January 1998
An Interview With Dr. Denham Harman
Free radicals are atoms or atomic groups that contain
unpaired electrons. Since electrons have a very strong
tendency to exist in a paired rather than an unpaired state,
free radicals rather indiscriminately pick up electrons from
other atoms, converting those other atoms into secondary free
radicals, and thus setting up a chain reaction that can cause
substantial biological damage.
Dr. Denham Harman, M.D., Ph.D., first proposed
a theory of aging as the indiscriminate chemical reactivity
of free radicals possibly leading to random biological
damage. His idea has met with much experimental success, and
is now considered a major theory of aging. The theory implies
that antioxidants such as vitamins E and C, which prevent
free radicals from oxidizing (removing electrons from)
sensitive biological molecules, will slow the aging process.
Dr. Harman launched his theory by showing, for the first
time, that feeding a variety of antioxidants to mammals was
able to extend their life spans.
In 1970, he founded the American Aging Association
(AGE), an organization of biomedical research scientists bent
on understanding and slowing the aging process. Dr. Harman is
a researcher at the University of Nebraska Medical Center,
and is also a co-founder of theInternational Association of
Biomedical Gerontology.
Dr. Harman, interviewed for Life Extension magazine by
Greg Fahy, Ph.D., reminiscences on the early days of his
research, and suggests future courses of study to more fully
understanding the aging process . . . and how to stop
it.
The Antioxidant Pioneer
Denham Harman, Life Extension magazine
scientific advisory board member, is the originator of the
free-radical theory of aging and pioneered research with
antioxidants. He is a true anti-aging pioneer.
Life Extension: Could you briefly recount how you decided
to start the American Aging Association (AGE), and some of
the early events in setting up AGE?
Denham Harman: A bunch of us were sitting around at the
meeting in 1969 of the International Association of
Gerontology. We realized at that time there were less than
300 people in the Gerontological Society who were in the
biological science section, and less than 100 were doing any
work. That was of immediate concern to us. We also were
bemoaning the fact that, if you went and spoke with the
average person about aging, he thought about old people. It
never crossed their minds how you got old, which was
something else.
In New York the following summer, there were maybe four,
five or six meetings held where we decided to do something.
We had the inaugural luncheon at the Waldorf Astoria hotel
that fall. The first meeting was held in 1971, just ahead of
the Gerontological Society meeting in Houston.
It's been an interesting experience. It's very difficult
to get scientists to agree on anything, but I would think at
least we might agree on the matter of money. Because if
you're going to have to compete with the sociologists and so
forth, you're going to get a fraction of the money. They're
going to take most of it. I wouldn't mind that, except it's
not doing anything in terms of what really needs to be done.
One of the sociologists was bemoaning the fact that she
thought too much money was being given to the biologists!
LE: I understand that you wanted the
American Aging Association to be like the March of Dimes, but
for aging instead of for birth defects.
DH: Oh, I don't know. The idea was a
forum where scientists could get together and speak with one
voice, and have a greater impact on Congress, say, and also
try to educate the people about aging research, and educate
the physicians about what could be done. There's no point in
doing this work if you don't transfer it to doctors and
transfer it to you and me.
LE: What do you think the most pressing
need is in this field today?
DH: (Laughs) We just need tremendous
help. It's absolutely ridiculous. Did you see the book that
came out a few years ago-from the National Academy of
Medicine-in which they advocated increasing the support for
aging research to a billion dollars a year? Most of the
research was going in support of more social studies. This is
one of my bones of contention. When groups like the members
of the Gerontological Society talk about aging research, to
them aging research is all the social programs they want
demonstrations for. But you could fund every social worker,
and they won't make one dent on this major problem. They're
taking, I guess, two-thirds of the money from the National
Institute on Aging.
LE: What's the total amount of money
that's actually spent on biomedical aging research?
DH: I figure it's $25 million to $50
million. Probably closer to $25 million.
LE: That would be only, what, a 20th of
the NIA budget?
