JOURNAL OF ANTI-AGING MEDICINE

Vol. 6, No. 4, pp. 285-291 (2003)

© Mary Ann Liebert, Inc.

Organizational Profile

Gerontology Research Group

L. Stephen Coles, M.D., Ph.D., is the Director and a co-founder of the Gerontology Research Group in Los Angeles. He is a stem-cell researcher in the Department of Surgery at the UCLA Geffen School of Medicine. In addition, he has organized a lecture series in gerontology for the past 12 years. He formerly taught Computer Science and Artificial Intelligence at UCLA, the University of Southern California, and the California Institute of Technology. Previously, he taught at Stanford University and at UC Berkeley, where he introduced the first graduate course in robotics in 1973. He received his bachelor’s degree in electrical engineering from Rensselaer Polytechnic Institute in Troy, NY, pursued graduate work in mathematical statistics at Columbia University, and received an M.S. in mathematics and a Ph.D. in systems and communication sciences from Carnegie-Mellon University. Later, Dr. Coles attended Stanford Medical School and did his Clinical Internship in Obstetrics/Gynecology at the University of Miami Jackson Memorial Hospital. He is a founding member of the JAAM Editorial Board.

Dr. Coles, please provide a brief historical perspective of the Gerontology Research Group (GRG). When and how was it founded and what were its initial mission and goals?

    Dr. Steven Kaye, M.D., and I co-founded the GRG during the spring of 1990. We met once a month for about six months in each other’s homes and along the way wrote a Charter, or Mission Statement, for the group, describing what we wanted to see done in our lifetimes in the field of Anti-Aging Medicine. We kept adding to our list based on what we knew might become possible someday. Steven was a family physician in private practice who, at that time, owned a series of clinics in the Los Angeles area. Then a third person joined us, Dr. Robert Nathan, Ph.D., from the Jet Propulsion Lab (JPL/CalTech), who was also interested in

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L. Stephen Coles, M.D., Ph.D.

Co-Founder, LA-GRG

experimental gerontology and attended our monthly meetings for another four or five months. A fourth member, Bernard L. Strehler, Ph.D., Professor of Biology at the University of Southern California, then joined our group. Soon, Steven Harris, M.D., from Roy Walford’s team at UCLA, joined us. From there, the group rapidly expanded to about 15 regular members.

    We started asking extremely detailed questions about what we thought would be feasible within what time frame, recalling that we wanted to achieve something useful in our own lifetimes. We quickly realized that, as a group,

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we did not have enough information, so we contacted two graduate students of a well-known Professor of Chemistry at CalTech to give us a lecture on their research involving the direct sequencing of DNA using an Atomic-Force Microscope. We suspected that if we better understood DNA sequencing, we would be on a critical path to understanding the future of Anti-Aging Medicine. That talk, in January of 1991, was our first formal lecture, and since then we have had at least one lecture per month for the past 12 years (including Summers) — 154 lectures and still going strong! In retrospect, our presenters have included world-famous researchers in gerontology. We videotaped each lecture and now have an extensive library of VHS tapes. Over the years we have also taken a half-dozen field trips to look at different labs (including some now-defunct clinics in Mexico).

    In recent years, our lectures have been mostly held in a standard lecture hall at the UCLA Medical School, but at least once a year we meet at CalTech and at USC. For any given lecture, 15 to 20 persons typically attend. About half the lectures are clinical in nature, while the other half focus on the basic sciences (or sometimes on engineering instrumentation), in which we talk about the chemistry and physics of molecular processes in the body. About half of our members are Ph.D.’s and about a quarter are M.D.’s. After each lecture, I generally review the latest news developments in gerontology and medicine.

    Today, the Los Angeles Gerontology Research Group consists of about 160 members: we have also founded Chapters in other cities, such as Washington, D.C. and New York City. About six years ago, we established a website (www.grg.org) which is filled with various sorts of resources for teaching gerontology, including “Breaking News” and “Editorial Opinions,” particularly about stem cells. It contains a master list of all of the previous lectures and summaries of the backgrounds of the lecturers. More recently, we have established a Gerontology Discussion Group associated with the GRG (a sort of loosely moderated Internet Chat Room) that has over a hundred members worldwide. It is impossible to predict when I might say something quite innocently, such as, “Aging should no longer be thought of as a disease,” and that

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could result in a five-week multi-part discussion with many sub-threads running in parallel. Although there are a number of frequent contributors to these discussions, most subscribers remain as quiet observers with what I suspect is amusement or bewilderment while these intense discussions are taking place.

