471:
25:
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of radical production occurs. The free radicals produced in such reactions often terminate by removing an electron from a molecule which becomes changed or cannot function without it, especially in biology. Such an event causes damage to the molecule, and thus to the cell that contains it (since the
482:
The mitochondrial theory of aging was first proposed in 1978, and two years later, the mitochondrial free-radical theory of aging was introduced. The theory implicates the mitochondria as the chief target of radical damage, since there is a known chemical mechanism by which mitochondria can produce
353:
Damage occurs when the free radical encounters another molecule and seeks to find another electron to pair its unpaired electron. The free radical often pulls an electron off a neighboring molecule, causing the affected molecule to become a free radical itself. The new free radical can then pull an
519:
Contrary to the usually observed association between mitochondrial ROS (mtROS) and a decline in longevity, Yee et al. recently observed increased longevity mediated by mtROS signaling in an apoptosis pathway. This serves to support the possibility that observed correlations between ROS damage and
314:
and most importantly mitochondrial DNA. This damage then causes mutations which lead to an increase of ROS production and greatly enhance the accumulation of free radicals within cells. This mitochondrial theory has been more widely accepted that it could play a major role in contributing to the
515:
Afanas'ev suggests the superoxide dismutation activity of CuZnSOD demonstrates an important link between life span and free radicals. The link between CuZnSOD and life span was demonstrated by Perez et al. who indicated mice life span was affected by the deletion of the Sod1 gene which encodes
544:
The metabolic stability theory of aging suggests it is the cells ability to maintain stable concentration of ROS which is the primary determinant of lifespan. This theory criticizes the free radical theory because it ignores that ROS are specific signalling molecules which are necessary for
255:
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
589:. ROS production in heart, skeletal muscle, liver and intact erythrocytes was found to be similar in parrots and quail and showed no correspondence with longevity difference. These findings were concluded to cast doubt on the robustness of the oxidative stress theory of aging.
511:
This theory has been widely debated and it is still unclear how ROS induced mtDNA mutations develop. Conte et al. suggest iron-substituted zinc fingers may generate free radicals due to the zinc finger proximity to DNA and thus lead to DNA damage.
242:
in the 1950s, when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems. This was also before anyone invoked free radicals as a cause of degenerative diseases. Two sources inspired Harman: 1) the
1396:
Gensler, H.L., Hall, J.J., and
Bernstein, H. (1987). The DNA damage hypothesis of aging: Importance of oxidative damage. In “Review of Biological Research in Aging.” Vol. 3 (M. Rothstein, ed.), pp. 451–465. Alan R. Liss, New
520:
aging are not necessarily indicative of the causal involvement of ROS in the aging process but are more likely due to their modulating signal transduction pathways that are part of cellular responses to the aging process.
346:
in atoms or molecules. Free radicals, which contain only a single electron in any orbital, are usually unstable toward losing or picking up an extra electron, so that all electrons in the atom or molecule will be paired.
212:, there is evidence that reducing oxidative damage can extend lifespan. However, in mice, only 1 of the 18 genetic alterations (SOD-1 deletion) that block antioxidant defences, shortened lifespan. Similarly, in
567:
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).
487:
are not as well protected as nuclear DNA, and by studies comparing damage to nuclear and mtDNA that demonstrate higher levels of radical damage on the mitochondrial molecules. Electrons may escape from
2088:
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".
1428:
Bamm VV, Tsemakhovich VA, Shaklai N. Oxidation of low-density lipoprotein by hemoglobin–hemichrome. The
International Journal of Biochemistry & Cell Biology. 2003;35(3) 349-58.
1415:
Pageon H, Asselineau D. An in Vitro
Approach to the Chronological Aging of Skin by Glycation of the Collagen: The Biological Effect of Glycation on the Reconstructed Skin Model"
559:
by inducing a secondary response to initially increased levels of ROS. In mammals, the question of the net effect of reactive oxygen species on aging is even less clear. Recent
35:
436:
are helpful in reducing and preventing damage from free radical reactions because of their ability to donate electrons which neutralize the radical without forming another.
644:
Erbas M, Sekerci H. "Importance of Free
Radicals and Occurring During Food Processing". Serbest Radïkallerïn Onemï Ve Gida Ïsleme Sirasinda Olusumu. 2011: 36(6) 349–56.
