EDITORIAL

Father of the Free Radical Theory of Aging

Longevity Theorist
Denham Harman Dies


His paradigm shifting ideas live on!

W ithout Dr. Denham Harman’s work, it is unlikely that the nutritional supplement industry would exist, or certainly not as we know it today. That’s because the concept of antioxidant nutrients grew out of Dr. Harman’s work. He asserted that antioxidant enzymes naturally produced by the body destroyed most free radicals—highly reactive molecules freed in the normal chemical processes. However, when the ­supply of antioxidants was ­insufficient, Dr. Harman speculated, the resulting cell damage triggers a cascade of events that leads to disease and death. Thus, he proposed treating aging and disease by taking antioxidant supplements.

Tomorrow You May Be Younger

Back in December of 1945, Dr. Harman—already a PhD in organic chemistry—first became interested in aging because of a paper that his wife drew to his attention.1 Written by the William Lawrence, who was the science editor of the New York Times, the paper was entitled “Tomorrow You May Be Younger,” and it was about the work of Dr. Alexander Bogomolets at the Gerontology Institute in Kiev, Russia, where he was investigating something called “antireticular-cytoxic serum.”


“I thought, thought, thought for four
months in vain and suddenly the idea
came” — Denham Harman


Bogomolets thought that the aging process and disease states could be related to the functional deterioration of the reticulo-endothelial system.2 If this system could be stimulated by means of specific cytotoxic sera, then general health would be improved, degenerative disease prevented or delayed, infectious disease more quickly overcome, and life prolonged. He inferred that antireticular-cytoxic serum would merely help the body help itself by stimulating the natural resistive and protective functions of the body. His theory proved to be wrong!

Upon reading Lawrence’s paper, Dr. Harman decided that in order to pursue the subject he needed to have a biological frame of reference. So he went to medical school at Stanford, eventually adding an MD to his PhD.

The Time to Look at the Aging Problem

After his internship as a doctor ended in June of 1954 Harman became a research associate at the Donner Laboratory of Medical Physics at UC Berkeley, where according to Harman,

At [UC Berkeley] I had time. So I decided to look at the aging problem. I felt number one that there had to be some common, some basic cause, which is killing everything. We all go through this cycle of birth, aging and death. Everything dies, not just you and I and other humans. Bacteria, everything, nothing lasts forever. And second, I figured there had to be some basic cause that was subject to genetic changes because we all know that both genetics and environment have some influence.1

And unstated is the fact that this is a chemical process of some kind. Since we’re dealing with molecules, chemicals … This is the simple basis in which we all exist.1

It Was Just Like Looking for a Needle in a Haystack

I had a lot of chemical background, almost 15 years in the chemistry laboratories of Shell Development Company.1

Dr. Harman joined the reaction kinetics department of Shell Oil in Emeryville, California immediately after earning his Ph.D., in 1943. He worked for six years as a Shell research chemist, in part studying free radical reactions in petroleum products. While working at Shell, his research produced 35 basic patents, including a compound to kill flies [“Shell No Pest Strip”].

… And I [continued] to look [for the cause of aging]. And I couldn’t come up with anything. It was just like looking for a needle in a haystack. I had some ideas but they led nowhere. I needed something, which was common to everything. I kept looking and I got more and more frustrated because nothing added up.1

I Just Could Not “See” the “Cause” of Aging

I spent my time sitting in front of the desk reading and thinking. Just like today there was a great amount of material on aging back then. In spite of the fact that I had just finished a superb course in biology, medical school and an internship, and the years I had spent as a chemist, I just could not “see” the “cause” of aging.1

I Was Getting Ready to Call it Quits

Oh, I wouldn’t have gotten anywhere without it [his chemistry background]. Anyway, this went on for four months; I was getting ready to call it quits, and I thought maybe I had made a mistake; maybe we didn’t know enough to put the information together; maybe we were just missing something. I didn’t know, except that I knew that I was just about out of everything. Nothing came up. It’s kind of hard to convey the feeling of frustration. Just all this background and I can’t figure out the answers!1

All of a Sudden the Phrase “Free Radicals” Crossed My Mind

I was sitting at my desk one morning … and I was sitting there reading. All of a sudden the phrase “free radicals” crossed my mind. You know just “out the blue”. I’m sure you’ve had the same experience working on a problem in chemistry, math, physics, you can work on it but you don’t “see it”, until you drop off to sleep at night; then you may have an answer, get up and write it down.1

According to Harman, he thought from July 1st, 1954 to November 9th 1954. For such an extended period, he had never spent that much time on any one thing in his life!

The Free Radical Theory of Aging

I couldn’t see it! I thought, thought, thought for four months in vain and suddenly the idea came. Everything had to fit all this background data. All I knew about chemistry, what I knew about biology, diseases and so forth, and from bacteria on up. And I was still looking for one thing, and that’s when free radicals occurred to me. I didn’t understand all the details, but I knew that free radicals could cause aging. Free radicals cause random damage, and depending on the type of radical, they can cause all kinds of damage from day one.