    We wrote the original Charter for our organization in the Fall of 1990. We have modified it slightly, with the consent of the members, maybe ten times over the past 10 years, but only to dot an “i” or cross a “t” here and there. There have been remarkably few changes made in emphasis and only occasional insertions of new jargon as it becomes fashionable; otherwise, the basic mission of the GRG remains the same as it did a decade ago — to discover the technical means for intervention in the human aging process within our lifetimes.

How does the group go about meeting those goals?

    One of the continuing interests of the group is to authenticate cases of the oldest humans in history, the population of so-called Supercentenarians (persons greater than 110 years old). We publish the most current list of living Supercentenarians on a bimonthly basis in this Journal of Anti-Aging Medicine. In 1998, we began to compile and publish this list on our website. We also maintain a photo gallery of over 100 pictures of these individuals, which are sent to us as E-mail attachments by interested relatives and nursing- home administrators.

    Our interest in this population began when we established a collaboration with the Chairman and Co-Chairman, located in New York and Atlanta, Georgia, respectively, of the International Supercentenarian Committee. This Committee consists of approximately 30 demographers and epidemiologists with representatives in each major country of the world. We communicate, seven days a week, almost exclusively by E-mail. We strive to maintain the list of Supercentenarians as accurately as possible. In order to create our database of the world’s oldest people, we established rigorous criteria for entry. Many unscrupulous individuals

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(or their friends/family members) have claimed to be very very old while, in fact, we regularly uncover fraudulent claims — people who have tried to get into The Guinness Book of Records, for example, as being acknowledged as the world’s oldest living person. Sometimes there is a more mundane motive, such as having avoided military service when they were younger. A young man could sometimes impersonate his father, if he had the same first and last name, and could use his Birth Certificate and/or Passport. Because old age is venerated in some cultures, there was no incentive to switch back at a later time. But such claims are obviously invalid, and we have taken it upon ourselves to do the investigative work to identify and expose these fraudulent cases whenever we can.

    In order to be included in our official database, a person needs to have at least three independent sources of documentation: a Birth Certificate, Baptismal Certificate, or Marriage Certificate; consistent US Census records dating back to 1900; and some other photo identification, such as an old driver’s license. A handwritten entry in a family bible is not sufficient. We have even seen one case in which a person’s birth was recorded in a family bible, but the bible was not even published until four years after the stated birth date! We include persons from all over the world, so a lot of our documentation is in various foreign languages, and we therefore require country-specific translators. All of our committee members offer their services on a volunteer basis. We have representatives in many countries, including all of the major European countries, Mexico, Canada, Japan, and Australia. Although we do not yet have anyone in China or India, we are actively working on that and hope to have new members from these countries before next year’s end.

    We routinely collect and scan into our database all of the documents we require. We record the person’s full name (maiden and married), birth date, the country or state (in the U.S.) where they were born, the country/state where they currently reside, and the name of the committee member who was responsible for endorsing the validity of the documents. Thus, we have become a de facto world authority on the

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authentication of Supercentenarians, without ever planning to take on such a role. As a result, we are regularly contacted by historians and journalists. We have discovered that there are a large number of obituary columnists in every city in the U.S. who write the human-interest side of obituaries of persons who have lived for an unusually long time, not just those who lived in their local area. Today, when one of our Supercentenarians dies, we get calls from the major wire services (AP, Reuters, etc.) and from journalists all over the world who want to know whether this individual was really the age that was claimed by their family. The Guinness Book of Records now cites us, as well, as a world authority for this type of factual information.

Do you collect any types of information related to family history or medical history, or solely demographic data?

