Free Radical Theory of Aging: An Update: Increasing the Functional Life Span
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Nrf2 is a pro-longevity signaling pathway.
“Nrf2 is a pro‐longevity signaling pathway (Harman, 2006) and also a key mediator of the beneficial effects of calorie restriction.”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Harman, 2006
Cites
Aging: a theory based on free radical and radiation chemistry
Harman, D. (1956) · Journal of Gerontology · doi:10.1093/geronj/11.3.298 · Cited by 8,567 · see citing works
Self-citationThe Pathophysiology and Treatment of Sepsis
Hotchkiss, R. S., & Karl, I. E. (2003) · New England Journal of Medicine · doi:10.1056/nejmra021333 · Cited by 4,098 · see citing works
Mitochondrial diseases in man and mouse
Wallace, D. C. (1999) · Science · doi:10.1126/science.283.5407.1482 · Cited by 3,060 · see citing works
Premature ageing in mice expressing defective mitochondrial DNA polymerase
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly-Y, M., Gidlöf, S., Oldfors, A., Wibom, R., et al. (2004) · Nature · doi:10.1038/nature02517 · Cited by 2,734 · see citing works
Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study
Møller, J. T., Cluitmans, P. P., Rasmussen, L., Houx, P. J., Rasmussen, H., Canet, J., Rabbitt, P., Jolles, J., Larsen, K., Hanning, C. D., et al. (1998) · The Lancet · doi:10.1016/s0140-6736(97)07382-0 · Cited by 2,407 · see citing works
Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome
Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J. I., Scott, L. J., Erdos, M. R., Robbins, C. M., Moses, T. Y., Berglund, P., et al. (2003) · Nature · doi:10.1038/nature01629 · Cited by 2,217 · see citing works
Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging
Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T., Seo, A. Y., Sullivan, R., Jobling, W. A., et al. (2005) · Science · doi:10.1126/science.1112125 · Cited by 2,165 · see citing works
The Biologic Clock: The Mitochondria?
Harman, D. (1972) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1972.tb00787.x · Cited by 1,991 · see citing works
Self-citationHarman, D. (1981) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.78.11.7124 · Cited by 1,915 · see citing works
Self-citationExtension of murine life span by overexpression of catalase targeted to mitochondria
Schriner, S. E., Linford, N. J., Martin, G. M., Treuting, P., Ogburn, C. E., Emond, M., Coskun, P. E., Ladiges, W., Wolf, N., Van Remmen, H., et al. (2005) · Science · doi:10.1126/science.1106653 · Cited by 1,724 · see citing works
Gray, M. W., Burger, G., & Lang, B. F. (1999) · Science · doi:10.1126/science.283.5407.1476 · Cited by 1,710 · see citing works
The Free Radical Theory of Aging
Harman, D. (2003) · Antioxidants and Redox Signaling · doi:10.1089/152308603770310202 · Cited by 926 · see citing works
Self-citationGlutathione-ascorbic acid antioxidant system in animals
Meister, A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36891-6 · Cited by 812 · see citing works
Sohal, R. S., Ku, H.-H., Agarwal, S., Forster, M. J., & Lal, H. (1994) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(94)90104-x · Cited by 788 · see citing works
Genome-Wide Transcript Profiles in Aging and Calorically Restricted Drosophila melanogaster
Pletcher, S. D., Macdonald, S. J., Marguerie, R., Certa, U., Stearns, S. C., Goldstein, D. B., & Partridge, L. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00808-4 · Cited by 568 · see citing works
Matthews, R. T., Yang, L., Browne, S., Baik, M., & Beal, M. F. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.15.8892 · Cited by 557 · see citing works
Barja, G. (1999) · Journal of Bioenergetics and Biomembranes · doi:10.1023/a:1005427919188 · Cited by 494 · see citing works
Ku, H., Brunk, U. T., & Sohal, R. S. (1993) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(93)90165-q · Cited by 488 · see citing works
Mitochondrial regulation of apoptotic cell death
Orrenius, S. (2004) · Toxicology Letters · doi:10.1016/j.toxlet.2003.12.017 · Cited by 482 · see citing works
Trinei, M., Giorgio, M., Cicalese, A., Barozzi, S., Ventura, A., Migliaccio, E., Milia, E., Padura, I. M., Raker, V. A., Maccarana, M., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205513 · Cited by 436 · see citing works
Harman, D. (2001) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2001.tb05631.x · Cited by 416 · see citing works
Self-citationHandbook of Aging and the Individual
Brozek, J. M. (1961) · Journal of Gerontology · doi:10.1093/geronj/16.2.129 · Cited by 338 · see citing works
Schorah, C., Downing, C. P., Piripitsi, A., Gallivan, L., Al-Hazaa, A., Sanderson, M., & Bodenham, A. R. (1996) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/63.5.760 · Cited by 314 · see citing works
Mitochondrial genotype associated with longevity
Tanaka, M., Gong, J., Zhang, J., Yoneda, M., & Yagi, K. (1998) · The Lancet · doi:10.1016/s0140-6736(05)78211-8 · Cited by 314 · see citing works
