By David Jay Brown
Michael Fossel, Ph.D., M.D., is a clinical physician and neurobiologist with a strong interest in the human aging process. He is currently the Clinical Professor of Medicine at Michigan State University, and Attending Physician at St. Mary’s Hospital Emergency Department in Grand Rapids, Michigan. Dr. Fossel is the author of Reversing Human Aging, and the recently published Cells Aging, and Human Disease. He believes that we are only about a decade away from a truly remarkable form of anti-aging therapy that holds the promise of perpetually renewable youth.
Dr. Fossel has dedicated years to studying progeria and other accelerated aging syndromes. Children with the progeric disease Hutchinson-Gilford syndrome die at an average age of twelve or thirteen. They usually die of heart disease, strokes, cancer and other illnesses that often strike the elderly. Children with progeria look uncannily like old men and women, with balding heads and wrinkled skin, and appear to suffer from many of the symptoms of old age.
Dr. Fossel believes that the evidence from these diseases (combined with the fact that germ cells and cancer cells do not age) indicates that aging is largely a regulated process; i.e., a function of gene expression. According to Dr. Fossel, the key to understanding, and possibly reversing human aging lies at the tips of our chromosomes. He thinks that one of the best places to intervene in the genetically-wired clock that determines our biological age is in the intracellular process of telomere replication.
Telomeres are the base pairs located at the end of our chromosomes that hold the DNA molecule together. With the exception of germ cells (sperm and eggs) and cancer cells, each time a human cell divides the telomeres become a little bit shorter. This is why, no matter how optimum a cell’s environment is, after a certain number of cell divisions, the telomeres become too short, gene expression changes, down-regulating cell repair and maintenance, and the cells age. The progeric disease Hutchinson-Gilford syndrome is caused by having telomeres that are too short at birth, so it doesn’t take too many divisions before the cells begin to show early aging.
The reason that germ cells and cancer cells don’t age—and can potentially divide forever—is because they produce an enzyme called telomerase, which keeps the telomeres intact when the cell divides. Dr. Fossel predicts that telomerase therapy could extend human life indefinitely by resetting the genetic clock in healthy somatic cells, and turning it off in runaway cancer cells. He imagines that very soon everyone will have the potential to live for centuries in a body that looks and functions like it’s about twenty years old.
Dr. Fossel earned his master’s degree in psychology at Weseyan University. He then earned his Ph.D. in neurobiology, and M.D. from Stanford University. In 1998, Dr. Fossel won the Achievement Award in Preventive Medicine from the American College for Advancement in Medicine. He was the founding editor of the Journal of Anti-Aging Medicine (now Rejuvenation Research), and served as its Editor-in-Chief for six years. Dr. Fossel is a widely published author of dozens of scientific papers and articles, and a popular international lecturer. He has also appeared on numerous radio and television shows, and in many science documentaries.
Michael speaks fast, yet somehow manages to say every word clearly and distinctly. He radiates a sense of warmth and humor. In a message that he sent me, he described himself by saying, “On the whole, I prefer data to fame, accuracy to eminence, and gardening to tenure.” I spoke with Michael about what he’s learned from working with progeric children, how telomeres are related to human aging, and the medical possibilities of telomerase therapy and biological age reversal. To follow is an excerpt from the interview. The full interview will appear in the forthcoming book Mavericks of Medicine.
Dr. Fossel: That’s an interesting question because it is usually asked incorrectly, and gets answered incorrectly. There are people who have said—and it’s simply not true—that I think telomeres cause aging. Not a bit. To me, there are two issues here. One is, what causes aging? And, frankly, I find that uninteresting, and I’ll come back to why I say it that way. Telomeres, per se, don’t cause aging. They’re a piece of the entire complex cascade and process of the aging organism. But the more important question for me is, where’s the most effective point of intervention?
I’ll give you a couple of examples of this. I get residents who come in to work with me clinically, who feel that if they’ve made a diagnosis, they’re done. Not a bit. Patients don’t come in for a diagnosis. They come in to be made better. Now it’s true that usually making a diagnosis helps you make patients better. But a patient doesn’t come in for a name. If you came in with a funny melanotic spot on your arm, you don’t so much care whether it’s melanoma or not. You want to know if I can make it never come back and kill you, or not.
