Free Radical Theory of Aging: An Update

Abstract:  Aging is the progressive accumulation of diverse, deleterious changes with time that increase the chance of disease and death. The basic chemical process underlying aging was first advanced by the free radical theory of aging (FRTA) in 1954: the reaction of active free radicals, normally produced in the organisms, with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. Aging changes are commonly attributed to development, genetic defects, the environment, disease, and an inborn aging process (IAP). The latter produces aging changes at an exponentially increasing rate with age, becoming the major risk factor for disease and death for humans after the age of 28 years in the developed countries. In them the IAP limits human average life expectancy at birth (ALE‐B)—a rough measure of the healthy life span—to about 85 years; few reach 100 years and only one is known to have lived to 122 years. In these countries, improvements in living conditions (ILC) have gradually raised ALE‐Bs to 76–79 years, 6–9 years less than the limit imposed by aging, with no change in the maximum life span (MLS). The extensive studies based on the FRTA hold promise that ALE‐B and the MLS can be extended, the ALE‐B possibly by a few years, and the MLS somewhat less.

[1]  D. Harman Role of antioxidant nutrients in aging: Overview , 1995, AGE.

[2]  D. Harman Aging: Prospects for further increases in the functional life span , 1994, AGE.

[3]  D. Harman Free radical theory of aging: Consequences of mitochondrial aging , 1983, AGE.

[4]  T. D. Pugh,et al.  Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging , 2005, Science.

[5]  M. Emond,et al.  Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria , 2005, Science.

[6]  B. Ames Delaying the Mitochondrial Decay of Aging , 2004, Annals of the New York Academy of Sciences.

[7]  Howard T. Jacobs,et al.  Premature ageing in mice expressing defective mitochondrial DNA polymerase , 2004, Nature.

[8]  S. Orrenius Mitochondrial regulation of apoptotic cell death. , 2003, Toxicology letters.

[9]  B. Vastag Cause of Progeria's Premature Aging Found , 2003 .

[10]  Laura Scott,et al.  Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome , 2003, Nature.

[11]  R. Hotchkiss,et al.  The pathophysiology and treatment of sepsis. , 2003, The New England journal of medicine.

[12]  Denham Harman,et al.  "I thought, thought, thought for four months in vain and suddenly the idea came"--an interview with Denham and Helen Harman. Interview by K. Kitani and G.O. Ivy. , 2003, Biogerontology.

[13]  B. Vastag Cause of progeria's premature aging found: expected to provide insight into normal aging process. , 2003, JAMA.

[14]  D. Riga SENS acquires SENSe: present and future anti-aging strategies. 10th Congress IABG - International Association of Biomedical Gerontology: SENS - Strategies for Engineered Negligible Senescence: reason why genuine control of aging may be foreseeble Queen's College, Cambridge, UK, September 19-23, 2003 , 2003, Journal of anti-aging medicine.

[15]  S. Minucci,et al.  A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis , 2002, Oncogene.

[16]  David B. Goldstein,et al.  Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster , 2002, Current Biology.

[17]  Robin A. J. Smith,et al.  Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants , 2002, Annals of the New York Academy of Sciences.

[18]  D. Harman Alzheimer's Disease: Role of Aging in Pathogenesis , 2002, Annals of the New York Academy of Sciences.

[19]  James C Bartholomew,et al.  Feeding acetyl-l-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[20]  D. Harman Aging: Overview , 2001, Annals of the New York Academy of Sciences.

[21]  D. Harman Alzheimer’s disease: A hypothesis on pathogenesis , 2000, Journal of the American Aging Association.

[22]  E. Mazzon,et al.  Effects of tempol, a membrane-permeable radical scavenger, in a rodent model of carrageenan-induced pleurisy. , 2000, European journal of pharmacology.