Hagen, T. M., Liu, J., Lykkesfeldt, J., Wehr, C. M., Ingersoll, R. T., Vinarsky, V., Bartholomew, J. C., & Ames, B. N. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.261708898 · Cited by 313 · see citing works
de la Asunción, J. G., Millan, A., Plá, R. C. I., Bruseghini, L., Esteras, A., Pallardó, F. V., Sastre, J., & Viña, J. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.2.8641567 · Cited by 299 · see citing works
Barja, G., Cadenas, S., Rojas, C., Pérez‐Campo, R., & Lopez‐Torres, M. (1994) · Free Radical Research · doi:10.3109/10715769409056584 · Cited by 267 · see citing works
(1963) · Food and Cosmetics Toxicology · doi:10.1016/s0015-6264(63)80681-1 · Cited by 262 · see citing works
Free radical theory of aging: Consequences of mitochondrial aging
Harman, D. (1983) · AGE · doi:10.1007/bf02432509 · Cited by 244 · see citing works
Self-citationKu, H., & Sohal, R. S. (1993) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(93)90132-b · Cited by 240 · see citing works
Immune Function in Patients Undergoing Open vs Laparoscopic Cholecystectomy
Redmond, H. P. (1994) · Archives of Surgery · doi:10.1001/archsurg.1994.01420360030003 · Cited by 237 · see citing works
Free Radical Involvement in Aging
Harman, D. (1993) · Drugs & Aging · doi:10.2165/00002512-199303010-00006 · Cited by 229 · see citing works
Self-citationRole of Free Radicals in Mutation, Cancer, Aging, and the Maintenance of Life
Harman, D. (1962) · Radiation Research · doi:10.2307/3571274 · Cited by 206 · see citing works
Self-citationSiblings of centenarians live longer
Perls, T. T., Bubrick, E. J., Wager, C. G., Vijg, J., & Kruglyak, L. (1998) · The Lancet · doi:10.1016/s0140-6736(05)61126-9 · Cited by 194 · see citing works
Prevention of Mitochondrial Oxidative Damage Using Targeted Antioxidants
Kelso, G. F., Porteous, C. M., Hughes, G., Ledgerwood, E. C., Gane, A. M., Smith, R. A. J., & Murphy, M. P. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb02098.x · Cited by 130 · see citing works
Biochemical Correlates of Longevity in Two Closely Related Rodent Species
Sohal, R. S., Ku, H.-H., & Agarwal, S. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.2208 · Cited by 114 · see citing works
Cancer prevention and diet: Help from single nucleotide polymorphisms
Ames, B. N. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.22.12216 · Cited by 110 · see citing works
Surface localization of sites of reduction of nitroxide spin-labeled molecules in mitochondria.
Quintanilha, A. T., & Packer, L. (1977) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.74.2.570 · Cited by 107 · see citing works
Free radical theory of aging: History
Harman, D. (1992) · Birkhäuser Basel eBooks · doi:10.1007/978-3-0348-7460-1_1 · Cited by 104 · see citing works
Self-citationAging: Prospects for further increases in the functional life span
Harman, D. (1994) · AGE · doi:10.1007/bf02435819 · Cited by 101 · see citing works
Self-citationOrigin and Comparison of the Effects of Time and High-Energy Radiations on Living Systems
Strehler, B. L. (1959) · The Quarterly Review of Biology · doi:10.1086/402632 · Cited by 100 · see citing works
Delaying the Mitochondrial Decay of Aging
Ames, B. N. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1297.073 · Cited by 94 · see citing works
Ionizing Radiation and the Aging Process: A Review
Upton, A. C. (1957) · Journal of Gerontology · doi:10.1093/geronj/12.3.306 · Cited by 85 · see citing works
Role of antioxidant nutrients in aging: Overview
Harman, D. (1995) · AGE · doi:10.1007/bf02432519 · Cited by 79 · see citing works
Self-citationMiquel, J., & Economos, A. C. (1979) · Experimental Gerontology · doi:10.1016/0531-5565(79)90039-1 · Cited by 78 · see citing works
Cuzzocrea, S., McDonald, M. C., Mota‐Filipe, H., Costantino, G., Mazzon, E., Santagati, S., Caputi, A. P., & Thiemermann, C. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(99)00910-3 · Cited by 65 · see citing works
Alzheimer's Disease: Role of Aging in Pathogenesis
Harman, D. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb02109.x · Cited by 64 · see citing works
Self-citationEffectiveness of antioxidants in refined, bleached and deodorized palm olein
Augustin, M. A., & Berry, S. K. (1983) · Journal of the American Oil Chemists Society · doi:10.1007/bf02540904 · Cited by 50 · see citing works
Alzheimer’s disease: A hypothesis on pathogenesis
Harman, D. (2000) · AGE · doi:10.1007/s11357-000-0017-6 · Cited by 16 · see citing works
Self-citationHarman, D. (1999) · Rejuvenation Research · doi:10.1089/rej.1.1999.2.199 · Cited by 16 · see citing works
Self-citationKitani, K., & Ivy, G. O. (2003) · Biogerontology · doi:10.1023/b:bgen.0000006561.15498.68 · Cited by 13 · see citing works
Fossel, M. (2003) · Rejuvenation Research · doi:10.1089/109454503769684793 · Cited by 9 · see citing works
Cause of Progeria's Premature Aging Found
Vastag, B. (2003) · JAMA · doi:10.1001/jama.289.19.2481 · Cited by 4 · see citing works