Anyway, this was the one thing that could fit everything, but just how it did, I didn’t know. And that’s when I started looking, and when I started looking I could see it. I spoke with some of the people at [US Berkeley], and they said, “Yes, well maybe”. The first part of December 1954, I walked around the Berkeley campus and spoke with quite a few very knowledgeable people, and said what do you think. And they said, “well, it’s a nice idea but it’s too simple to account for aging.”
1

Was the Theory Wrong? Did I Miss Something or What?

Following his conceptualizing of the Free Radical Theory of Aging and extensive experimentation, Dr. Harman had expected both of them, mean and maximum life spans to be increased in his continued animal experiments.

The Mitochondrial Theory of Aging

So, I came to a halt for quite a while, I couldn’t figure out what was going on. I eventually wrote a paper that was published in the May 1972 issue of the Journal of the American Geriatric Society. It was a short paper entitled, “The Biological Clock: The Mitochondria?” In this I basically said, the mitochondria determine how long we live because it’s the free radicals produced by the mitochondria that cause the trouble. This is the basis of the “Mitochondrial Theory of Aging.” I was just plain lucky, I hit two things. This paper was expanded in 1983 in the Journal AGE, “Free Radical Theory of aging: Consequences of mitochondrial aging.[3]1

It has now been over 45 years since his path-breaking hypothesis of mitochondria as a key element in the aging process, requiring the development of free radical chemistry, hormesis, the human genome, and more in order to reach the substantial support required for the Nobel. To date, Dr. Harman has been nominated for the Nobel Prize six times, but he never received it.

Dr. Harman theorized that free radical reactions were also common to the chemistry of living organisms. It was not until researchers developed electron scanners capable of testing that notion in the 1980s that his hunch was proved correct.

By the 1990s, researchers were drawing many of the same connections that Dr. Harman first identified in 1954 — between free radical cell damage and the aging process, in particular the early stages of atherosclerosis, cancer and chronic conditions like sagging skin, bone breakage and memory loss. Those at the highest risk for that kind of cell damage, they found, were people whose diet was low in fruits, vegetables and other foods containing high levels of vitamins E and C and other antioxidants.

Free-radical reactions are implicated in as many as 80 disorders. These “free radical diseases” include cancer, heart attacks, strokes, rheumatoid arthritis, cataracts, and Alzheimer’s disease — the major cause of admission to nursing homes. The list keeps growing.

Following His Own Advice

Beginning in his 60s, though, Dr. Harman followed his own advice and took large doses of vitamins E and C and other antioxidants. He also jogged two miles a day until his mid-80s and followed a diet high in antioxidant-rich fruits and vegetables.

“Accept the fact that you’re not going to live forever,” he said. But consider the possibility, he added that, “if you work at it, you might make 100.” He nearly did.

Quotes:

Dr. Harman is a true genius. Unfortunately, much of his research was too early to be appreciated. He was too far ahead of his time.

— Richard Passwater1

Dr. Harman created a paradigm shift not only in how we think about aging, but also in the understanding of several chronic diseases. It is not possible to pick up any major text on aging or on chronic disease without reading about free radicals. He was among the most influential scientists of his generation and had a major impact on research in aging, cardiovascular disease and cancer. All of us at UNMC [University of Nebraska Medical Center] should feel honored to have been associated with him. As a scientist and as a wonderful person, he will be greatly missed.

— Jane Potter, M.D., Neumann and Mildred Harris Geriatrics Professor and division chief of geriatrics at UNMC4

If we are able to extend human lifespan it is only by standing on the shoulders of giants like Dr. Harman … Dr. Harman embodies the best of American scientific pursuit, having made seminal contributions to knowledge and giving generously to students and to the wider community.

Dr. Harman is one of the most influential scientists of the past 50 years, bringing world-class science to what was once a backwater of biology. His Free Radical Theory of Aging is a cornerstone of the aging field. He has inspired thousands of young scientists to work on aging, including myself.

— David Sinclair, Ph.D., professor at Harvard Medical School and a leading expert in aging who gained notoriety for his discovery that resveratrol, a compound in red wine, activates a protein that promotes health and longevity in animal models.4

Dr. Denham Harman is one of the true pioneers of aging research. The free radical hypothesis has been a central element of the field ever since Dr. Harman’s landmark paper. Beyond his own work and continued exploration of the free radical hypothesis, Dr. Harman’s contribution to science has helped lay the foundation for important, related areas of inquiry such as the mitochondrial and DNA damage hypotheses. We can trace the field of stress response, its role in aging and the significant inroads provided in understanding metabolic syndrome back, in significant measure, to Dr. Harman’s work as well.