All right, now the fact is I usually have to establish whether it’s melanoma. But it’s not the name, per se, that holds your interest. It’s—will this kill me? Can you prevent it? That’s the critical issue.
The same thing’s true for me in aging. The issue for me is not what causes aging, and how does the cascade work. But what can we do to intervene; to prevent age-related disease and suffering.
Dr. Fossel: Now there are an awful lot of people who will start discussions with me about whether or not aging is a disease. Frankly, I don’t think that’s an important issue. Whatever you want to define age-related diseases as, the important issue is, can we intervene in them? For me, aging may or may not be a disease, but it certainly increases your likelihood of having a disease. So the question is, where can we intervene? Given that, my answer usually is, the most effective point of intervention is probably the human telomere—not because it causes aging, but because it’s probably the most effective point of intervention.
If I’m looking at heart disease (actually, atherosclerosis, causing both strokes and heart attacks), which is the major killer worldwide, I ask myself not what causes it, but where can I intervene? There are literally dozens of critical points of intervention—everything from high blood pressure to cholesterol levels, to a number of genetic factors, to smoking, and behavioral effects. But again, while I can intervene in your risk of heart disease by lowering your cholesterol, with say, Lipitor, it may be that a more effective and efficient point of intervention would be the telomere. So that’s my question. Now to answer that question you really have to understand some of the processes. But it’s not the process, per se, that interests me in an intellectual fashion. It’s a totally concrete interest.
Dr. Fossel: I started studying progeria in basically the mid-1970’s. In graduate school I think I used to have the world’s literature on progeria under my bed. I found much more interest when I began to attend the annual progeric reunions for the Hutchinson-Gilford progerics. For me there are two interests here. One is, what can we do for these children? The answer is, not only not much, but to the extent you’ll be able to, it’ll be too late for most of the children that you know. The life span is about twelve and a half years, and that’s a pretty narrow research horizon.
The other question is, what can they teach us about normal aging? I find that the most effective point. The most promising way to look at almost any research question is to ask yourself, where are the outliners? Where are the anomalies? Where are the exceptions? To understand aging I think there’s a certain benefit from just looking at normal human aging. But I think you learn a lot more by looking at organisms that either don’t age, age slowly, age quickly, or age in a peculiar fashion.
Now, the latter two are true of progerics. They age quickly, but they age in a peculiar fashion. Not all of the body seems to age. In fact, you could reasonably ask whether this is aging at all. Is it accelerated aging? Is it aging? Does it tell us anything? I think the answer is, it does. I think what you’re seeing in the arterial supplies in the skin and the joints in the bones reflects, if not real aging, at least something that can offer us a great deal of insight into aging. Whereas, if you’re looking at the immune system, or the nervous system, frankly, there’s very little it can offer us—except, again, as an anomaly. Why is it that the arteries of these children seem to show rapid aging, and the brain cells don’t? Again, it’s the anomalies, I think, that can teach us more than just the routine humdrum process.
Dr. Fossel: To put it bluntly—and again, there’s a certain inaccuracy in saying this, but just by saying it this way, I think it prompts a great deal of both insight and appropriate criticism—I think the answer is that all aging is cell aging. Organisms age, and if you look at an organism aging, what you’re really looking at is organ aging and tissue aging. And if you look at organ aging and tissue aging, you look at cellular aging. The human body is composed of cells, and while it’s appropriate to keep in mind the gestalt involved, the real process occurs not only at the cellular level, but between cells. It’s like looking at society. Society isn’t a thing, it’s a collection of individuals. It’s not only the individuals, but the way they interact. It’s the same thing here. If you really want to understand a society, you want to understand the individuals. If you really want to understand aging, you want to understand how the cells are effected.
Dr. Fossel: The quick answer is that the best way to reset gene expression is to increase telomere length. But the best way to increase telomere length is to use one of three process. One is something that we’re technically capable of now—although we haven’t tried it yet in human volunteers—is to insert a new hTERT gene that’s turned on. That can and has been done in the cells, and has been done in reconstituted tissue.
