Mitochondrial Theories of Aging Part II: Oxygen Radical-Mitochondrial Hypothesis of Aging
By Ward Dean, MD
I first met Jaime Miquel, Ph.D., in 1978, shortly after I graduated from medical school and moved to San Francisco for my internship at Letterman Army Medical Center. Dr. Miquel is a pharmacologist, and one of the leading free radical biochemistry experts in the world. At that time Dr. Miquel was at NASAs Moffet Field Research Center near San Francisco conducting research on the effects of antioxidants on fruit flies. It was at Moffet that Dr. Miquel developed his oxygen radical-mitochondrial-injury hypothesis of aging—a variant of the original free radical theory first proposed by Dr. Denham Harman. [Dr. Harman credited Miquels contributions to his theory during his talk on the free radical theory at the VRP-sponsored Second Monaco Anti-Aging Conference (Vitamin Research News, August 2001).] Miquel is an energetic, creative scientist with a mischievous sense of humor and a twinkle in his eye that belie his distinguished, erudite scientific writing. After a number of years in the United States Miquel returned to his home in Spain, where he is currently a Professor of neurochemistry at the University of Alicante.
Jaime Miquel, Ph.D.
Like Professor Imre Nagy, whose Membrane Theory of Aging was described in the February 2001 issue of Vitamin Research News, Dr. Miquel believes that mitochondrial damage is caused by oxygen free radicals.1-7 However Miquel proposes that the target of free radical damage is mitochondrial DNA (mtDNA), not mitochondrial membranes, as proposed by Zs.-Nagy.
Miquel proposes that cell aging is the result of the following chain of events:
- Cell differentiation—associated with cell growth—increases demands on cellular energy production, leading to higher rates of metabolic respiration;
- Production of increasingly high levels of oxygen radicals in the inner mitochondrial membranes exceeds the regenerative and detoxifying capacity of these cells;
- Peroxidative damage to the inner mitochondrial membrane, particularly at the level of the slowly turning over cardiolipin, or of the mitochondrial DNA (mtDNA)-coded proteins;
- Mitochondrial DNA injury by oxygen radicals due to mtDNA being relatively unprotected;
- Progressive loss of the cells ability to regenerate its mitochondria; and,
- Breakdown of the damaged mitochondria and decrease in the number of healthy mitochondria, with concomitant decline in ATP production, energy-dependent protein synthesis, and specialized cellular function (Fig. 1).8
Harmans original theory proposed that free radicals caused mitochondrial damage in all cell types; Zs.-Nagy believed that free radical damage occurred primarily in the cellular membranes; Miquel believes that such breakdown is only significant in the mitochondrial DNA of terminally differentiated cells (i.e., nerves and muscles).3 Thus, the most significant aspect of Miquels hypothesis is his proposal that the specific sites of free-radical-induced cellular damage that are responsible for the aging process are mitochondrial DNA (mtDNA) of differentiated and especially fixed-postmitotic cells. The result of mtDNA damage from free radicals is structural and biochemical alterations of the mitochondria that lead to a decrease in the number of functional mitochondria and a subsequent decline in bioenergy production.3 Miquel hypothesizes that if enough mitochondria are injured or lost as a result of mtDNA damage, the reduced number of functional mitochondria will not be able to produce enough ATP to meet the bodys energy requirements, nor to repair damage to the surviving mitochondria. Thus, a vicious cycle of downward-spiraling energy production leads to further energy loss and degradation of homeostasis.2,3
Exercise and Mitochondria
Physical exercise has been shown to increase mitochondrial proliferation in young adults. In a comparative study on the effects of training on mitochondrial size and function, Kiessling and colleagues showed that physical exercise in young men resulted in a doubling (100 percent increase) of the total mitochondrial volume.10 However, in older men a similar exercise program only increased mitochondrial volume by 20 percent. The larger mitochondrial volume in young adults was due to an increase in the number of mitochondria, without an enlargement in mitochondrial size. In older men, the increased mitochondrial volume was the result of an increase in mitochondrial size, without an increase in number of mitochondria. The larger mitochondria of the older individuals are less efficient than the more numerous, more efficient, rapidly replicating mitochondria characteristic of youth.
Kiesslings findings suggest—in agreement with Miquels hypothesis—that with increased age mtDNA replication is impaired.3 Harding confirmed that respiratory chain activity in muscle tissue also decreases with age, adding further evidence that accumulating mtDNA damage contributes to the aging process, and that aging may be the most widespread mitochondrial disease of all!11
Preventing and Reversing Mitochondrial Damage
Miquel recently proposed that compounds such as deprenyl, Coenzyme Q10, alpha-lipoic acid, and the glutathione precursors, thioproline and N-acetyl-cysteine (NAC), may help to preserve mitochondria and mitochondrial DNA and aid in maintaining the structural integrity of these energy-producing organelles, leading to increases in functional lifespan.12
1. Miquel, Jaime. Aging of male Drosophila melanogaster, histological, histochemical and structural observations, in: Advances in Gerontological Research, Vol. 3, by Bernard Strehler (ed), 1971, Academic Press, London, 39-71.
2. Miquel, Jaime. An integrated theory of aging as the result of mitochondrial DNA mutation in differentiated cells. Arch Gerontol Geriatr, 1991, 12: 99-117.
3. Miquel, Jaime. An update on the mitochondrial-DNA mutation hypothesis of cell aging, Mutation Research, 1992, 275: 209-216.
4. Miquel, Jaime, Tappel, C.J., Dillard, C.J., Herman, M.M., and Bensch, K.KG. Fluorescent products and lysosomal components in aging Drosophila melanogaster, J. Gerontol, 1974, 29: 622-637.
5. Miquel, Jaime, Oro, J., Bensch, K.G., and Johnson, J.E. Lipofuscin: Fine structural and biochemical studies, in Free Radicals in Biology, Vol III, by W. Pryor (ed), 1977, 133-182.
6. Miquel, Jaime, Lundgren, P.R., and Johnson, J.E. Spectrophotometric and electron microscopic study of lipofuscin accumulation in the testis of aging mice. J Gerontol, 1978, 33: 5-19.
7. Miquel, Jaime, Economos, A.C., Fleming, J., and Johnson, J.E. Mitochondrial role in cell aging, Exp Gerontol, 1980, 15: 575-591.
8. 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.
9. Fleming, J.E., Miquel, J., and Bensch, K.G. Age-dependent changes in mitochondria. Molecular Biology of Aging, 1985, Plenum, New York, 143-155.
10. Kiessling, .H., Pilstrom, I., Karlsson, J., and Piehl, K. Mitochondrial volume in skeletal muscle from young and old physically untrained and trained healthy men fand from alcoholics. Clin Sci, 1973, 44: 547-554.
11. Harding, A.E. Growing old: The most common mitochondrial disease of all? Nature Genetics December, 1992, 2: 251-252.
12. Miquel, Jaime. Can antioxidant diet supplementation protect against age-related mitochondrial damage? Ann NY Acad Sci, 2002, 959 (Increasing The Healthy Life Span), 508-516.