DH: Whatever, it's a small fration. Yet I
can't get the scientists to stick together. That was one of
the reasons for forming the American Aging Association in the
first place, so we'd have a place where scientists could
associate, so to speak, have a bigger voice. But instead of
that, we have a drop of sand here, a drop of sand there, and
nobody's talking with a single voice.
LE: Could you recount for us some of the
events leading up to your idea that free radicals might be
important in aging?
DH: At the time, I was a research chemist
for Shell Development Co., working in the reaction kinetics
department, which is basically free radical chemistry. I
became interested in aging, but I hadn't made any connection
whatsoever between free radical chemistry and aging. I
thought about free radicals only in terms of straight
chemistry. I was working at that time on free radical
reactions involved with oxygen and organic compounds, sulphur
compounds, phosphorous compounds-that sort of thing. It was
interesting chemistry.
LE: What peaked your interest in
aging?
DH: I came home from work one night and
my wife showed me a magazine article by William Lawrence, who
at that time was a science editor for The New York Times. It
was entitled, "Tomorrow You May Be Younger," but it was a
very well written article about the work of Dr. Bogomolets at
the Gerontology Research Center in Kiev, Russia. Anyway, it
was an interesting article. I didn't understand what he was
talking about. I didn't even know some of the vocabulary, but
it was interesting.
LE: What was the general gist of it?
DH: Trying to increase life span, that
sort of thing.
LE: This would have been when?
DH: December of 1945. While in medical
school I was intrigued by some things I learned. I took a
psych course in the department of biochemistry and cancer,
and I also became aware of the work by Carrel at Rockefeller
University on chicken cells. [Editor's note: This was a
famous series of experiments that seemed to show that cells
could divide without limit in tissue culture; they seemed to
be, in effect, immortal.] And I felt sure there was something
haywire with that experiment, because the human experience is
that everything dies. It was subsequently shown that they
were actually inadvertently transferring new cells into that
old bunch.
Anyway, I sat down and asked the question, What is the
cause of aging? I thought, Mother Nature finds something that
works, and uses it over and over again with variations on the
theme. So I thought that since aging was universal, since
everything aged and died, there should be one common cause
that was modifiable by genetics and by environment. So that
was the premise on which I was looking at this problem.
It's only when I look back that I realized I was in
somewhat of a unique situation. I had a B.S. and Ph.D. in
chemistry and had about 15 years work in laboratories, the
last seven years on my own. I had just finished a superb
course in biology at medical school and an internship. But it
was like looking for a needle in a haystack. Nothing meshed.
Everything I could think of went exactly nowhere. I was just
about ready to give up on the whole thing. I felt like I was
wasting my time. But you hate to give up-you think there's
something there, but you're just not bright enough to see
it.
So anyway, I was sitting at the desk in my office one
morning and it suddenly dawned on me-free radicals flashed
through my mind. You know you have the answer, but you don't
know how you got there, but that was it.
LE: When was this, as nearly as you can
figure?
DH: This was the first part of November
1954. I had finished my internship at the end of June. In the
first part of December, I wandered around the Berkeley campus
talking to people to get their reaction to this idea. They
said it's interesting, but just too simple to explain a
complex problem like aging. I tried to explain that free
radical chemistry only looked simple, that it was far more
complex than that. Anyway, I didn't make much headway, with
the exception of two people. They were both organic chemists
who were doing some biological work-one was a virologist and
one was a photosynthesist. And they said, Yeah, maybe there's
something there.
We first started looking at catalase because of the
connection with the Fenton reaction [an iron-catalyzed free
radical generation reaction that does not require living
systems to work]. Somebody over at the physics department had
built an EPR [an electron paramagnetic resonance
spectrometer, a device for detecting free radicals], but I
couldn't detect free radicals with that system. I also did a
number of studies trying to modify this system, and studies
with catalase activity, but nothing came of it.
LE: You were just trying to find free
radicals in living systems at this point?
DH: Yes.