[23]  B. Ames Cancer prevention and diet: help from single nucleotide polymorphisms. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  G. Barja Mitochondrial Oxygen Radical Generation and Leak: Sites of Production in States 4 and 3, Organ Specificity, and Relation to Aging and Longevity , 1999, Journal of bioenergetics and biomembranes.

[25]  D. Wallace Mitochondrial diseases in man and mouse. , 1999, Science.

[26]  D. Harman Free Radical Theory of Aging: Increasing the Average Life Expectancy at Birth and the Maximum Life Span , 1999 .

[27]  S. Browne,et al.  Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  L. Kruglyak,et al.  Siblings of centenarians live longer , 1998, The Lancet.

[29]  P. Rabbitt,et al.  Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study , 1998, The Lancet.

[30]  K. Yagi,et al.  Mitochondrial genotype associated with longevity , 1998, The Lancet.

[31]  A. Bodenham,et al.  Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. , 1996, The American journal of clinical nutrition.

[32]  J. Sastre,et al.  Mitochondrial glutathione oxidation correlates with age‐associated oxidative damage to mitochondrial DNA , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  E. Kobayashi,et al.  Immune function in patients undergoing open vs laparoscopic cholecystectomy. , 1995, Archives of surgery.

[34]  S. Cadenas,et al.  Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds. , 1994, Free radical research.

[35]  R. S. Sohal,et al.  Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse , 1994, Mechanisms of Ageing and Development.

[36]  A. Meister Glutathione-ascorbic acid antioxidant system in animals. , 1994, The Journal of biological chemistry.

[37]  R. S. Sohal,et al.  Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. , 1993, Free radical biology & medicine.

[38]  R. S. Sohal,et al.  Comparison of mitochondrial pro-oxidant generation and anti-oxidant defenses between rat and pigeon: possible basis of variation in longevity and metabolic potential , 1993, Mechanisms of Ageing and Development.

[39]  R. S. Sohal,et al.  Biochemical correlates of longevity in two closely related rodent species. , 1993, Biochemical and biophysical research communications.

[40]  D. Harman Free Radical Involvement in Aging , 1993 .

[41]  D. Harman Free radical involvement in aging. Pathophysiology and therapeutic implications. , 1993, Drugs & aging.

[42]  D. Harman Free‐Radical Theory of Aging , 1992, Mutation research.

[43]  D. Harman Free radical theory of aging: history. , 1992, EXS.

[44]  G. Jantzen 1988 , 1988, The Winning Cars of the Indianapolis 500.

[45]  M. A. Augustin,et al.  Effectiveness of antioxidants in refined, bleached and deodorized palm olein , 1983 .

[46]  D. Harman,et al.  The aging process. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Miquel,et al.  Favorable effects of the antioxidants sodium and magnesium thiazolidine carboxylate on the vitality and life span of Drosophila and mice , 1979, Experimental Gerontology.

[48]  L. Packer,et al.  Surface localization of sites of reduction of nitroxide spin-labeled molecules in mitochondria. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Denham Harman,et al.  The Biologic Clock: The Mitochondria? , 1972, Journal of the American Geriatrics Society.

[50]  D. Harman,et al.  Role of free radicals in mutation, cancer, aging, and the maintenance of life. , 1962, Radiation research.

[51]  Hardin B. Jones,et al.  The relation of human health to age, place, and time , 1960 .

[52]  B. Strehler Origin and Comparison of the Effects of Time and High-Energy Radiations on Living Systems , 1959, The Quarterly Review of Biology.

[53]  Stanley L. Miller,et al.  THE FORMATION OF ORGANIC COMPOUNDS ON THE PRIMITIVE EARTH , 1957, Annals of the New York Academy of Sciences.

[54]  A. Upton Ionizing radiation and the aging process; a review. , 1957, Journal of gerontology.

[55]  D. Harman Aging: a theory based on free radical and radiation chemistry. , 1956, Journal of gerontology.

[56]  Donna L. Hoyert,et al.  Vital Statistics of the United States , 1940, Nature.