The second way, which is much more elegant, is simply to turn on and off the existing hTERT gene in human cells. That process has been looked at, and we’re very close, tantalizingly close, but to the best of my knowledge, it hasn’t been accomplished yet.
The third approach would be to put in hTERT. That is, essentially, to put telomerase into the cells, and that was regarded as technically impossible, perhaps, as late as five years ago. Now it looks like it’s probably possible, but, again, to the best of my knowledge hasn’t been accomplished.
If, right now, what I wanted to do was to run a study trying to use telomerase, or telomere maintenance approaches, to correct, say, osteoarthritis, I would try insertion of a new hTERT gene into the cells of human joints. It’s not the most elegant approach, but it’s the process we’re most able to perform right now technically.
Dr. Fossel: The simple answer is both. In the hematopoietic cells in your bone marrow the latter is what happens. That is, you use recurrent and well-controlled telomerase expression to almost maintain the length of your hematopoietic stem cells. This is a very delicate, very carefully crafted process, but the end result is that over the, say, hundred years you might live, you don’t lose much in the way of hematopoietic stem cell potential for division. You more or less maintain telomere length during your entire lifespan. You certainly don’t shorten it as much as would be expected otherwise. Telomerase can not only be used that way, but it can be used to reset or relengthen telomeres.
Dr. Fossel: Certainly to me, I think it’s probably the most interesting and tantalizing approach to controlling cancer now. The reason I say that is that it’s probably the most universal approach. You remember back when I was talking about interventions in aging, and I said the question is, where’s the most effective single point of intervention? With joints, for example, you could replace them, or you can try to use something to control inflammation and so forth. And the same thing in cancer. There are lots of approaches, some of which may be very effective with particular cancers, in particular patients. But if you’re looking for an overall single approach, I think the most promising one is probably control of telomerase expression and function.
Dr. Fossel: I think that you’ll see the first human trials within ten years. Having said that, the telomerase trials in terms of cancer are already in progress now. But if you’re looking at using telomerase to, in effect, control or reverse aging pathology, I think you’ll see the first human trials within ten years. We almost began that about two years ago. We had a donor who wanted to underwrite the whole process, but they pulled out, actually the night before they were to sign the final financial contracts, or we’d probably be in progress now. So it depends. It depends on the market. It depends on people’s beliefs. And it certainly depends on whether this entire approach is accurate or not.
Dr. Fossel: I think the answer to that parallels the question that you would have asked in 1953 or 1952 with regard to polio. What can we do to prevent our children from having polio? And you would get the same sort of answers. You need to have a healthy diet, avoid swimming pools, avoid people with polio, and keep an eye out for other risk factors. This is the same thing that you could have said in, say, 1870, with regard to tetanus. How do we prevent lockjaw (that is, tetanus)? The answers are similar. You certainly want somebody who’s relatively healthy, and avoids skin breaks that are near horse manure and so forth.
But as far as therapy goes for either of those, on those two dates, the answer was pretty dismal. I think the same thing is true of aging. The best you can do is hope to ameliorate your current gene expression. If you want to avoid heart disease as an aging process there is lots of advice I could give you. Your grandmother probably gave you similar advice. Just as your doctor certainly gives you advice now. But the truth of it is, that’s all it does. It ameliorates the risks you have from gene expression. People who have bad genes tend to get bad atherosclerosis. That’s not to say they should smoke and not exercise and so forth. No, they should certainly follow standard, appropriate medical recommendations. But the real answer is, if you want to make a significant change in the outcome of that pathology, you’re going to have to do something more dramatic and fundamental, like effect telomere expression.
Dr. Fossel: They’re closely linked, and you’re right, it sort of depends on what you’re addressing, which one you want to focus on as you’re answering the question. As I said before, my primary interest is the pathology. I’m not interested in wild intellectual discussions about aging and disease. No, I’m interested in people who actually have disease, and where we can intervene. So when you ask questions like that, I tend to magnetically hone back to specific diseases, like osteoarthritis and so forth, and bring it back to what I see as practical intervention, rather than far-flung discussions, like aging in general. But no, in one sense, it’s all one process. Aging and age-related diseases are very entangled with one another.
