Free-radical theory.html



The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. In general, a "free radical" is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, this is not true of most biologically-relevant oxygen free radicals. For most biological structures, free radical damage is closely associated with oxidative damage. Oxidative damage is familiar by analogy with the process of rust formation of iron exposed to oxygen. As the name suggests, antioxidants like vitamin C prevent oxidation, because they are reducing agents.

Strictly speaking, the free radical theory is only concerned with free radicals, but it has since been recognized that oxidative damage can also be caused by non-radical oxygen derived oxidants (hence, the term reactive oxygen species is used to collectively refer to several oxidizing oxygen dervied compounds, such as O2-, H2O2, OH*, ROOH). The theory is more approriately called the oxidative damage theory of aging, but the name "free radical theory" has stuck.

Denham Harman first proposed the FRTA in the 1950s ¹ and extended the idea to implicate mitochondrial production of ROS in the 1970s². Of all the theories of aging, Harman's has been most extensively tested. In some model organisms, such as yeast and Drosophila, substantial evidence exists that reducing oxidative damage, does, as the theory would predict, extend lifespan. In mice, treatments/interventions that enhance oxidative damage generally shorten lifespan, however, whether reducing oxidative damage is sufficient to extend lifespan is presently controversial.

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 diabetes. This involvement is not at all surprising as free radical chemistry is an important aspect of phagocytosis, inflammation, 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 For and Against

• A large body of comparative biochemical evidence suggests that longer lived species exhibit decreased levels of oxidative damage, decreased susceptibility to oxidative stress, and decreased generation of reactive oxygen species.
• Results have demonstrated that the overexpression of catalase, an enzyme involved in the decomposition of hydrogen peroxide, increased both the average lifespan and maximum lifespan of mice by 20%³. 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 shortened lifespan ⁴. However, increasing atmospheric oxygen tension above the normal 21% O2, does not meaningfully decrease lifespan of C. elegans. On the other hand, consistent with the free radical theory, it does shorten lifespan of the fruit fly Drosophila.
• Drosophila that have mutations in enzymes relating to ROS metabolism have also been shown to have dramatically reduced life-spans, increased susceptibility to oxidative stress and ionizing radiation, partial female and complete male sterility, and a general “enfeebled” phenotype (characterized by deformed wings and abdomen).⁵
• 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.

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. A possible exception is PBN (phenybutylnitrone), which was shown to produce about a 10% extension of maximum lifespan in experimental animals ⁶ in one laboratory, however, this finding has not been reproduced by other laboratories.

Mitohormesis

While there is good evidence to support the idea of FRTA in model organisms such as Drosophila melanogaster⁷ and Caenorhabditis elegans,⁸ 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.⁹ This process was previously named mitohormesis or mitochondrial hormesis on a purely hypothetical basis.¹⁰. The situation in mammals is even less clear.¹¹¹²¹³ Recent epidemiological findings support the process of mitohormesis, and even suggest that antioxidants may increase disease prevalence in humans (although this meta-analysis included large studies on smokers, for whom it was already known that beta-carotene supplements are harmful).¹⁴

Calorie restriction

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 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 ¹⁵⁹

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).

Antioxidant therapy

This theory implies that antioxidants (e.g. Vitamin A, vitamin C, vitamin E and Superoxide dismutase) — which prevent free radicals from 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.

See also

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

References

External links

Calorie restriction

• Calorie Restriction Society.

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