SENS Acquires SENSe: Present and Future Anti-Aging Strategies
Riga, D. (2003) · Rejuvenation Research · doi:10.1089/109454503322733081 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · see citing works
The mitochondrial energy transduction system and the aging process
Navarro, A., & Boveris, A. (2007) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00213.2006 · Cited by 646 · see citing works
Systemic adaptation to oxidative challenge induced by regular exercise
Radak, Z., Chung, H. Y., & Goto, S. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.01.029 · Cited by 623 · see citing works
Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
Wang, R., Yu, Z., Sunchu, B., Shoaf, J., Dang, I., Zhao, S., Caples, K., Bradley, L., Beaver, L. M., Ho, E., et al. (2017) · Aging Cell · doi:10.1111/acel.12587 · Cited by 360 · see citing works
Vascular biology of ageing—Implications in hypertension
Harvey, A., Montezano, A. C., & Touyz, R. M. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.04.011 · Cited by 330 · see citing works
Exercise and the aging immune system
Simpson, R. J., Lowder, T. W., Spielmann, G., Bigley, A. B., LaVoy, E. C., & Kunz, H. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2012.03.003 · Cited by 281 · see citing works
Abnormal lung aging in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis
Faner, R., Rojas, M., MacNee, W., & Agustí, A. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201202-0282pp · Cited by 268 · see citing works
The clinical implications of ageing for rational drug therapy
Shi, S., Mörike, K., & Klotz, U. (2008) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-007-0422-1 · Cited by 244 · see citing works
Nimgampalle, M. (2017) · JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH · doi:10.7860/jcdr/2017/26106.10428 · Cited by 241 · see citing works
Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence
Hara, H., Araya, J., Ito, S., Kobayashi, K., Takasaka, N., Yoshii, Y., Wakui, H., Kojima, J., Shimizu, K., Numata, T., et al. (2013) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00146.2013 · Cited by 219 · see citing works
Cellular signaling in the aging immune system
Fulop, T., Le Page, A., Fortin, C., Witkowski, J. M., Dupuis, G., & Larbi, A. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.05.007 · Cited by 158 · see citing works
Brandenberger, C., & Mühlfeld, C. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2511-x · Cited by 152 · see citing works
Callaghan, T. M., & Wilhelm, K. ‐. (2008) · International Journal of Cosmetic Science · doi:10.1111/j.1468-2494.2008.00454.x · Cited by 149 · see citing works
Oxidative stress modulation and T cell activation
Larbi, A., Kempf, J., & Pawelec, G. (2007) · Experimental Gerontology · doi:10.1016/j.exger.2007.05.004 · Cited by 102 · see citing works
Olivieri, F., Lazzarini, R., Babini, L., Prattichizzo, F., Rippo, M. R., Tiano, L., Di Nuzzo, S., Graciotti, L., Festa, R., Brugè, F., et al. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.05.033 · Cited by 84 · see citing works
Mitochondrial dynamics: orchestrating the journey to advanced age
Biala, A. K., Dhingra, R., & Kirshenbaum, L. A. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.04.015 · Cited by 82 · see citing works
Tung, B. T., Rodríguez-Bies, E., Ballesteros-Simarro, M., Motilva, V., Navas, P., & López-Lluch, G. (2014) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt102 · Cited by 60 · see citing works
Mehdi, M. M., Solanki, P., & Singh, P. (2021) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2021.104413 · Cited by 54 · see citing works
The importance of mitochondrial DNA in aging and cancer
Desler, C., Marcker, M. L., Singh, K. K., & Rasmussen, L. J. (2011) · Journal of Aging Research · doi:10.4061/2011/407536 · Cited by 49 · see citing works
Age-Related Changes in Antioxidant Enzymes Related to Hydrogen Peroxide Metabolism in Rat Inner Ear
Coling, D., Chen, S., Chi, L.-H., Jamesdaniel, S., & Henderson, D. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.08.015 · Cited by 46 · see citing works
- Authors
- HARMAN, D.
- Affiliations
- Nebraska Medical Center (US)
- Corresponding author
- HARMAN, DENHAM
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2006-05
- Volume
- 1067
- Issue
- 1
- Pages
- 10-21
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W1951314249
- Cited by
- 601
- References
- 54
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 16 · 2023: 18 · 2022: 26 · 2021: 32 · 2020: 36 · 2019: 31 · 2018: 35 · 2017: 33 · 2016: 33 · 2015: 45 · 2014: 39 · 2013: 40 · 2012: 36
- FWCI
- 2.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Physical Sciences › Chemistry › Organic Chemistry › Free Radicals and Antioxidants
- Keywords
- free radical theory of aging, free radicals, maximum lifespan, healthspan, aging and disease
- MeSH terms
- Aging, Biological Evolution, Free Radicals, Humans, Life Expectancy, Longevity, Models, Biological, Mortality
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
