In Part I, Dr. Denham Harman shared the development of the free radical
theory of aging with us. In Part II, he will discuss aspects of calorie
restriction and free radical theory of aging, as well as heart disease and
how you can help aging research.
Passwater: Dr. Harman, in Part I, you mentioned that eating less
food reduces oxygen consumption and the load on the mitochondria. There
is good evidence that calorie restriction -- cutting calorie intake by 30%
or so while maintaining high micronutrient levels slows aging. Calorie restriction
seems to lower the levels of undesirable sugar-damaged proteins called Advanced
Glycosylation End-products (AGE).
Harman: Yes. These products are formed by the Maillard reaction.
Interest in the deleterious effects of glucose (blood sugar) in diabetes
focused attention on this reaction, now an active area of research. The
Maillard reaction is initiated by glycation, a reversible non-enzymatic
reaction between reducing sugars such as glucose and ribose, and primary
amino groups on proteins to form Schiff bases (a class of derivatives of
the condensation of aldehydes or ketones with primary amines): these can
form Amadori (rearrangement) compounds . The Amadori compounds slowly --
over months or years -- form a heterogeneous group of irreversible compounds
by oxidation, condensation, rearrangements, and elimination reactions collectively
called AGE. Free-radical reactions are involved in the slow-peroxidation
Passwater: In Part I, you mentioned that reduced food intake meant
that the mitochondria had to work less and there would be less oxygen cycling.
Harman: It was first shown in the mid-1930s that reducing caloric
intake would increase both the average and maximum life spans and decrease
disease incidence. I believe that this result was due to decreased free
radical damage owing to decreased oxygen utilization. Glycosylation may
play a minor role in this effect as glucose levels go down when calories
Passwater: In Age (15:134, 1992(, Drs. Gary Evans and L. Meyer reported
an increase in both average and maximum lifespan in mice fed chromium picolinate.
The mechanism involved is probably that the chromium picolinate potentiates
insulin and helps prevent glycosylation.
Harman: That was a very interesting experiment. I think the experiment
should be repeated with a greater number of mice. I am sure they, and others,
are going to do this.
Passwater: Do you feel that there might be an additive role if we
could reduce both the free radicals and the resultant oxidation products,
and the glucose levels and the resultant formation of the reversible products,
the two processes may go hand in hand in reducing the amount of irreversible
Advanced Glycosylated End-products.
Harman: I think this would help. Another area of research interest
at the present time concerns the action of deprenyl, a compound used in
the treatment of Parkinson's disease. Deprenyl has been shown to increase
the life span of laboratory rats.
Passwater: Does deprenyl involve free radical protection?
Harman: I suspect that deprenyl serves as an antioxidant.
Passwater: In 1963, you reported in "Circulation" that
serum copper might be related to coronary atherosclerosis. Copper and iron
are only now becoming of serious interest to heart disease researchers.
Harman: Copper is interesting. It is an excellent catalyst for the
reaction between lipids and oxygen. Our studies in miniature pigs were suggestive,
but not adequate to prove that excess dietary copper increased the
rate of atherogenesis. An examination of serum copper levels across the
United States also suggested that excess copper was linked to atherosclerosis,
but again we could not be certain. In this connection, we carried out studies
on isolated serum lipoproteins and showed that their mobility was changed
Passwater: Most people didn't even know about lipoproteins in those
Harman: Most of the initial research on serum lipoproteins and atherosclerosis
was done by Dr. John Gofman and his group at the Donner Laboratory of Medical
Physics at the University of California in Berkeley. I was exposed to these
studies during 1954 to 1958 while I was at Donner. The studies on copper
that you mentioned stem from the first paper I wrote on aging and free radicals,
and a subsequent paper published in 1957 in the Journal of Gerontology entitled
"Atherosclerosis: A hypothesis concerning the initiating steps on pathogenesis."
Passwater: I want to follow that up later, but let's talk some more
about excess copper.
Harman: I did a number of studies with copper. Some were published
as abstracts of lectures. In one study, we determined the serum copper levels
of men with and without a history of a heart attack. The study was presented
as a talk at the 1963 annual meeting of the American Heart Association and
the abstract published in 1963 in "Circulation." Because of the
possibility that the higher serum copper levels in men with a past history
of a myocardial infarction might be caused by a "leakage" from
damaged myocardium, I was not able to have the full paper published.
One summer, members of the Framingham study put together serum samples taken
from individuals before and after they had a heart attack; the samples were
crushed during shipment so that we were not able to determine if elevated
copper levels predisposed an individual to atherosclerosis.
Passwater: We need copper to form superoxide dismutase (SOD), one
of the major antioxidants our body makes to protect us from free radicals,
and thus, protect us from oxidation of lipoproteins and subsequent atherosclerosis.
So are you suggesting that there is an optimal range of copper intake?
Harman: You have to have some copper as well as some iron, manganese
and so forth, but the question is how much. If you have too much, you may
be exposed to damaging free radical reactions.
Passwater: Do you see the serum copper level being related primarily
to dietary copper or is another factor involved that can produce various
serum copper levels with the same amount of dietary copper?
Harman: I do not know a factor that can produce various serum copper
levels with the same amount of dietary copper. Most of the copper in the
serum is bound to ceruloplasmin. Some copper is also bound to proteins such
as albumin and to histidine and small peptides.
Passwater: What are you working on today?
Harman: Two things. I am writing a report on the pathogenesis of
Alzheimer's disease. This disorder may be caused by a mutation in a mitochondrial
DNA molecule early in life -- possibly within the first two to three weeks
after conception, that increases the rate of aging in the neurons associated
with Alzheimer's disease.
The second thing I am doing is raiding money for the American Aging Association.
I resigned recently as Executive Director of the American Aging Association.
Arthur Balin, M.D., Ph.D. now holds this position: he is very competent.
I have been appointed chairman of the Capital Fund Drive of the American
Aging Association. We wish to raise five million dollars. The money would
be placed in a trust fund. The interest, after adjusting for inflation,
will help support the operation of the organization. The fund drive is needed
because membership dues from the small number of scientists working in basic
biomedical aging research would need to be very high in order to just continue
our present activities.
Fund-raising is going to keep me busy. It is very important. I would like
to contact five million people and say, "Please, would you like to
contribute to this organization?" Although this is not possible, I
hope that we can get small donations from many people. I can't overemphasize
the importance of continuing to promote basic biomedical aging research.
Passwater: Perhaps, if there was an American Aging Association years
ago to support your research, we would all be younger and healthier now.
I have been a member of the American Aging Association since you help found
it in 1970. I, and many other scientists, benefit from the scientific journal
that is published, "The Journal of the American Aging Association,"
and from the annual scientific sessions. How can our readers join the American
Aging Association and what benefits can they get in addition to helping
research that may help them live better longer? Where can readers send donations
to help support the organization and fund aging research?
Harman: They will receive first reports of the latest research in
aging through the newsletter and the journal "Age." They will
also have the satisfaction of knowing that they are helping to promote research
that will benefit everyone.
Donations, membership dues and subscriptions can be sent to: