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
fraction. 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
