Free-radical theory

From Wikipedia, the free encyclopedia

The free-radical theory of aging (FRTA) is that organisms age because protein, lipid and nucleic acids (DNA, RNA) accumulate free radical damage with the passage of time. Free radical attack on protein, lipid and nucleic acids leads to a reduction in their respective function, thereby decreasing cell function, then organ function, and finally, organismal function.

Any element that has an unpaired electron in its outermost shell is considered to possess a "free radical". For most biological structures free radical damage is closely associated with oxidative damage. Oxidation and reduction are redox chemical reactions. Most people can understand oxidation damage as they are familiar with the process of rust formation of iron when exposed to oxygen. Oxidation does not necessarily involve oxygen, after which it was named, but is most easily described as the loss of electrons from atoms and molecules. The inverse reaction, reduction, occurs when a molecule gains electrons. As the name suggests, antioxidants like vitamin C can minimize oxidation and are often electron donors.

In biochemistry, the free radicals of interest are often referred to as reactive oxygen species (ROS) because the most biologically significant free radicals are oxygen-centered. But not all free radicals are ROS and not all ROS are free radicals. For example, the free radicals superoxide and hydroxyl radical are ROS, but the ROS hydrogen peroxide (H₂O₂) is not a free radical species.

Denham Harman first proposed this theory, that aging was a consequence of free radical damage in the 1950s ^[1] and extended the idea to implicate mitochondrial production of ROS in the 1970s^[2]. Of all the theories of aging, Harman's has the most consistent experimental support. However models exist (i.e. Sod2+/- mice) that demonstrate increased oxidative stress, without any effect on lifespan. Hence, more data is needed to identify the role of free radicals/oxidative stress in aging.

1 Theory of disease
2 Evidence
3 Antioxidant therapy
4 Calorie restriction
5 See also
6 References
7 External links
- 7.1 Calorie restriction
- 7.2 Biology of Aging

[edit] Theory of disease

One of the underlying concepts that guided Harman to his theory of aging was the involvement of free radicals in disease. 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 Harmon's work.

[edit] Evidence

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% (PMID 15879174). However, the extent of lifespan extension in this model yielded a lifespan equal to that of wild type in some animal colonies (i.e. at the VA Medical Centers at Michigan and San Antonio, for example).
Making a well-studied roundworm, Caenorhabditis elegans, more susceptible to free radicals has led to premature aging (PMID 11237107).
A press release by the American Physiological Society shows that mitochondria (which provide the body with most of its energy) become more effective when they contain fewer products that have been generated by free radicals (PMID 16020519).

[edit] Antioxidant therapy

This theory implies that antioxidants (e.g. Vitamin A, vitamin C, and vitamin E) — 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. A particularly interesting development, the dynamic flow model, is a hypothesis originating with the suggestion by Dr. Robert Cathcart that massive intakes of ascorbate can quench disease processes.

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. Similarly, Cutler et al report increased levels of naturally-occurring antioxidants such as uric acid are related to maximum lifespan in Primates.

[edit] Calorie restriction

See main article: Calorie restriction

Calorie restriction, or severely cutting the intake of energy, has been found to reduce mitochondrial ROS production and to increase the life-span of rodents. 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).

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).

[edit] See also

[edit] References

^ Harman, D (1956). "Aging: a theory based on free radical and radiation chemistry". JOURNAL OF GERONTOLOGY 11 (3): 298-300. PMID 13332224.
^ Harman, D (1972). "A biologic clock: the mitochondria?". JOURNAL OF THE AMERICAN GERIATRICS SOCIETY 20 (4): 145-147. PMID 5016631.