Mitochondrial Theory of Aging – The Free-Radical Related Membrane Theory

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

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.

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.

The Free Radical Diseases
Atherosclerosis Osteoarthritis
Cancer Senile macular degeneration
Essential hypertension Senile cataract
Senile dementia Parkinsons disease
Amyloidosis Diabetes mellitus
Table 1. The Free Radical Diseases (Harman, 1984).

Free Radical Related Theories

Other scientists further elaborated on Harmans 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.-Nagys membrane hypothesis of aging (Fig. 4.) combined aspects of Harmans free radical approach with the crosslinking concepts of Bjorksten.10 Zs.-Nagys 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 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-001s 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.


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 Alzheimers 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.


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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