LE: Did you have an idea that free
radicals would increase with age or did you think that it was
just a constant onslaught that would eventually overwhelm the
organism? Did you have an idea as to how free radicals would
participate in aging?
DH: I knew, for example, that in
radiation biology, if the free radical level was high enough,
you could kill an animal. We worked on several things at the
same time. Most of the work was on life span studies. We used
AJR and C3H mice, relatively short-lived strains, but we were
dealing with a very complex system. The idea was that
free-radical reactions were involved in aging, and that if
you could decrease the level, you might be able to increase
life span. You give an antioxidant to an animal, it's taken
in and distributed to the tissues. Where in the tissues it
goes, to what part of the cell, we didn't know.
LE: What agents did you choose? Was that
the 2-MEA [2-mercaptoethylamine] study?
DH: 2-MEA was chosen because that
compound was synthesized by the Atomic Energy Commission as a
radiation protection compound. It is a very effective
compound.
LE: How did you pick your dose?
DH: Maybe this had to do with something
in a radiation study. I don't recall exactly. We were just
lucky. In terms of life span, we might easily have had too
much or too little. It seems to me that when we went above 1
percent [in the diet], we would get in trouble. Anyway, we
used 2-MEA, we used ascorbic acid, we used cysteine, and we
used hydroxylamine once in a later study. Knowing what I know
now, I wish I could go back and do that hydroxylamine study
again. I'd use different concentrations and also some
different hydroxylamine molecules.
LE: When you published your first study
showing that MEA could extend life span, did that suddenly
change a lot of people's thinking? Did that drastically
increase interest in this area or did you find that people
still resisted your idea?
DH: I was essentially talking to myself
for about 10 years. The biologists at that time knew very
little chemistry, certainly nothing about free radical
chemistry, but it was vice versa with the chemists. The first
life span study was presented as an abstract at the American
Federation of Clinical Research. I think it was in 1956 or
1957 in Carmel, Calif. There was gradual interest. Then in
the mid 1960s it started to increase further, and when the
SOD business [the discovery of superoxide dismutase, a
natural enzyme that destroys superoxide free radicals in the
body] came out in 1969, it took off.
We gradually accumulated a lot of data in the mid-1960s
that showed, yes, we increased the average life expectancy,
which is what I expected to see. But I did not see such an
increase that I could really be sure, in terms of maximum
life span. On that basis, the question came up, is the
failure to increase maximum life span because the theory is
wrong or because it should be modified? I kind of concluded
it should be modified, and I wrote a small paper that was
published in the April issue of The Journal of the American
Geriatrics Society in 1972. The title was, "The Biologic
Clock: The Mitochondria?" I followed it up subsequently with
a paper in 1983, I think, which was published in AGE, called
"The Free Radical Theory of Aging: the Consequences of
Mitochondrial Aging."
There is a great deal of work going on today in that area,
but at that time, I didn't know a lot about mitochondria, per
se. But it didn't take much imagination to figure that your
DNA or your membranes could be subject to free radical
attack. So basically, the paper suggested that free radicals
generated by the mitochondria would kill us, so to speak.
At any rate, right now, I think what's important, aside
from the past history, is that there's a growing consensus
that aging changes are induced by free radical reactions,
largely initiated by the mitochondria, and that the rate of
damage to the mitochondria determines our life span. I think
that's the essence. People still disagree with it. But the
point is that people have been going in so many different
directions that a lot of people could not be brought to bear
on one subject. I think that is changing now.
LE: Certainly, the free radical theory
has inspired more research than any other concept in aging,
there's no question about that. There are more data related
to that theory than on any other subject in aging. Most facts
are consistent with the theory.
DH: Well, I think you have to actually
accept that at some point in time you establish a fact, and
maybe we're reaching that point now. Probably, we're past
that point, or past the point when something which is called
a theory becomes a fact and you just take it as such.
LE: One thing that I think will help is
to establish how a given level of oxidant stress governs life
span.
DH: Are you familiar with the work on
pigeons that was done here by Sohol and also by Barjillian in
Madrid, Spain? He showed that pigeons divert a smaller
fraction of the oxygen they consume to the superoxide
radical. They suggest, and I think this is correct, that this
is the same thing as food restriction. On the one hand,
you're cutting down free radical initiation rates
genetically, and on the other you're doing it by decreasing
your consumption of substrate. Almost certainly the people
who work on the senescence-accelerated mouse have shown that
the peroxidation is much higher in that mouse than in the
longer-lived mouse.
LE: How far do you think can we go? What
is the expectation as to how far we can push out the life
span by an absolutely optimum approach to dealing with free
radical damage?
DH: Who knows? Free radical reactions are
almost impossible to stop. You can slow them up, and that
depends on how good you are. You can cut down on initiation
of free radicals by the mitochondria and then you use some
antioxidants to scavenge the rest of them. Nobody can answer
your question.
From a practical standpoint, I think today we're reaching
a point where we can actually intervene in the aging process
and increase our functional life span and probably also the
maximum life span. And that's where I think we are today. If
you and I are around 100 years from now, we can debate what
we do from there, but right now the immediate thing is to try
to do something about where we are at the moment.
LE: You have also been a geriatrician in
the background all these years, but we never hear about that.
What can you tell us about your own practice?
DH: I can't remember exactly when this
was, but sometime probably in the 1970s they needed some help
over in the Douglas County Hospital, and so the chairman
said, 'You're interested in aging, we need someone to go over
there and do some work, so you're it.' Very crudely, that was
about it. So until four years ago, I was taking care of
geriatric patients. I'd put it like this: it was interesting,
but also somewhat depressing, because a lot of these people
were Alzheimer's disease patients, and there was not much you
could do.
LE: What supplements do you
recommend?
DH: I would recommend that adults take a
gram to a gram and a half of vitamin C a day. I'd also
recommend they take vitamin E. Many, many people are taking
at least 400 IU a day.
LE: Do you think 400 IU of vitamin E
would be the target dose, the best?
DH: I don't know. The thing you have to
worry about is that you don't do any damage. The trouble is,
we've had experience with single doses of things like vitamin
E that were used for years and years, but we don't know what
is the long-term effect of taking a variety of antioxidants
at levels which you think individually are fine. But some may
be too much.
LE: What about the role of selenium
supplementation?
DH: Well, again nobody really knows. I
take 100 micrograms a day, on the average, and 25,000 IU
every other day of beta-carotene. When I say these things, I
realize perfectly well I really don't know for sure that
these are the optimum. I just don't know the optimum. At
least, I think these are reasonably safe amounts to take. And
I take some vitamin B6 and I take magnesium.
LE: Any differences in the need for
antioxidants between men and women?
DH: I'm interested in trying to find out
if there are any data on the effects of antioxidants on
pregnancy. I would like to see women, by and large, get a
great deal more antioxidants than they're getting. We might
be able to get at this indirectly by giving it to women who
have been diagnosed as having Down syndrome. These women
oftentimes will want to keep the baby rather than having it
aborted, and maybe they could be given an option, if they
want to do it, and see if they'll take an increase in
antioxidants: vitamin E, C and beta-carotene, for
example.
Theoretical data are suggesting that the major factor in
Alzheimer's disease of the sporadic late onset type-that's 90
to 95 percent of Alzheimer's cases-is a mutation in earlier
life that affects mitochondrial function, either a mutation
of mitochondrial DNA or of nuclear DNA that influences
mitochondrial function. In essence, it looks as though at
least this large category of Alzheimer's disease cases is a
mitochondrial disorder. It's not simply in the brain, it's a
widespread disorder, involving platelets, fibroblasts,
etc.
LE: Some Alzheimer's patients have
language-use differences in their 20s.
DH: Yes, and this indicates that the
problem started way back. If this is the case, then we can
make the argument that women should take more
antioxidants.
Dr. Steven B. Harris, M.D., assisted with this
interview
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