Article - Dr.

Denham Harman Dr Denham Harman free radicals free radical aging an Página 1 de 6

Mitochondrial Theories of Aging

The Free-Radical Related Membrane Theory

by Ward Dean, MD

In 1956, Dr. Denham

Harman proposed that
highly reactive molecular
fragments known as free
radicals caused aging
(Fig. 1). (1) Free radicals
are created in the body
from a number of causes,
including radiation and
the uncontrolled oxidation
of fats. These radicals
readily attach themselves
to other molecules of the
body—to the long, fibrous
structures of protein, to
cell membranes and
organelles, and to the
DNA and RNA within the
cells. Whatever free
radicals link with, they
alter, both structurally and
functionally. In 1972,
Harman extended his
theory by proposing that
the cellular component
most vulnerable to free
radicals were the
mitochondria—the ATP-
generating intracellular
powerhouses found in
every cell of the body
(Fig. 2). (2) Harman
furthermore suggested
that antioxidants and
other nutrients, at
concentrations that would
not also significantly
depress cellular functions, could potentially slow mitochondrial aging and should increase the maximum
lifespan. (3,4)

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Harman also proposed that the aging process is now the major risk factor for disease and death after age
28 in developed countries, and takes the 'politically incorrect' view that aging may also be viewed as a
disease, implying that the diseases of aging may be considered to be symptoms of this underlying 'super
disease' (Table I). (5) These free radical related diseases include cancer, atherosclerosis, amyloidosis,
age-related immune deficiency, senile dementia, and hypertension.

The Free Radical Diseases

Atherosclerosis Osteoarthritis

Cancer Senile macular degeneration

Essential hypertension Senile cataract

Senile dementia Parkinson's disease

Amyloidosis Diabetes mellitus

Table 1. The Free Radical Diseases (Harman, 1984).

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.

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Free Radical Related Theories

Other scientists further elaborated on Harman's original ideas in an attempt to establish a direct link
between free radical damage and aging, resulting in a number of free radical-related theories.

An early theory was that of Richard Hochschild—the Lysosomal Membrane Hypothesis of Aging. (6)
Although Hochschild is best known in the anti-aging community for his computerized aging measurement
instrument, the H-SCAN, he is also a distinguished gerontologist who published a number of
groundbreaking papers in the 1970s. Lysosomes have been described as 'bags of enzymes' that act as
'intracellular garbage men' which clean up intracellular waste products. Hochschild proposed that aging
and many age-related pathologies are caused by the increase in lysosomal activity due to destabilized
lysosomal membranes, and that free radicals and lipid peroxidation were the cause of the destabilized
lysosomal membrane. Hochschild suggested that membrane stabilizers like dimethylaminoethanol
(DMAE) might have a positive effect in delaying aging, as indicated in one of his studies (Fig. 3).

A second free radical-derived theory is the Membrane Theory of Aging, proposed by Professor Imre Zs.-
Nagy from the University Medical School, Debrecen, Hungary which held that physicochemical changes of
the mitochondrial membrane were a primary cause of aging. (7,8) These changes were believed to cause
increased rigidity and altered permeability of the cell membrane, resulting in cellular dysfunction, disease
and aging.

A third theory is the Oxygen Radical-Mitochondrial Injury Hypothesis of Professor Jaime Miquel, which
placed the site of free radical induced damage on the mitochondrial DNA (mtDNA). (9) These three related
theories all emphasize the importance of cellular membrane integrity in aging, and imply that free radicals
and lipid peroxidation are the underlying causes of membrane deterioration of mitochondria, lysosomes,
and cell nuclei. Cellular membranes are important to these theories because it is in the membranes where
the majority of free radicals are produced, and because membranes suffer the greatest damage from free
radicals.

The Membrane Hypothesis of Aging

Zs.-Nagy's membrane hypothesis of aging (Fig. 4.) combined aspects of Harman's free radical approach
with the crosslinking concepts of Bjorksten. (10) Zs.-Nagy's theory holds that the primary site of free
radical-induced damage to the cell is the cellular membrane. He believes that free radical damage occurs
in the mitochondrial membrane since membranes are the densest part of the cell, making it the most likely
site for free radical damage to occur. He reasoned that in the largely water, highly diluted cytosol (interior),
hydroxyl radicals would not generate intermolecular crosslinks because the dissolved molecules are too

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far away from one another. If, however, hydroxyl radicals are formed in a system of high density (like the
membranes), the probability of the formation of intermolecular crosslinks is much greater.