Dr. Fossel: I think that using the sort of approaches that we’ve been talking about in this conversation we can probably extend the lifespan well into the several century range. Could be more. My usual answer to that is the human lifespan becomes either indeterminate, or as you might say, indefinite. Again, I don’t mean by that infinite. I simply mean it’s indefinite. It’s hard to say. I don’t know any way to get a firm grasp on that question. You could say several hundred years, as I just implied, but I say that to stress that we’re not dealing with just an extension of two or three years of lifespan, and partly to say that I don’t know how you can reasonably talk about several thousand years. But I want people to understand that it’s a significant change. The prospects are enormous, as are the implications of it in all regards, socially and otherwise.
Dr. Fossel: I think that the major, single advance that’s been made in the last ten years really has been to show that we can reverse aging in reconstructed human tissues. In 1996, we showed that we could prevent or reverse aging in individual cells, but that was in limited cases. Since that time not only has the work on cell types expanded, but we’ve shown that you can reverse aging in reconstituted human tissue. The next step we want to take would be to look at other tissues, and more importantly, a whole body approach.
The tissue that’s been looked at already has been human skin. Putting this in its simplest form, what has been shown is this. If we use young cells we can grow young skin. If we use old cells we can grow old skin. But if we take old cells and telomerase them, we can now grow young skin. So the argument that things just fall apart, that’s the way it is and they can’t be fixed, is not only wrong at the cellular level, but it’s wrong at the tissue level. That doesn’t prove that we can use it clinically, but it does prove that the blanket assertion that aging can’t be changed or reversed is simply wrong, at least with regard to a couple of tissues that we’ve looked at. So that’s very promising.
Dr. Fossel: Yeah, let me give you this, just because I suppose it interests people. Sometimes people ask me—and you sort of got at this, but you didn’t follow up—when will we reverse human aging? That’s it asked in its most bald-faced sense. It’s like asking, are we interfering with God’s will? People like to ask these things. When will we reverse human aging? The answer to me is kind of interesting. If you had asked me, when did we step on the moon, we can answer to the second. In fact, with a little research, we can answer to the millisecond, as close as you want, even allowing for the time delay between here and the moon.
If you asked me, when did we cure polio, the answer gets curiously slippery, and yet definite. If I ask most people on the street they’ll say, well, it was 1954 wasn’t it? And they’re very right. That’s when the commercial vaccine was released, then taken back, and then released again, at least in the U.S. But if you asked anybody who has a little more knowledge, they’ll first point out immediately that we haven’t cured polio. It’s still around in this world, and we have high hopes.
They might also go on to point out that in the theoretical, or the research sense, we cured polio sometime in the early 1950’s, before the release of the vaccine, because that’s when we (meaning Salk) first had a grasp of how things worked in polio. So, in a conceptual sense, we cured polio in 1951 or '52 perhaps. But leaving that aside, one, you notice it’s really hard to pin it down, and two, probably the best we can do is ask the man on the street, and that’s not a bad way of asking the question, as long as you understand limitations.
The same thing pertains here. If you ask, when will we reverse human aging, there’s no way we could answer anyway. Even looking back from the future, I think you wouldn’t be able to answer it anymore than you can about when we cured polio. But what you could do, is you could go forward a hundred or two hundred years and poll the person on the street, and say, when do you think we reversed human aging? I think that if you took the mean of those answers, in the same sense that polio was “cured” in 1954, that the answer will be a date sometime in the next decade.
David Jay Brown is the author of four volumes of interviews with leading-edge thinkers, Mavericks of the Mind, Voices from the Edge, Conversations on the Edge of the Apocalypse, and Mavericks of Medicine. (Mavericks of Medicine will be published by Smart Publications as a book in late 2006.) He is also the author of two science fiction novels, Brainchild and Virus. David holds a master’s degree in psychobiology from New York University, and was responsible for the California-based research in two of British biologist Rupert Sheldrake’s bestselling books on unexplained phenomena in science: Dogs That Know When Their Owners Are Coming Home and The Sense of Being Stared At. To find out more about David’s work visit his award-winning web site: www.mavericksofthemind.com.