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The free radical theory of aging
Nathan C. Nelson

Department of Physics, Ohio State University, Columbus, OH 43201

Abstract. Free radicals are atoms with unpaired electrons. According to the free radical theory, radicals damage cells in an organism, causing aging. Mitochondria, regions of the cell that manufacture chemical energy, produce free radicals and are the primary sites for free radical damage. By eliminating free radicals from cells through genetic means and dietary restriction, laboratories have extended the maximum age of laboratory animals. The administration of antioxidants, which eliminate radicals, to laboratory animals fails to increase maximum lifespan.

The nucleus of an atom is surrounded by a cloud of electrons. These electrons surround the nucleus in pairs, but, occasionally, an atom loses an electron, leaving the atom with an unpaired electron. The atom is then called a "free radical," or sometimes just a "radical," and is very reactive. When cells in the body encounter a radical, the reactive radical may cause destruction in the cell. According to the free radical theory of aging, cells continuously produce free radicals, and constant radical damage eventually kills the cell. When radicals kill or damage enough cells in an organism, the organism ages.1

The production of radical oxygen, the most common radical in biological systems, occurs mostly within the mitochondria of a cell. Mitochondria are small membrane-enclosed regions of a cell that produce the chemicals a cell uses for energy. Mitochondria accomplish this task through a mechanism called the "electron transport chain." In this mechanism, electrons are passed between different molecules, with each pass producing useful chemical energy. Oxygen occupies the final position in the electron transport chain. Occasionally, the passed electron incorrectly interacts with oxygen, producing oxygen in radical form.2

The primary site of radical oxygen damage is mitochondrial DNA (mtDNA). Every cell contains an enormous set of molecules called DNA which provide chemical instructions for a cell to function. This DNA is found in the nucleus of the cell, which serves as the "command center" of the cell, as well as in the mitochondria. The cell fixes much of the damage done to nuclear DNA. However, mitochondrial DNA (mtDNA) cannot be readily fixed. Therefore, extensive mtDNA damage accumulates over time and shuts down mitochondria, causing cells to die and the organism to age.4

Protection of mtDNA from radicals slows aging in laboratory animals. Some laboratories have produced fruit flies that live one-third longer than normal fruit flies. These labs genetically altered the fruit flies to produce more natural antioxidants. Antioxidants are molecules that eliminate radicals, so elevated levels of antioxidants prevent much of the mtDNA damage done by radicals.3 Other labs severely restricted the food intake of laboratory rats, causing a 50% increase in maximum lifespan compared to rats allowed to eat freely.2 The mitochondria of starved rats are not provided with enough material to function at full capacity. Therefore, the electron transport chains in mitochondria of the starved rats pass fewer electrons. With fewer electrons passed, fewer oxygen radicals are produced, so aging slows.

One main problem with the free radical theory is the failure of antioxidants administered as dietary supplements, like vitamins E and C, to significantly increase maximum lifespan. Proponents of the radical theory believe that dietary antioxidants, unlike natural antioxidants produced by cells, do not reach mitochondrial DNA, leaving this site susceptible to radical attack. Interestingly, even though supplemental antioxidants fail to increase maximum lifespan, they do increase the chances of living to the maximum lifespan. This may be due to antioxidant protection of other parts of the cell, like cellular proteins and membranes, from radical damage.2

The goal of all research on the free radical theory is to slow aging and increase maximum lifespan. The achievements so far are astounding; increasing the lifespan of fruit flies and rats is an impressive feat. Despite such success, no practical applications of the theory have been perfected. Genetic alteration is both controversial and difficult for humans. Starvation, while lengthening lifespan, is an unappealing alternative. Dietary antioxidants fail to increase maximum lifespan. However, the production of radicals and their role in aging is well understood. Further research may apply this knowledge in the development of a practical method to prevent or repair mtDNA radical damage.

References

1. D. Harman, J. Gerontol. 11, 298-300 (1956).

2. R.J. Mehlhorn, in Physiological Basis of Aging and Geriatrics, edited by Paola S. Timiras (CRC Press, Ann Arbor, 1994), pp. 61-72.

3. JA Knight, J. Annals of Clinical and Laboratory Science 28, 331-346 (1998).

4. Takayuki Ozawa in Understanding the Process of Aging, edited by Enrique Cadenas and Lester Packer (Marcel Dekker, New York, 1999), pp. 265-292.