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Free-radical theory of aging

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The free-radical theory of aging (FRTA) states that organisms age because cells accumulate free radical damage over time. 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, most biologically-relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with oxidative damage. Antioxidants are reducing agents, and limit oxidative damage to biological structures by passivating free radicals.

Strictly speaking, the free radical theory is only concerned with free radicals such as superoxide ( O2- ), but it has since been expanded to encompass oxidative damage from other reactive oxygen species such as H2O2, or OH-.

Denham Harman first proposed the free radical theory of aging in the 1950s,[1] and in the 1970s extended the idea to implicate mitochondrial production of reactive oxygen species.[2]

In some model organisms, such as yeast and Drosophila, there is evidence that reducing oxidative damage can extend lifespan. In mice, interventions that enhance oxidative damage generally shorten lifespan. However, in roundworms (Caenorhabditis elegans), blocking the production of the naturally occurring antioxidant superoxide dismutase has recently been shown to increase lifespan.[3] Whether reducing oxidative damage below normal levels is sufficient to extend lifespan remains an open and controversial question.

Background

The free radical theory of aging was conceived by Denham Harman in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems, and before anybody had invoked free radicals as a cause of degenerative diseases. Two sources inspired Harman: 1) the rate of living theory, which holds that lifespan is an inverse function of metabolic rate. In turn, this is proportional to oxygen consumption, and 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 include not only 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. 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 signaling. 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 more generalized theory 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 is presently controversial pending further investigation. Both models trace back to Harman's work.

Evidence

  • Mutant strains of the roundworm Caenorhabditis elegans that are more susceptible to free radicals have shortened lifespans, and those with less susceptibility have longer lifespans.[4][5]
  • Drosophila that have mutations in enzymes relating to reactive oxygen species 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.[6][7]
  • While genetic manipulations that increase the levels of oxidative damage generally do shorten lifespan in mice, there is at present very limited evidence that decreasing free radicals below their normal levels actually extends average or maximum lifespan.[8][9]
  • Consumption of high levels of antioxidants, which should increase lifespan under the theory, may extend average but not maximum lifespan in mice. The effect, if present, is weak and only inconsistently observed.[citation needed]
  • In one laboratory, Phenybutylnitrone (PBN) was shown to produce about a 10% extension of maximum lifespan in experimental animals[10]. However, this finding has not been reproduced by other laboratories.
  • Antioxidant supplementation has not been conclusively shown to produce an extension of lifespan in a mammal.[citation needed]

Mitohormesis

Oxidative stress may promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species.[11] This observation was initially named mitohormesis, or mitochondrial hormesis on a purely hypothetical basis.[12] In mammals, the question of the net effect of reactive oxygen species on aging is even less clear.[13][14][15] Recent epidemiological findings support the process of mitohormesis in humans, and even suggest that the intake of exogenous antioxidants may increase disease prevalence in humans (according to the theory, because they prevent the stimulation of the organism's natural response to the oxidant compounds which not only neutralizes them but provides other benefits as well).[16]

Calorie restriction

Main article: Calorie restriction

Severe caloric restriction has been found to reduce reactive oxidative species and to increase the life-span of rodents, possibly by promoting mitohormesis. Studies have shown that both calorie restriction and reduced meal frequency or 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.[17] Extreme calorie restriction, over 50%, resulted in increased mortality.[11][18]

One of the most prominent 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

The free radical theory of aging implies that antioxidants such as Vitamin A, vitamin C, vitamin E, and Superoxide dismutase will slow the process of aging by preventing free radicals from oxidizing sensitive biological molecules or reducing the formation of free radicals. The antioxidant chemicals found in many foods are frequently cited as the basis of claims for the benefits of a high intake of vegetables and fruits in the diet.

Nonetheless, some recent studies tend to show that antioxidant therapy have no effect and can even increase mortality.[19][20][21][22][23][24] Proponents of the theory claim that this phenomenon can be explained by hormesis: The addition of antioxidants can lead to a decrease of normal biological response to free radicals and lead to a more sensitive environment to oxidation. [citation needed] Furthermore, a recent study tracking the eating habits of 478,000 Europeans suggests that consuming lots of fruits and vegetables has little if any effect on preventing cancer.[25]. More recently, it has been suggested [1][2] that in humans extraordinarily-high levels of endogenous antioxidants such as uric acid do not leave a lot of "therapeutic room" for ectopic antioxidants to work.