Another factor in the membrane hypothesis is the damage induced by residual heat. With each impulse
transmitted by nerve fibers, there is a considerable amount of heat produced. About 10 percent of this
heat is not dissipated from the membrane, and has been called residual heat. The residual heat
production in the membrane during each discharge of its electrical polarity alters the membrane structure,
reducing membrane fluidity and permeability, and increasing membrane density. This altered membrane
structure decreases passive potassium ion (K+) permeability of the membrane, and causes an increase of
the intracellular K+ content. The increased K+ content of the cells causes an increasing condensation of
the intracellular colloids, which leads to an increase of the damaging efficiency of the OH- free radicals on
the cytosol. The more-and-more condensed (and crosslinked) colloidal system causes a loss of water
content. This is because the intracellular colloid osmotic pressure (which is the most important force which
keeps the water in the cells) decreases. The increased intracellular density also causes a decrease in
cellular enzyme activities. Zs.-Nagy believes that this increased cellular density may alone adequately
explain the age-dependent declines of practically all cell, tissue or organ functions. (11) However, the
decrement in enzyme activities also results in a decreased rate of RNA- and protein-synthesis, and an
accumulation of waste products (especially, lipofuscin, also known as age pigment).

Zs.-Nagy believes that the best approaches to counteract the ravages of free radical-induced membrane
damage are to use antioxidant membrane stabilizers like dimethylaminoethanol (DMAE) or
centrophenoxine (Fig 5). Zs.-Nagy has synthesized an analog of centrophenoxine, BCE-001, (12) which he
claims is an even more effective radical scavenger than centrophenoxine. BCE-001's biological effects are
similar to centrophenoxine and dimethylaminoethanol, but can be used in lower doses, and therapeutic
results occur sooner. (13) BCE-001 is available only for experimental use at this time.

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DMAE is an efficient OH- radical scavenger that is incorporated into the cell membrane of neurons where
it may provide site-specific radical protection in nerve cells. It not only prevents the accumulation of
lipofuscin (the pigment that accumulates in cells with age and which causes the well known 'age-spots'
that occur in many older people), but also often causes the spots to completely disappear. Finally, it is a
mild cerebral stimulant, which has been used to treat both Attention Deficit Disorder and Alzheimer's
disease. It is a safe, effective cognitive enhancer in normal adults, as well. For a complete review of the
anti-aging effects of DMAE, see the article, DMAE and PABA—An Alternative to Gerovital, (GH3), the
Romanian Youth Drug, Vitamin Research News, Sept. 2001, Vol. 15, Num, 9.

Next Month: Prof. Jaime Miquel's Oxygen Radical-Mitochondrial Hypothesis.

References
1. Harman, Denham. Aging: A theory based on free radical and radiation chemistry. J. Gerontol, 1956, 11: 298-300.
2. Harman, Denham. The biologic clock: the mitochondria? Jam geriatr Soc, 1972, 20: 145-147.
3. Harman, Denham. Free radical theory of aging: Consequences of mitochondrial aging, Age, 1983, 6: 86-94.
4. Harman, Denham. Free radical theory of aging: Role of free radicals on the origination and evolution of life, aging and disease processes,
in: Free Radicals, Aging and Degenerative Disease, by Johnson, J.E., Walford, R., Barman, D., and Miquel, J. 1986, Alan R. Liss, New York,
3-49.
5. Harman, Denham. Free radicals and age-related diseases, in: Free Radicals in Aging, by Byung Pal Yu (ed). CRC Press, Boca Raton,
1993, 205-222.
6. Hochschild, R. Lysosomes, Membranes and aging. Exp Gerontol, 1971,6: 153.
7. Zs.-Nagy, Imre. A membrane hypothesis of aging. J Theor Biol, 1978,75: 189-195.
8. Zs.-Nagy, Imre. The role of membrane structure and function in cellular aging: a review. Mech Aging Dev, 1979,9: 237-246.
9. Miquel, Jaime, and Fleming, J .E. Theoretical and experimental support for an 'oxygen radical-mitochondrial injury' hypothesis of cell
aging, in: Free Radicals, Aging and Degenerative Diseases, by J.E. Johnson, R. Walford, D. Harman, and J. Miquel (eds), 1986, Alan R.
Liss, New York, 51-74.
10. Dean, W. The Crosslinkage Theory of Aging, Part I. Vitamin Research News, Dec. 2001, Vol. 15, No. 12.
11. Damjanovich, S., Zs.-Nagy, I., and Somogyi, B. Application of a molecular enzyme kinetic model for aging cells and tissues. Arch
Gerontol Geriatr, 1989,8: 37-45.
12. U.S. Patent No.4661618 (1985). Owned by BIOGAL Pharmaceutical Works Ltd, Debrecen, Hungary.
13. Zs.-Nagy, I., Ohta, M., and Kitani, K. Effect of centrophenoxine and BCE-001 treatment on the lateral diffusion and constant of proteins in
the hepatocyte membrane as revealed by fluorescence recovery after photo bleaching in rat liver smears. Exp Gerontol, 1989, 24: 317-330.

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