    So far, the database we publish on our Internet website contains strictly demographic data, along with statistical tables of interest to epidemiologists. For example, we recently got a call from a physician with the Social Security Administration who wanted to know how to cut down on fraud from within their own database by calculating the probability that someone in the US of a given claimed age was likely to be alive. Ultimately, however, we hope that this data will become a resource for exploring scientifically interesting questions about what these very old people have in common. When I interview the Supercentenarians who live in the U.S., I systematically videotape the interviews and try to learn everything I can about each person’s family history, their medical history, their lifestyle, nutrition, exercise, occupation, religion, etc. Based on the information we have gathered, I can safely testify that these people have virtually nothing in common, other than their parents having lived a long time (if they did not die of a traumatic injury or in a flu epidemic); however, their spouses generally do not. We can say that their siblings

(and their children) tend to live a long time as well. So there is something going on in the genes that could explain the inheritance of longevity, but we do not know what that is yet.

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    When people ask us what they themselves can do to live a long time, the answer is “the dice were already rolled when your genes were determined by your parents.” Many of our Supercentenarians lived what we, today, would call an “unhealthy lifestyle.” One woman who smoked heavily most of her life, and whose doctor had told her over and over that smoking was bad for her, continued to smoke because she liked to. She was also fond of pointing out that she had outlived several of her doctors.

     One of the more humiliating conclusions that I can share with our physician readers is that, as a profession, physicians have virtually no claim to being able to extend the maximum human lifespan, even though they certainly do regarding the extension of average life expectancy (for the population as a whole). Obstetricians, pediatricians, infectious disease specialists, and public health practitioners as a group do have an important claim, as they collectively have added nearly 30 years to the average life expectancy at birth over the last century, and tripled it since Roman times. But doctors in general are helpless in the face of maximum lifespan, since most of the Supercentenarians in our database never saw a doctor until they were 90, especially those who were born in rural areas. They never needed to, because they were always so very healthy. They had no “weak link,” so to speak, in their physical makeup. Also, they never did anything risky enough to cause themselves to be “taken out of the game” by repeated traumatic injury. Thus, it is very complex to try and predict what component of your personal lifestyle will help you to live an extremely long time, once you state the obvious precautions, such as “wearing a seat belt.”

    But this does not invalidate in any way the routine recommendations that doctors and dentists make when they tell their patients to exercise, floss their teeth, take vitamins, not smoke, be scrupulous about not over-indulging in alcohol, and so forth. We do see clear lifestyle differences in longevity in laboratory studies with mice, which are our close cousins as mammals. However, people who are lucky in their genetic makeup can get away with a bad lifestyle (including smoking and drinking heavily) and still live a long time. I would like

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to make it very clear that they do not live a long time because of smoking and drinking heavily. No doctor should recommend that you follow the lifestyle of Supercentenarians in order to try and emulate them. That may be a tempting, seductive trap; the real secret lies in their genes and in not inheriting a “weak link.”

    If we are going to learn anything about the inheritance of super-longevity, we are going to have to identify the genes that control the aging process itself. Chromosome 4 seems to be an attractive candidate, but a cholesterol-aggregation gene recently discovered by researchers in New York looks promising. Formal medical studies are underway in the Boston area, where one of our colleagues, Dr. Tom Perls, Director of the New England Centenarian Study, is actively tracking about 150 centenarians. His group includes only one Supercentenarian. By contrast, the GRG has chosen not to track people who are “merely” 100 years old, simply because there are literally hundreds of thousands of them.

    The next goal of the GRG is not only to gather historical biomedical information, but to do a standard blood-chemistry laboratory analysis. Ultimately, we will need to perform a routine DNA analysis. The cost of DNA sequencing is still too expensive today, but in

about five years, the price will come down to about $1,000 per patient. That will be a reasonable target, enabling us to apply to a medical foundation or the NIA for a grant to allow us to preserve tissue samples and do DNA sequencing on the people included in our database.

    I am embarrassed to admit that we do not even have standard autopsy data on the people in the database. Typically, the family is not predisposed toward having a formal autopsy performed. Basically, from their point of view, their relatives are going to die of “old age,” and the families see no need for further obscure medical details. Furthermore, there is typically no forensic basis for doing an autopsy. Nevertheless, the GRG would like to know which tissues, like the hair cells from the inner ear or the rods-and-cones of the retina, age more rapidly on average; we should be able to learn a great deal of medically useful information, since many of these people are blind or deaf or both.

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What has been the source of funding for your organization?

