Free-radical theory

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 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.

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. The free-radical theory of aging also encompasses damage due to these compounds, however.

Denham Harman first proposed the FRTA in the 1950s [cite journal | author=Harman, D | title=Aging: a theory based on free radical and radiation chemistry | journal=Journal of Gerontology | volume=11 | issue=3 | year=1956 | pages=298–300 | pmid=13332224 ] and extended the idea to implicate mitochondrial production of ROS in the 1970s [cite journal | author=Harman, D | title=A biologic clock: the mitochondria? | journal=Journal of the American Geriatrics Society |volume=20 |issue=4 |year=1972 |pages=145–147 |pmid=5016631 ] . 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.

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

* 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% [cite journal |author=Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS |title=Extension of murine life span by overexpression of catalase targeted to mitochondria |journal=Science |volume=308 |issue=5730 |pages=1909–11 |year=2005 |pmid=15879174 |doi=10.1126/science.1106653] . 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 [cite journal |author=Ishii N |title=Oxidative stress and aging in Caenorhabditis elegans |journal=Free Radical Research |volume=33 |issue=6 |pages=857–64 |year=2000 |pmid=11237107 |doi=10.1080/10715760000301371] . 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). [ T Parkes, K Kirby, J Phillips, A Hilliker. 1998. "Transgenic analysis of the cSOD-null phenotypic syndrome in Drosophila". "Genome" 41: 642–651. ]
* 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 [cite journal |url= |author=Saito K, Yoshioka H, Cutler RG |title=A Spin Trap, N-"tert"-Butyl-"α"-phenylnitrone Extends the Life Span of Mice |journal=Bioscience, Biotechnology, and Biochemistry |volume=62 |issue=4 |pages=792–794 |year=1998 |pmid=9614711 |doi=10.1271/bbb.62.792 ] in one laboratory, 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" [cite journal |author=Helfand S, Rogina B |title=Genetics of aging in the fruit fly, Drosophila melanogaster |journal=Annu Rev Genet |volume=37 |issue= |pages=329–48 |year= 2003|pmid=14616064 |doi=10.1146/annurev.genet.37.040103.095211] and "Caenorhabditis elegans", [cite journal |author=Larsen P |title=Aging and resistance to oxidative damage in Caenorhabditis elegans |url= |journal=Proc Natl Acad Sci U S A |volume=90 |issue=19 |pages=8905–9 |year=1993 |pmid=8415630 |doi=10.1073/pnas.90.19.8905] 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. cite journal |author=Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M |title=Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress |journal=Cell Metabolism |volume=6 |issue=4 |pages=280–93 |year=2007 |pmid=17908557 |url= |doi=10.1016/j.cmet.2007.08.011] This process was previously named mitohormesis or mitochondrial hormesis on a purely hypothetical basis. [ cite journal |author=Tapia PC |title=Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality |journal=Medical Hypotheses |volume=66 |issue=4 |pages=832–43 |year=2006/2005(epub) |pmid=16242247] . The situation in mammals is even less clear. [cite journal |author=Sohal R, Mockett R, Orr W |title=Mechanisms of aging: an appraisal of the oxidative stress hypothesis |journal=Free Radic Biol Med |volume=33 |issue=5 |pages=575–86 |year=2002 |pmid=12208343 |doi=10.1016/S0891-5849(02)00886-9] [cite journal |author=Sohal R |title=Role of oxidative stress and protein oxidation in the aging process |journal=Free Radic Biol Med |volume=33 |issue=1 |pages=37–44 |year=2002 |pmid=12086680 |doi=10.1016/S0891-5849(02)00856-0] [cite journal |author=Rattan S |title=Theories of biological aging: genes, proteins, and free radicals |journal=Free Radic Res |volume=40 |issue=12 |pages=1230–8 |year=2006 |pmid=17090411 |doi=10.1080/10715760600911303] 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). [ cite journal |url= |author=Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C |title=Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis |journal=The Journal of the American Medical Association |volume=297 |issue=8 |pages=842–57 |year=2007 |pmid=17327526 |doi=.See also the [ letter] to JAMA by Philip Taylor and Sanford Dawsey and the [ reply] by the authors of the original paper.]

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 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 [cite journal |author=Mattson MP |title=Energy intake, meal frequency, and health: a neurobiological perspective |journal=Annual Review of Nutrition |issue=25 |pages=237–60 |year=2005 |pmid=16011467 |doi=10.1146/annurev.nutr.25.050304.092526 |volume=25] ff]

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.

ee also

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


  • cite journal | author=Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. | title=Trends in oxidative aging theories | journal=Free Radical Biology & Medicine | volume=43 | issue=4 | year=2007 | pages=477–503 | pmid=17640558 | doi=10.1016/j.freeradbiomed.2007.03.034
  • 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]

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