2396:
1145:"Oxidative stress induces protein and DNA radical formation in follicular dendritic cells of the germinal center and modulates its cell death patterns in late sepsis"
2355:
2127:
Montgomery MK, Hulbert AJ, Buttemer WA (2012). "Does the oxidative stress theory of aging explain longevity differences in birds? I. Mitochondrial ROS production".
283:. There has been some evidence to suggest that free radicals and some reactive nitrogen species trigger and increase cell death mechanisms within the body such as
362:
The chain reaction caused by free radicals can lead to cross-linking of atomic structures. In cases where the free radical-induced chain reaction involves
1091:
Speakman JR, Selman C (2011). "The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan".
504:. These radicals then damage the mitochondria's DNA and proteins, and these damage components in turn are more liable to produce ROS byproducts. Thus a
2269:
654:
Herrling T, Jung K, Fuchs J (2008). "The role of melanin as protector against free radicals in skin and its role as free radical indicator in hair".
1720:
Afanas'ev I. Signaling and
Damaging Functions of Free Radicals in Aging-Free Radical Theory, Hormesis, and TOR. Aging And Disease. 2010;1(2) 75–88.
448:
One of the main criticisms of the free radical theory of aging is directed at the suggestion that free radicals are responsible for the damage of
138:
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
440:, for example, can lose an electron to a free radical and remain stable itself by passing its unstable electron around the antioxidant molecule.
470:
2391:
146:, most biologically relevant free radicals are highly reactive. For most biological structures, free radical damage is closely associated with
430:. Specifically, an increase in superoxide affects aging whereas a decrease in nitric oxide formation, or its bioavailability, does the same.
230:
lifespan. Whether reducing oxidative damage below normal levels is sufficient to extend lifespan remains an open and controversial question.
603:
318:
Since Harman first proposed the free radical theory of aging, there have been continual modifications and extensions to his original theory.
2188:
96:
1284:
Orchin M, Macomber RS, Pinhas A, Wilson RM, editors. The
Vocabulary and Concepts of Organic Chemistry. 2 ed: John Wiley & Sons; 2005.
68:
563:
findings support the process of mitohormesis in humans, and even suggest that the intake of exogenous antioxidants may increase disease
2214:
1936:"Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress"
1887:"Age-related transcriptional changes in gene expression in different organs of mice support the metabolic stability theory of aging"
632:
Hekimi S, Lapointe J, Wen Y. Taking a "good" look at free radicals in the aging process. Trends In Cell
Biology. 2011;21(10) 569-76.
536:
shift and impaired mitochondrial function". This mitochondrial impairment leads to more sedentary behaviour and accelerated aging.
75:
2335:
508:
of oxidative stress is established that, over time, can lead to the deterioration of cells and later organs and the entire body.
378:
247:, which holds that lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption, and 2)
82:
613:
465:
381:, and such damages have been proposed to play a key role in the aging of crucial tissues. DNA damage can result in reduced
64:
43:
2386:
1406:
Dizdaroglu M, Jaruga P. Mechanisms of free radical-induced damage to DNA. Free
Radical Research. . 2012;46(4) 382–419.
456:
and organismal aging. Several modifications have been proposed to integrate current research into the overall theory.
350:
The unpaired electron does not imply charge; free radicals can be positively charged, negatively charged, or neutral.
532:
signalling effects in aging. Brewer's theory suggests "sedentary behaviour associated with age triggers an oxidized
263:, but also age-related diseases. Free radical damage within cells has been linked to a range of disorders including
2224:
1195:
Jang YC, Remmen HV (2009). "The mitochondrial theory of aging: Insight from transgenic and knockout mouse models".
1045:
Harman D (2009). "Origin and evolution of the free radical theory of aging: a brief personal history, 1954–2009".
415:. These are examples of how the free-radical theory of aging has been used to neatly "explain" the origin of many
54:
39:
2279:
1835:"Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories"
2181:
493:
195:
first proposed the free radical theory of aging in the 1950s, and in the 1970s extended the idea to implicate
2254:
475:
295:
170:
159:
2381:
2345:
2305:
1975:
Sohal R, Mockett R, Orr W (2002). "Mechanisms of aging: an appraisal of the oxidative stress hypothesis".
