. They reverse it. Lithium reverses depression, prozac reverses depression, but here we have native hormones that are reversing it. A group from St. Louis has really solid data on this with pregnenolone, and Wolkowitz at the University of California at San Francisco has found that DHEA is effective for treating depression in the elderly. He is giving DHEA to an elderly population, carrying out a very good study to see if DHEA can effect dementia. This is an area that has not yet been proven, by itself, to have any long lasting value. But on a theoretical basis it might have some value. Additionally, there's evidence that DHEA can effect platelet aggregation, preventing platelets from clumping to form blood clots.

DHEA also lowers blood cholesterol dramatically. I think this should really be examined and used for the treatment of diabetes ? for both adult-onset and juvenile diabetes. This is because DHEA enhances the action of insulin. Also, as mentioned earlier, juvenile diabetes may be due to a sensitivity to the Coxsackie-B-entero virus which can be prevented with DHEA, however in mice. Unfortunately I don't know of anybody who's really doing a good human study.

David: I wasn't aware that juvenile diabetes is caused by a virus that attacks the pancreas.

Dr. Regelson: One of the concepts about why some people get juvenile diabetes is that their islet cells (insulin secretory cells of the pancreas) get wiped out. You see, there's an irony here, because most people think that islet cells beget islet cells, so that if you've wiped out your islet cells you've had it. But that's not necessarily true.

See, there are two cell populations in the pancreas. There's the acinar cells, which are the digestive secretory cells of the pancreas, and then there are the islet cells which give rise to insulin. And everybody thinks that insulin cells give rise to insulin cells. No, it's the acinar stem cells that give rise to the insulin-making islet cells. The islet cells are made by the asinar cells. So it's wrong to assume that because you have no islet cells you've had it. It's theoretically possible that the islet cells could come back from acinar stem cells of the pancreas that are involved in digestion.

One of the potential values of DHEA is that if it can block auto-immunity in the case of lupus, perhaps it could block auto-immunity in regard to acinar cell sensitivity in juvenile diabetes. One of the concepts is that juvenile diabetes may be due to a virus, and that may stimulate an autoimmune reaction. In other words, you come down with the virus, and you react to it in the cell, and then you now have an autoimmune reaction.

The concept is that the Coxsackie virus sets up an autoimmune disease. But how do you explain, if you've come down with a Coxsackie virus infection, why you permanently wind up with juvenile diabetes? Does that mean that you've wiped out every islet cell, and they'll never come back? That's kind of absurd, I think. You see, what I think you've done is every time a new generation of islet cells attempts to come from the acinar stem cells they get wiped out. But it isn't as if you may not be able to regenerate them. That's my concept. Now, I don't know whether I'm right or not, as it's not my field. But it strikes me as being very logical, and there are occasional diabetes patients that have been treated with DHEA who have shown improvement. But nobody's done a good, consistent study on this.

David: What are some of the latest developments that you've made in your research with DHEA?

Dr. Regelson: I'm working with Muhammad Kalimi (also on staff at Medical College of Virginia, Virginia Commonwealth University), my best friend as well as my collaborator. We're growing hippocampal cells in tissue culture. The hippocampus is a tiny little brain nucleus that looks like a seahorse. It's involved in short-term memory and sexual cyclicity. It's very susceptible to stress. If you stress an animal, you knock the hell out of the hippocampus.Saperstein has shown that. So we grow these human embryonic cells in tissue culture, and if you add glutamate, beta amyloid, or hydrogen peroxide, you destroy these hippocampal cells in culture. But if you throw in DHEA, pregnenolone, or estrogen, then you protect them. So here are hormones with neuro-protective capabilities. These are all neurocrines ? they're all found in the brain ? which actually protect the hippocampus from destruction by agents which we know damage it. In addition, the stress-mouse model and DHEA has a profound effect on protecting the animal from stress. It's a two-hour experiment in which the mouse's movement is restricted. This is a real stress to a mouse. It causes muscle wasting and stress-related death of the animal. By giving them DHEA they are protected.

David: What are some of the future directions that you see for research in this area?

Dr. Regelson: I think that one of the researchers who's really done some of the best work in relation to pointing the way to mechanisms where DHEA is valuable is Raymond A. Daynes' work at the University of Utah. Daynes has shown that DHEA affects IL-6, corticosteroid-mediated cytokine, which is a stress-mediating factor. This factor also promotes the growth of certain tumors, and DHEA inhibits the production of this stress factor. So it has an anti-stress effect. It can also have anti-tumor activity and has value in septic shock (inadequate blood circulation due to pathogenic microorganisms in the blood). DHEA also protects mice from wasting from stress. Stress causes sarcopenin (muscle-wasting), and we can prevent that with DHEA. More work has to be done in these areas.

The person I'm working with now, who I'd like to see succeed, is Tim Cochran of the Cochran Foundation. He has a poly-pharmacy (multiple drug therapy) preparation of DHEA and other hormones, etc. with which he's treating congestive heart failure. He also is treating Parkinson's Disease, and this is a very promising area. The problem is it's poly-pharmacy, so people don't take it seriously. But I think he's made a major breakthrough.