    All of the work is done on a volunteer basis. We have taken in some small tax-deductible donations over the years, in the range of a few hundred dollars. However, we have not yet been able to obtain a grant of the sort that we would need to do the types of studies described above. Without any funding, though, we have been able to create the database, which is proving to be a valuable statistical resource in itself, due to the dedicated efforts of our volunteer committee members.

How did you become interested in the field of aging?

    I have taken it upon myself to become a self-appointed custodian of all aspects of Anti-Aging Medicine. I spend almost all of my time doing theoretical studies and analysis, rather than bench-style laboratory research. My primary interest is in stem-cell biology, because that is where I believe the future payoff will be. In my opinion, if you were to list the things that gerontologists study today in the laboratory, I believe that someday you will be disappointed to discover that it was all largely irrelevant.

    I attended a major International Conference on Gerontology (IABG-10) held at Cambridge University at the end of September. The conference was organized by Dr. Aubrey de Grey, who is a fellow member of the Editorial Board of this journal, and who contributes original articles on a regular basis. Aubrey hosted about 270 people from 27 countries for a four-day meeting that was the most wonderful gerontology meeting that I have ever attended. There were presentations by world-famous scientists covering almost every aspect of gerontology. I have to admit, though, that, in my opinion, almost all of the technical information presented was essentially useless, because it will soon be deemed obsolete. We are all like the famous blind men who are trying to feel the true shape of an elephant without a clue as to what the beast really looks like.

    I would like to propose what I believe to be an even better metaphor than the mythological blind men and the elephant — that of a doctor trying to save the life of a pregnant woman who

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has just given birth to a normal baby and is now suffering a life-threatening hemorrhage. She is losing blood so fast that she will surely die unless she gets a transfusion quickly. This was a real problem for doctors in the 1700s, who witnessed such events with great regularity and were helpless to do anything about it. In the early 1800’s, someone thought that maybe doing blood replacement could be useful. At Oxford University, members of the local Philosophical Society (philosophers, it seems, were more empirically active in those days) discovered that if you replaced the blood of a dog with the blood of a second dog, sometimes the recipient dog would turn out to be fine and would recover fully. But sometimes the dog would die almost immediately of shock. They did not have a clue as to why this happened. They reasoned, however, that maybe if it worked sometimes, it would be worth trying in humans. So a British doctor tried this procedure in the case of a woman who gave birth and then began to hemorrhage. They used the blood of her husband (for want of a better volunteer donor) to replace some of the lost blood of the mother following childbirth. When the results were in, after multiple attempts at blood replacement, some of the women got better and wound up perfectly healthy, while in other cases, the procedure failed catastrophically and the women died. The delivery doctor had no clue as to why the procedure worked sometimes but not others. (A lack of understanding of the absolute requirement for sterile technique was an important factor that contributed to the long-term failure of the procedure, even if you the physician was lucky enough to have a good “cross match,” which happens about half the time just by chance, depending on the distribution of the ABO types in the local population). Finally, laws were passed forbidding the use of transfusions for human patients in virtually every western European country. In retrospect, given the deplorable state of our knowledge, such prohibitions were not unreasonable.

    Then, around the year 1900, a discovery was made, which was published in German in an obscure medical journal but finally translated into English in New York about the year 1910. The medical appreciation of this discovery of

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blood compatibility led to our initial understanding of the ABO blood-typing system. During World War I, it became very important to learn how to do transfusions quickly, efficiently, and under non-sterile battlefield conditions. Today, we do transfusions routinely. During the relatively short span of 200 years, we went through a transition from not knowing anything about how to do a transfusion safely to being able to do it routinely. In fact, we would now charge a doctor with medical malpractice if he/she did not do it correctly! The ability to understand the ABO system back in the early 1900’s required having an appreciation of events that were taking place at a microscopic/molecular level. There was no way to solve the problem without that knowledge.

    Today, I believe that we in the field of gerontology are in a similar situation. We find ourselves in circumstances similar to the surgeon in 1800, who was trying to figure out if the husband’s blood would work. There are things that we just don’t know. In the 1800’s, some “experts” I am sure proposed that the secret to success lay in the “color” of the blood, whereas others suggested the “taste,” and a third group probably claimed that it was the “smell.”

