Free-radical theory

The Free Radical Theory of Aging

The free radical theory of aging was conceived by Harman at a time when most scientists still believed that free radicals were too unstable to exist in biological systems and before anybody had invoked them as a cause of degenerative diseases. Harman drew inspiration from two sources: 1) the rate of living theory, which held that lifespan was an inverse function of metabolic rate, oxygen consumption. 2) Rebbeca Gershman's observation that hyperbaric oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon: oxygen free radicals. Noting that radiation causes "mutation, cancer and aging" Harman argued that oxygen free radicals produced during normal respiration would cause cumulative damage which would eventually lead to organismal loss of functionality, and ultimately, death. In later years, the free radical theory was expanded to not only include aging per se, but also age related diseases. Free radical damage within cells has been linked to a range of disorders including cancer, arthritis, atherosclerosis, Alzheimer's disease, and apoptosis. Cell suicide, or apoptosis, is the body's way of controlling cell death and involves free radicals and redox signalling. Redox factors play an even greater part in other forms of cell death such as necrosis or autoschizis.

More recently, the relationship between disease and free radicals has led to the formulation of a greater generalization about the relationship between aging and free radicals. In its strong form, the hypothesis states that aging per se is a free radical process. The "weak" hypothesis holds that the degenerative diseases associated with aging generally involve free radical processes and that, cumulatively, these make you age. The latter is generally accepted, but the "strong" hypothesis awaits further proof. Both models trace back to Harman's work.

Evidence

• Results have demonstrated that the overexpression of hydrogen peroxide, increased both the average lifespan and maximum lifespan of mice by 20% (PMID 15879174). However, the authors of that paper also indicated that the lifespan extension effect had apparently lessened in new generations of these mice.
• Making a well-studied roundworm, Caenorhabditis elegans, more susceptible to free radicals has led to shortned lifespan (PMID 11237107). However, increasing atmospheric oxygen tension above the normal 21% O2, does not meaning fully decrease lifespan of C. elegans. On the other hand, consistent with the free radical theory, it does shorten lifespan of the fruit fly Drosophila.
• While genetic manipulations that increase the levels of oxidative damage generally do shorten lifespan in mice, there is as yet very limited evidence that decreasing free radicals below their normal levels, actually extends lifespan (see above).
• Feeding of antioxidants, which should increase lifespan if the theory is correct, can extend average but not maximum lifespan in mice, even so, this effect is weak when it is observed and overall inconsistent.

Antioxidant therapy

This theory implies that oxidizing sensitive biological molecules, or reduce the formation of free radicals — will slow the aging process and prevent disease.

The antioxidant chemicals found in many food-stuffs (such as the well known vitamins A, C and E) are frequently cited as the basis of claims for the benefits of a high intake of vegetables and fruits in the diet. In particular, antioxidant therapy forms the basis of many basic pharmacological interventions and particularly orthomolecular medicine.

One possible strike against the FRT of Aging (but not necessarily the FRT of certain diseases) is that antioxidant supplementation has not yet been convincingly shown to produce a mammalian extension of lifespan. One exception is PBN (phenybutylnitrone), which produces about a 10% extension of maximum lifespan in experimental animals [1]. However, this finding has not been reproduced by other laboratories.

While there is good evidence to support the idea of FRTA in model organisms such as Drosophila melanogaster and Caenorhabditis elegans,^[3][4] recent evidence suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species.^[5] This process was previously named hormesis on a purely hypothetical basis.^[6]. The situation in mammals is even less clear.^[7][8][9] Recent epidemiological findings support the process of mitohormesis, and even suggest that antioxidants may increase disease prevalence in humans.^[10]

Calorie restriction

See main article: Calorie restriction

Calorie restriction, or severely cutting the intake of energy, has been found to reduce ROS and to increase the life-span of rodents possibly by promoting a process called mitohormesis. Studies have shown that both calorie restriction and reduced meal frequency/intermittent fasting can suppress the development of various diseases and can increase life span in rodents by 30-40% by mechanisms involving stress resistance and reduced oxidative damage. Severe calorie restriction over 50% resulted in increased mortality (PMID 16011467, PMID 17908557).

One of the most popular proponents of calorie restriction as a way to longer life was the late Dr. Roy Walford (1924-2004), formerly Professor of Pathology at the University of California, Los Angeles School of Medicine. Dr. Walford died of Amyotrophic Lateral Sclerosis (ALS).

See also

• American Aging Association
• Antioxidant
• Life extension
• List of life extension-related topics
• Senescence
• Mitohormesis

References

1. ^ Harman, D (1956). "Aging: a theory based on free radical and radiation chemistry". JOURNAL OF GERONTOLOGY 11 (3): 298-300. PMID 13332224.
2. ^ Harman, D (1972). "A biologic clock: the mitochondria?". JOURNAL OF THE AMERICAN GERIATRICS SOCIETY 20 (4): 145-147. PMID 5016631.
3. ^ Larsen P (1993). "Aging and resistance to oxidative damage in Caenorhabditis elegans". Proc Natl Acad Sci U S A 90 (19): 8905-9. PMID 8415630.
4. ^ Helfand S, Rogina B. "Genetics of aging in the fruit fly, Drosophila melanogaster". Annu Rev Genet 37: 329-48. PMID 14616064.
5. ^ Publication demonstrating that oxidative stress is promoting life span
6. ^ Publication that first used the term mitohormesis
7. ^ Sohal R, Mockett R, Orr W (2002). "Mechanisms of aging: an appraisal of the oxidative stress hypothesis". Free Radic Biol Med 33 (5): 575-86. PMID 12208343.
8. ^ Sohal R (2002). "Role of oxidative stress and protein oxidation in the aging process". Free Radic Biol Med 33 (1): 37-44. PMID 12086680.
9. ^ Rattan S (2006). "Theories of biological aging: genes, proteins, and free radicals". Free Radic Res 40 (12): 1230-8. PMID 17090411.
10. ^ Publication demonstrating negative effects of antioxidants on human health

3 Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. (2007) Trends in oxidative aging theories. Free Radic. Biol. Med. 43, 477-503

Biology of Aging

• Damage-Based Theories of Aging Includes a discussion of the free radical theory of aging.
• The Free Radical Theory of Aging
• Free Radicals and Human Disease--a Review