Then you have Henry Lardy, at the University of Wisconsin, who has come out with his own derivative of DHEA ? which he's patented ? and is now trying to market. What Lardy has shown is that DHEA can protect mitochondria, which are important for each cell's energy system. In the final analysis, we're only as young as our cell's energy system. So if you can maintain the integrity of mitochondria, you can maintain the quality of survival.

DHEA can protect the mitochondria of the energy systems, and your youthful state is dependent on how you use energy. Aging occurs when you can't utilize energy to maintain the integrity and repair capacity in the cell. That's basically what aging is. So I think the final common pathway that relates to aging is our ability to maintain our mitochondrial cell energetics-- those are the little furnaces in the cell that provide us with the ability to burn food, and turn it into energy. There's evidence that DHEA can protect mitochondria, and that may be the final common pathway that is vital to aging.

I'm not concerned with the length of life, so much, as I am with the quality of survival. I mean, I'm not a Kevorkian. What I mean to say is that life for life's sake has no meaning, unless there's quality to it. That's the fundamental problem that we're faced with in our society, which we're only just beginning to do something about. At my university the administration is acting in a very stupid fashion. I want to develop a successful aging program that will appeal to the baby boomers, so that we can develop a program of bio-quantification, and rational intervention. Unfortunately it's moving very slowly. But that university which starts programs of this kind will make it in a very big way, both economically and socially. What we want to do is prevent people being debilitated and dependent.

I'm currently 73, and I know what my future is, unless I can do something about it. But I'm concerned with the quality of my survival, not necessarily the length of my survival. I want to be productive, and physically and sexually active until the day that I die. That's what I want. I want to go like James Whitcomb Riley's "Wonderful One-Horse Shay". I want to fall apart-- boom-- once, and not hang on to life. I don't want to be crippled and dependent in the process if I can avoid it. And that's what our direction should be-- how do we keep animals alive and healthy? And that's where hormone replacement comes in.

That 's the whole concept of my book The Super-Hormone Promise. The promise is in our replacing hormones that decline with aging, to reproduce the reproductive state, that period of our life where we're most physically fit, and most active. I think that really is my fundamental philosophy that has to do with embracing aging. Unfortunately gerontology has gotten a bad name. It's nursing homes, and elder-hostile, and putting a patchwork on problems that already exist.

What we have to do is prevent these problems from developing, because our society can't afford to develop an aging society that's debilitated. Who's going to pay for it? We have to change our way of thinking. I mean, we have enough information that indicates there's certain things that can be done. For example, if you could prevent osteoporosis in women, you can avoid 200,000 hip fractures a year.

We need to find a way to maintain people so that they're functional until the very end of their lives. This doesn't necessarily mean that they're working, but that they're taking advantage of life in the full sense of the word. I mean, look what's happening now. People in their seventies are still youthful. It's when you get into the upper seventies, and the eighties, that you start seeing this severe debility in our society.

The potential for DHEA is hormone replacement. We shouldn't be saying "Oh my God, we don't know anything about it, and it may do this." Fortunately, right now, we have Gene Labs and van Vollenhoven's group, which are studying it in lupus, and they're doing a good double-blind study. They're being secretive about their data, because they want to meet FDA requirements. But the preliminary work of van Vollenhoven's, where he's giving DHEA at a fairly large, pharmacologic dose-- 200 milligrams a day-- shows that he's not seeing any major toxicity. And his patients are improving. It's a safe hormone. We have to learn to use it.

I resigned from the local lupus society because we have about fifteen doctors in the Richmond community that are rheumatologists who deal with lupus, and not one of them is giving DHEA. I don't deal with this patient population. So I sent out a memo, and I said read the literature. I sent them copies of van Vollenhoven's paper, and I said start treating your lupus patients with DHEA. But nobody listens. They're waiting for an FDA clearance, which is still a couple of years away. In the meantime, people are dying of lupus and coricosteroid toxicity. People should read and do something about it. That's why we have to go beyond lupus, and see what it does for other autoimmune diseases, including maybe asthma.

DHEA, incidentally, will suppress mastis sarcomas, which are mass-cell tumors. We've shown this and reported it. The mass cells play a major role in autoimmune reactivity, particularly in regard to asthma, and cutaneous allergy. DHEA suppresses that mass cell. So people have to start looking. The trouble is that the action on the part of the National Institute on Aging is very slow. They're finally beginning to put out research requests, and people are beginning to get money to do the work. But, I think, they're ten years behind the times because they're so slow and conservative. If a drug company could see it as a profit-making enterprise, it would have moved a long time ago. I tried to get Hoffmann-La Roch interested it twenty years ago, but they said they couldn't patent it, so they weren't interested.

REFERENCES

1. Regelson W.; Kalimi M. Dehydroepiandrosterone (DHEA) the multifunctional steroid: II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action? Ann NY Acad Sci. 1994;719:564-575.

2. Loria RM, Inge TH, Cook SS, Szakal AK, Regelson W. Protection against acute lethal viral infections with the native steroid dehydroepiandrosterone (DHEA). J Med Virol. 1988;26:301-314.

3. van Vollenhoven RF, Morabito LM, Engleman EG, McGuire JL. Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol. 1998;25:285-289.

4. Labrie F, Belanger A, Van LT, Labrie C, Simard J, Cusan L, Gomez JL, Candas B. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids 1998;63:322-328.

5. Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY. Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J Immunol. 1993;150:5219-5230