    At the Conference this past September, many different groups argued passionately that they had the answer to aging. Unfortunately, we don’t know what it is that we don’t know. One of my missions is to educate people about what we don’t know, how close we are to knowing what we don’t know, what we should still try to know, and what we should forget about trying to know because it is just not going to happen in our lifetimes. We need to make judgment calls about how to spend scarce resources to figure out the things that are currently unknown. We need to decide what we need to know to carry out our mission and what could be knowable in the next five to ten years, assuming the proper expenditure of resources. This brings us to the topics of the genetics of aging and stem cells. That is where I have focused my personal resources and effort.

    I first became interested in gerontology during the Summer of 1960. I audaciously formed an organization, with three other friends, to study Anti-Aging Medicine. We optimistically wrote many white papers.

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We wrote to Sir Arthur Clarke for his advice, and he wrote back from Sri Lanka wishing us luck. That organization has not really had an independent existence, but that is when my interest began. I have attempted to build up a perspective on what people have tried and not tried, and what has worked and not worked. My final analysis is that we are going to have to do an experiment that has never been done in nature before in any species — to allow stem cells to become active in the context of an adult body, whether it be in a dog, a cat, a mouse, or a rat. We have to perform this experiment in order to find the signals that turn on in situ stem cells in the adult body — stem cells that will allow the regeneration of new tissue, whether that be a new liver, pancreas, kidney, lung, heart, brain, etc. Nature has never done this in an adult. Only during embryogenesis does nature fabricate brand new organs. We are presently unable to turn on adult stem cells and have them create de novo organs in our bodies.

    The first doctor who tries this experiment and does it badly will find that he or she may have created a teratoma, a tumor that occasionally forms in the body in which a new embryo develops in an ectopic place. When you remove a teratoma surgically, you will find every tissue-type represented (bones, hair, teeth, and so forth), with all of the tissues mixed up, randomly, in a confused pattern. The normal architecture of the tissue has been obliterated. The worst thing one could possibly imagine would be the creation of thousands of teratomas while we are really trying to rejuvenate tissues.

    We need to learn how to stimulate adult stem cells throughout the body to recapitulate organogenesis in the context of adult tissues. That is, we want to rejuvenate existing tissues while preserving the architecture of adult tissue. To be able to do this, we need to find the cytokines that turn on our adult stem cells. Stem cells are essentially ignorant — they seem to become activated only when an injury occurs. This ability of the body to heal itself as a result of an injury is largely due to the presence of stem cells in the tissues. The stem cells are there, waiting for the time when they are needed to take care of a potential problem. However, if I were to cut your arm off, you

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would not be able to grow a new arm. A salamander, on the other hand, is able to grow a new tail. It is that secret in salamanders vs. humans that we need to understand. We need to identify the molecules that turn on such stem cells.

    I predict that within the next five to ten years we will have compiled a complete catalog of all the signals for both embryonic and adult stem cells; we will have identified and characterized all of the cytokines that turn them on. We will then be able to stimulate a stem cell to become any particular type of tissue at will in situ. Adult stem cells are present, mostly in the bone marrow, waiting for the proper commands to trigger them to migrate and differentiate into specific types of tissues.

    We need to learn not only the signals that turn them on, but also the signals that turn them off. Our immediate goal in Anti-Aging Medicine is to learn the full set of commands needed to regulate the adult stem cells that are already present in our bodies, while avoiding the predicament illustrated in the story of The Sorcerer’s Apprentice. The apprentice knows just enough to be dangerous. He can turn things on, but he needs the help of the sorcerer to stop a runaway process that could get out of control. The commands are all there, written in the “Book of Life,” a text composed of the letters “A,” “T,” “C,” and “G,” otherwise known as DNA. We do not have to invent any new commands. We just need a Rosetta Stone to read the language. So, let’s get reading!

Thank you, Dr. Coles

—Interview by Vicki Glaser

NOTE ADDED IN PRESS:

    After this interview was conducted, Dr. Coles was appointed General Chairman of the Program Committee for the Primedia Annual Conferences on Longevity Medicine to be held in Miami, FL in September 2004 and Las Vegas, NV in October 2004. Visit the Committee’s website for further details at www.antiagingconference.com.