Denham Harman, M.D. -
Father of the Free Radical Theory of Aging Looks Ahead
by Franklin Cameron

Denham Harman, M.D., was honored with the National Nutritional Foods Association's (NNFA) 1998 Burton Kallman Award, which was presented July 15 at Marketplace '98 in San Antonio during the group's annual business meeting. The award, named after Burton Kallman, Ph.D., NNFA's scientific director emeritus, is given to individuals for their outstanding scientific achievements relevant to the natural products industry. The recipient must be a published and credentialed scientist whose knowledge has implications for public health and furthering the natural products industry's health missions. --Ed.

What causes humans to age? Death is inevitable, but must we accept that the maximum human life span is unalterable and that getting older also means becoming physically infirm and increasingly senile? These are questions Denham Harman, M.D., of Omaha, Neb., began asking in 1945, spurred by Russian research then being conducted on the possibilities of prolonging life and by a highly publicized study known as the Rockefeller experiment. This experiment involved a chicken cell culture and purportedly proved that individual cells were immortal. Although the experiment proved flawed--the life span of cells turned out to be finite, just like that of the organisms they formed--for Harman, the experiment's original premise initiated a process of deep brooding and questioning.

As years passed, his studies and work would uniquely position him to contemplate the question of aging. His graduate work, concerned with mechanisms of organic reactions, culminated in a doctorate in chemistry in 1943. From 1945 to 1949 he worked in the chemical research division of Shell Oil Co., most pertinently in the reaction kinetics department, where he concentrated on free radical chemistry--primarily molecular oxygen and compounds of phosphorus and sulfur. Then, between 1949 and 1954, he completed what he characterizes as a superb course in biology--namely, medical school at Stanford University in California, and residencies in internal medicine at Stanford University and Veterans Administration hospitals.

After his medical internship, he became a research associate at the Donner Laboratory of Medical Physics Research at the University of California at Berkeley. The year was 1954. He was 38 years old and on the verge of originating a theory whose implications are still unfolding. Looking back, Harman re-creates the ground from which his insight arose; then he looks ahead to where he hopes it will evolve.

Cameron:
You had been contemplating the cause of aging since 1945. When did a theory finally appear?

Harman:
My situation at the Donner Laboratory was quite unusual. Basically, I could do anything I wanted with my time, except Wednesday mornings when I worked in the hematology clinic. So I asked myself, "What kills us?" I knew when Mother Nature finds something that works, she uses it over and over, like variations on a theme. I approached the problem with the idea that there is a single cause of aging. This cause would be responsible for the aging and death of everything, modified by genetics and environment.

The problem frustrated me for four months. Everywhere I looked I found only dead ends. I began to wonder if the problem was solvable. To make a complicated story short, early in November 1954 I was sitting at my desk reading, and the words free radical crossed my mind; I had found the common denominator. Free radical reactions, however initiated, could be responsible for the progressive deterioration of biological systems over time because of their inherent ability to produce random change.

Cameron:
How did you test the theory?

Harman:
It was a theory that could not be directly proved or disproved. It had to be reduced to practice. Studies began in a number of areas, such as the action of catalase, an enzyme we all have that breaks down hydrogen peroxide. This was one way of showing that free radicals are involved in living things. The data, however, were not conclusive. Free radicals were first detected in yeast by an electron spin resonance spectrometer in 1954. But it wasn't until 1964-65 that free radicals were detected in human serum.

Cameron:
When did you start correlating free radical activity with cancer and atherosclerosis?

Harman:
Almost at once. The first paper based on the theory, "Reducing compounds as chemotherapeutic agents in cancer," was published as an abstract in 1956 in Clinical Research. Another paper on atherosclerosis postulated that the peroxidation of lipids in serum and cell walls was involved in atherogenesis. In 1958 I was offered the chair of cardiovascular research at the University of Nebraska College of Medicine in Omaha. During my first years there I was involved primarily with atherosclerosis research. Gradually, my emphasis shifted back to aging.

Cameron:
How do you define aging?