— Richard Hodes, the director of the National Institute on Aging4

Dr. Harman’s Free Radical Theory brought needed perspective to the differences in species’ life span regarding protection against these processes, and it offered testable hypotheses regarding interventions. As my career in aging expanded past my graduate training, it was most gratifying to finally meet Dr. Harman in person at various scientific meetings. It was even more delightful to discover the warm and inviting person behind this great intellect. He was so supportive and encouraging of young investigators and would gladly discuss issues in the biology of aging. Through the force of his science and his leadership of the American Aging Association, Dr. Harman created an enduring legacy which will stand strongly through the years.

— Donald Ingram, Ph.D., professor, Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, Louisiana State University System

Denham’s contribution to both the understanding and the eventual medical control of aging cannot be overstated. His original free radical theory of 1954 and his incredibly prescient extension of it to mitochondria in 1972 were among the foremost theoretical contributions to our field in its century-long history. Equally momentous has been his stout defense of the view that biogerontology’s ultimate goal is the elimination of age-related physical and mental decline, even in the decades when such a position was viewed as politically suicidal. Without him as a role model, I seriously doubt that I would have had half the success in this field that I have.4

— Aubrey de Grey Ph.D., biomedical gerontologist, chief science officer of SENS Research Foundation, Mountain View, Calif.

Denham Harman is the visionary who saw the connection between radiation-causing free radical oxidative damage and premature aging, and free radical by-products of mitochondria in normal metabolism contributing to the aging process. I am one of the many scientists who have followed in his footsteps. We celebrate his pioneering vision.

— Bruce Ames, Ph.D., professor of molecular and cell biology at the University of California, Berkeley, and senior research scientist at the Children's Hospital Oakland Research Institute4

Dr. Harman believes the healthy active human lifespan can be increased 5 to 10 or more years by keeping body weight down (at a level compatible with a sense of well-being), while ingesting diets that are adequate in essential nutrients but which minimize free radical reactions in the body. Such diets would contain increased amounts of substances such as alpha tocopherol (vitamin E), ascorbic acid (vitamin C), selenium, and the effective natural antioxidants present in some foods like fruits and vegetables, as well as one or more synthetic antioxidants.

— Ward Dean, MD, Medical Editor, Life Enhancement

One potential Nobel prize winner who immediately comes to our minds is Dr. Denham Harman, particularly for his free radical theory of aging (1954) extended to the mitochondrial theory of aging (1972). As Dr. Harman is now in his 90s, he may very well be one of those who will miss out on a Nobel Prize simply because his work involves a very complex subject; it has now been over 40 years since his pathbreaking hypothesis of mitochondria as a key element in the aging process, requiring the development of free radical chemistry, hormesis, the human genome, and more in order to reach the substantial support required for the Nobel.

— Durk Pearson & Sandy Shaw5

We are writing to express our gratitude to you [Dr. Harman’s son, Robin Harman] for letting us know of the passing of your father Denham Harman. While we are greatly saddened by his passing, it is good to know that he was able to remain in good health (except for being hard of hearing) until the age of 99. Denham was one of our heroes as a scientist of the highest caliber and having the qualities of the finest scientists along with the intellectual courage to go where the data led him rather than to supposed consensuses that reflected politics not science. Despite the controversy surrounding the free radical theory of aging (unsurprising in such a complex phenomenon—in fact there really isn’t any theory of aging that isn’t to some extent controversial), it is a testament to its scientific vitality that even after 60 years, it is still discussed as a serious contribution to the understanding of aging. Had we been on the Nobel Prize committee, we would have thought him eminently qualified to receive a Nobel Prize in medicine for free radicals have become well accepted as major factors in a large variety of age-associated diseases, including cardiovascular disease, cancer, and diabetes, even if not fully accepted as the major cause of aging itself.

— Durk Pearson & Sandy Shaw6

References

  1. Harman D, Harman H. “I thought, thought, thought for four months in vain and suddenly the idea came”—an interview with Denham and Helen Harman. Interview by K. Kitani and GO Ivy. Biogerontology. 2003;4(6):401-12.
  2. Bogomolets, A. A.: Antireticular Cytotoxic Serum as a Means of Pathogenetic Therapy. Am Rev Sov Med.1943;1:101.
  3. Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145-7.
  4. O’Connor T. Denham Harman, M.D., Ph.D., left legacy of discovery. University of Nebraska Medical Center Newsroom. November 26, 2014. http://www.unmc.edu/news.cfm?match=16111. Accessed: January 4, 2015.
  5. Pearson D, Shaw S. One Requirement For the Nobel Prize: You Have to Live Long Enough to Receive It. Life Enhancement, July 2014 in The Durk Pearson & Sandy Shaw Life Extension News Volume 17 No. 6 • July 2014.
  6. Personal correspondence. December 18, 2014.

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