See also

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. ^ Jeremy M. Van Rammsdonk, Siegfried Hekimi (2009). Kim, Stuart K. (ed.). "Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans". PLoS Genetics. 5 (2): e1000361. doi:10.1371/journal.pgen.1000361. PMC 2628729. PMID 19197346.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  4. ^ Larsen P (1993). "Aging and resistance to oxidative damage in Caenorhabditis elegans". Proc Natl Acad Sci USA. 90 (19): 8905–9. doi:10.1073/pnas.90.19.8905. PMC 47469. PMID 8415630.
  5. ^ Ishii N (2000). "Oxidative stress and aging in Caenorhabditis elegans". Free Radical Research. 33 (6): 857–64. doi:10.1080/10715760000301371. PMID 11237107.
  6. ^ Helfand S, Rogina B (2003). "Genetics of aging in the fruit fly, Drosophila melanogaster". Annu Rev Genet. 37: 329–48. doi:10.1146/annurev.genet.37.040103.095211. PMID 14616064.
  7. ^ Parkes T, Kirby K, Phillips J, Hilliker A (1998). "Transgenic analysis of the cSOD-null phenotypic syndrome in Drosophila". Genome. 41 (5): 642–651. doi:10.1139/gen-41-5-642. PMID 9809435.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ de Magalhães JP, Church GM (2006). "Cells discover fire: Employing reactive oxygen species in development and consequences for aging". Experimental Gerontology. 41 (1): 1–10. doi:10.1016/j.exger.2005.09.002. PMID 16226003. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Sohal RS, Mockett RJ, Orr WC (2002). "Mechanisms of aging: an appraisal of the oxidative stress hypothesis". Free Radic Biol Med. 33 (5): 575–86. doi:10.1016/S0891-5849(02)00886-9. PMID 12208343. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Saito K, Yoshioka H, Cutler RG (1998). "A Spin Trap, N-tert-Butyl-α-phenylnitrone Extends the Life Span of Mice" (– Scholar search). Bioscience, Biotechnology, and Biochemistry. 62 (4): 792–794. doi:10.1271/bbb.62.792. PMID 9614711. {{cite journal}}: External link in |format= (help)CS1 maint: multiple names: authors list (link) [dead link]
  11. ^ a b Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007). "Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress". Cell Metabolism. 6 (4): 280–93. doi:10.1016/j.cmet.2007.08.011. PMID 17908557.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Tapia PC (2006/2005(epub)). "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". Medical Hypotheses. 66 (4): 832–43. doi:10.1016/j.mehy.2005.09.009. PMID 16242247. {{cite journal}}: Check date values in: |year= (help)CS1 maint: year (link)
  13. ^ 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. doi:10.1016/S0891-5849(02)00886-9. PMID 12208343.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Sohal R (2002). "Role of oxidative stress and protein oxidation in the aging process". Free Radic Biol Med. 33 (1): 37–44. doi:10.1016/S0891-5849(02)00856-0. PMID 12086680.
  15. ^ Rattan S (2006). "Theories of biological aging: genes, proteins, and free radicals". Free Radic Res. 40 (12): 1230–8. doi:10.1080/10715760600911303. PMID 17090411.
  16. ^ Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007). "Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis". The Journal of the American Medical Association. 297 (8): 842–57. doi:10.1001/jama.297.8.842. PMID 17327526.{{cite journal}}: CS1 maint: multiple names: authors list (link). See also the letter to JAMA by Philip Taylor and Sanford Dawsey and the reply by the authors of the original paper.
  17. ^ {http://www.ncbi.nlm.nih.gov/pubmed/16446459 Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency].
  18. ^ Mattson MP (2005). "Energy intake, meal frequency, and health: a neurobiological perspective". Annual Review of Nutrition. 25: 237–60. doi:10.1146/annurev.nutr.25.050304.092526. PMID 16011467.
  19. ^ The Alpha-Tocopherol, Beta Carotine Cancer Prevention Study Group (1994). "The effect of vitamin E and beta carotine on the incidence of lung cancer and other cancers in male smokers". New England Journal of Medicine. 330 (15): 1029–35. doi:10.1056/NEJM199404143301501. PMID 8127329.
  20. ^ Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A; et al. (1996). "Effects of a combination of beta carotine and vitamin A on lung cancer and cardiovascular disease". New England Journal of Medicine. 334 (18): 1150–5. doi:10.1056/NEJM199605023341802. PMID 8602180. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  21. ^ Bjelakovic G, Nikolova D, Simonetti RG, Gluud C (2004). "Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis". Lancet. 364 (9441): 1219–28. doi:10.1016/S0140-6736(04)17138-9. PMID 15464182.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LG, Guallar E. (2005). "Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality". Annals of Internal Medicine. 142 (1): 37–46. PMID 15537682.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  23. ^ Heart Protection Study Collaborative Group (2002). "MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,356 high-risk individuals: a randomised placebo-controlled trial". Lancet. 360 (9326): 23–33. doi:10.1016/S0140-6736(02)09328-5. PMID 12114037.
  24. ^ Age-Related Eye Disease Study Research Group (2001). "A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E and Beta Carotene for Age-Related Cataract and Vision Loss: AREDS Report No. 9". Arch Ophthalmol. 119 (10): 1439–52. doi:10.1001/archopht.119.10.1439. PMC 1472812. PMID 11594943.
  25. ^ Boffetta P, Couto E, Wichmann J; et al. (2010). "Fruit and vegetable intake and overall cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC". J Natl Cancer Inst. 102 (8): 529–37. doi:10.1093/jnci/djq072. PMID 20371762. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  2. Muller, F. L., Lustgarten, M. S., Jang, Y., Richardson, A. and Van Remmen, H. (2007). "Trends in oxidative aging theories". Free Radical Biology & Medicine. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Calorie restriction

Biology of Aging

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