Harman:
Aging is the accumulation of changes that increase the risk of death. These changes can be attributed to such factors as development, genetic defects, disease, the environment and the inborn aging process. Today, support for the theory that aging is caused fundamentally by free radical reactions in the body is extensive.

Cameron:
How long can people in developed countries reasonably expect to live?

Harman:
On average, one could expect to get within three or four years of the potential "natural" maximum value of 85 years. This can be achieved by keeping one's body weight down and eating foods adequate in essential nutrients. Lots of fruits and vegetables can minimize free radical reactions in the body. As we get older, however, diet alone can't provide antioxidants in the amounts necessary to slow the aging process. Supplements are critical, especially beta-carotene and vitamins C and E. Also, it is important to minimize the accumulation of metals such as iron, copper and manganese in the body, which are capable of initiating adverse free radical reactions, and of the metals lead, mercury and cadmium, which can impair the action of sulfur- and selenium-containing enzymes.

Cameron:
In your work you consistently distinguish between average life expectancy at birth (ALE-B) and maximum life span (MLS). How did your expectations regarding increasing MLS fare in early experiments?

Harman:
Not well. By the mid-1960s there were enough data to show that although ALE-B could be increased by decreasing endogenous free radical reactions with antioxidant supplementation, MLS was not affected at all. I modified the theory by suggesting that life span was determined by the rate of free radical damage to the mitochondria, where mammals use 90 percent of their oxygen.

Cameron:
I understand mitochondria are organelles within each cell that produce energy by means of cellular respiration. How do the mitochondria promote aging?

Harman:
I wrote a paper that came out in the Journal of the American Geriatrics Society in 1972, the same year in which I said MLS was probably determined by the rate of aging of the mitochondria themselves. And that's where we stand today. The role of mitochondria in the aging process and disease is presently an active field of research. A small fraction of the oxygen consumed by a cell is diverted to the formation of the superoxide radical. This radical can lead to mitochondrial damage. Thus begins a vicious cycle. As you produce more superoxide radicals, you get more damaged tissue--damage to the mitochondrial respiratory chain in particular. The net result is that more superoxide radicals and hydrogen peroxide are produced. When you decrease your caloric intake, you get a proportionate decrease in oxygen consumption; with that you get a decrease in superoxide radical production. Reducing food consumption, however, is never going to be popular. I understand researchers are working on food sources that will make people feel full yet will be low in calories. Until then, people should try to keep their weight a little below normal.

Cameron:
Or take antioxidant supplements?

Harman:
The research in that arena is quite interesting. A gerbil experiment was conducted by John Carney, Ph.D., of the University of Kentucky, Robert Floyd, Ph.D., of the Oklahoma Research Institute, and colleagues, then published in The Proceedings of the National Academy of Science in 1991. In the experiment, a group of old and a group of young gerbils were injected with the free radical inhibitor N-tert-butyl-beta-phenylnitrone (PBN). After two weeks, there was no effect on the behavior of the young gerbils, which indicated they already had a low rate of deleterious oxidative change. The old gerbils, however, became almost like the young animals as measured by their ability to run a maze--a measure of memory. The oxidization level of their proteins also decreased to that of the young. Just how PBN produced these effects is unknown. I tend to think PBN decreased the initiation rate of adverse free radical reactions by the mitochondria.

Cameron:
The oldest documented age reached by a human is 122 years--the current MLS. Do you think it is possible to increase MLS beyond that?

Harman:
I do. I think we're just on the threshold. The three phases of free radical reaction are initiation, propagation and termination. We can manipulate fairly easily the initiation and propagation phases, making them faster or slower. For example, in the initiation step you produce a free radical. That free radical reacts with other molecules and is regenerated, so to speak. The number of times it is regenerated is the chain length. If you want to stop a free radical reaction, you can stop initiation reactions or decrease the chain length. It is known that you can slow these steps without significantly interfering with maintenance and function reactions by using antioxidants. During the last 40 years, many people have used lots of antioxidants in their studies. This work shows you can increase the ALE-B of mice as well as many other laboratory animals. Innumerable epidemiological studies show the benefits of antioxidants in fighting cancer and cardiovascular disease. However, in all the experiments with laboratory animals there has been no certain evidence demonstrating an increase in MLS. ALE-B can be increased, but MLS does not budge.

