Free-radical theory

The free-radical theory of aging is that organisms age because cells accumulate free radical damage with the passage of time. In general, a "free radical" is any molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are stable over eons, most biologically-relevant free radicals are fairly reactive. For most biological structures free radical damage is closely associated with oxidation damage. Oxidation and reduction are redox chemical reactions. Most people can equate to oxidation damage as they are familiar with the process of rust formation of iron 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 the atoms and molecules forming such biological structures. The inverse reaction, reduction, occurs when a molecule gains electrons. As the name suggests, antioxidants like vitamin C prevent oxidation and are often electron donators.

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 the FRTA in the 1950s and extended the idea to implicate mitochondrial production of ROS in the 1970s. 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.

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.

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).
 * 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).

Antioxidant therapy
This theory implies that antioxidants (e.g. Vitamin A, vitamin C, and vitamin E) &mdash; which prevent free radicals from oxidizing sensitive biological molecules, or reduce the formation of free radicals &mdash; 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.

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. 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).

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