Cameron:
In the face of that, you still believe it can?

Harman:
Yes. Three compounds have been claimed to increase MLS, but research results have not been repeated. In the gerbil experiment I mentioned earlier, the animals were injected with the spin-trap PBN. Spin-traps are synthetically engineered antioxidants, so called because they literally trap free radicals. Specifically, they are nitrones or nitroso-compounds that react with free radicals to form relatively stable nitroxides that are readily reduced to hydroxylamines.

Cameron:
Can they be found in nature?

Harman:
Possibly, but I don't know where. In the gerbil experiment, the result was that the PBN made the old gerbils seem younger. What I think happened is the nitroxides, formed by reaction of PBN with a free radical, interacted with the electron-rich areas of the mitochondrion respiratory chain to remove an electron. This is what oxygen does. So nitroxides are competing with oxygen. If this explanation is correct, other compounds like hydroxylamines and nitroxides could work just as well as spin-traps. If you could slow the rate of production of superoxide radicals, you could increase MLS.

Cameron:
Would this come down to taking a supplement?

Harman:
It may. We don't know right now. We do know for sure that reducing food intake will let you live a little longer. Cut calorie consumption by 10 percent, and you'll cut oxygen consumption by 10 percent, and presumably you'll be cutting down the rate of production of superoxide radicals. By reducing your caloric intake, you're decreasing the substrate responsible for the production of superoxide radicals. By taking spin-traps or some other compound such as hydroxylamines or nitroxides, you're decreasing the ability of oxygen to remove an electron from the respiratory chain of the mitochondria. You might, therefore, be able to block out oxygen. A compound that would stick with the electron-dense areas of the respiratory chain of the mitochondria might slow the production of superoxide radicals.

Cameron:
Are there such compounds?

Harman:
There may be many. [The concept of] Bucky balls [so named for Buckminster Fuller, 1895-1983, the American engineer and architect best known for designing geodesic domes, which have the same structure as the carbon molecule] may be useful. They're hollow spheres made up of 60 carbon atoms, and they have a strong affinity for free radicals. They've even been called "free radical traps" because free radicals literally stick to their surface.

Cameron:
Do you ingest them as pills?

Harman:
We don't know. They're pure carbon. In recent experiments they have been altered to be more water soluble. If not Bucky balls, then some other compounds, which I'm sure chemists could come up with, that have an affinity for electron-dense areas of the mitochondria. The compounds would essentially sit on top of the mitochondria. When an oxygen atom came by, it could not reach the mitochondria to steal an electron, thereby reducing the production of superoxide radicals. These are all conceptual possibilities. I'd like to see a life-span study run with hydroxylamines and another with nitroxides.

Cameron:
How long do you imagine human beings could live if all things came together as you describe?

Harman:
That's a tricky question. Some of the changes that take place in our bodies are irreversible and will probably remain so: Collagen gets stiffer; our DNA changes. But to answer your question, I would say maybe 125 to 130 years. The likelihood is that a larger percentage of us could reach 100, 105 or 110.

Cameron:
May I assume you're imagining longer, healthier lives?

Harman:
Absolutely. The fact is, if you get sick at 65, you're going to be sick for a long time. But if you're healthy and productive well into your 90s and you get sick at, say, 95 or 100, at that age the body cannot tolerate trauma. You die quickly. With the kind of longevity I'm postulating, society gets the benefit of many more years of experience from the elderly (65 and older) and oldest old (85 and older) without the old being a burden on society. Mother Nature did not mean for us to live forever, but that does not mean we should not try to increase our functional life span. In the ideal scenario one would live a long, active, useful life, then die quickly.

Cameron:
Like ripe fruit falling from the tree.

Harman:
Exactly so. I lecture and write about aging, but I don't have a laboratory anymore. I can only express these ideas and hope others will be excited by them. I hope this interview inspires others to conduct the experiments necessary to turn a lot of very interesting possibilities into facts that could someday give us all longer, healthier lives.

Franklin Cameron is a freelance writer based in Denver, Colo. His writing specialties are history and natural approaches to physical and mental health.