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505:
276:
218:
143:
89:
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1781:"The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity Response to Mitochondrial ROS in C. elegans"
244:
1133:
Clancy D, Birdsall J. Flies, worms and the Free
Radical Theory of ageing. Ageing Research Reviews. (0).
165:
Strictly speaking, the free radical theory is only concerned with free radicals such as superoxide ( O
2350:
1626:
842:
663:
489:
223:
2376:
2325:
2229:
2174:
1504:"Signaling and Damaging Functions of Free Radicals in Aging-Free Radical Theory, Hormesis, and TOR"
453:
388:
1454:
Afanas'ev IB (2005). "Free radical mechanisms of aging processes under physiological conditions".
1143:
Chatterjee S, Lardinois O, Bhattacharjee S, Tucker J, Corbett J, Deterding L, et al. (2011).
2152:
2070:
1552:, Chemical abstracts. 1979 v. 91 N 25 91:208561v.Deposited Doc., VINITI 2172-78, 1978, p. 48
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1347:"Intrastrand G-U cross-links generated by the oxidation of guanine in 5′-d(GCU) and 5′-r(GCU)"
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In 1972, Harman modified his original theory. In its current form, this theory proposes that
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Role of mitochondrial processes in the development and aging of organism. Aging and cancer
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2010:
Sohal R (2002). "Role of oxidative stress and protein oxidation in the aging process".
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155:
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1988:
1615:"Stochastic drift in mitochondrial DNA point mutations: a novel perspective ex silico"
995:
Harman D (Jul 1956). "Aging: a theory based on free radical and radiation chemistry".
2370:
2045:
Rattan S (2006). "Theories of biological aging: genes, proteins, and free radicals".
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Brewer proposed a theory which integrates the free radical theory of aging with the
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741:
Harman, D (1956). "Aging: a theory based on free radical and radiation chemistry".
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In later years, the free radical theory was expanded to include not only aging
2320:
2219:
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1902:
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1008:
937:"Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in
754:
675:
608:
564:
423:
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Free radicals that are thought to be involved in the process of aging include
374:
213:
208:
1730:
PĂ©rez VI, Bokov A, Van Remmen H, Mele J, Ran Q, Ikeno Y, et al. (2009).
407:, and this is a key event in the formation of plaque in arteries, leading to
854:
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268:
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1996:
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496:, and these electrons may in turn react with water to form ROS such as the
169:), but it has since been expanded to encompass oxidative damage from other
1707:
1312:
935:
Van
Rammsdonk, Jeremy M.; Hekimi, Siegfried (2009). Kim, Stuart K. (ed.).
886:
PĂ©rez VI, Bokov A, Remmen HV, Mele J, Ran Q, Ikeno Y, et al. (2009).
807:
339:
311:
288:
280:
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iron-replaced zinc finger generates free radicals and causes DNA damage"
1544:
1439:"Normal oxidative damage to mitochondrial and nuclear DNA is extensive"
529:
400:
139:
53:
if you can. Unsourced or poorly sourced material may be challenged and
2300:
582:
412:
392:
307:
264:
1934:
Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007).
1598:
Weindruch, Richard (January 1996). "Calorie Restriction and Aging".
1243:"The mitochondrial free radical theory of ageing—where do we stand?"
829:
Fontana, Luigi; Partridge, Linda; Longo, Valter D. (16 April 2010).
338:
Free radicals are atoms or molecules containing unpaired electrons.
1086:
1084:
656:
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
2315:
586:
533:
484:
325:
222:), blocking the production of the naturally occurring antioxidant
203:
131:
1259:
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1566:
Biogenesis of mitochondria during cell differentiation and aging
2170:
1449:
1447:
403:
molecules, which leads to wrinkles. Free radicals can oxidize
366:
molecules in a strand of DNA, the DNA can become cross-linked.
334:
is any atom, molecule or ion with an unpaired valence electron.
404:
396:
18:
1572:, Deposited Doc. VINITI 19.09.85, â„–6756-Đ’85, 1985, p. 28
1497:
1495:
1493:
1613:
Poovathingal SK, Gruber J, Halliwell B, Gunawan R (2009).
702:"Free radicals and antioxidants: updating a personal view"
786:
Harman, D (1972). "A biologic clock: the mitochondria?".
391:
can in turn lead to various effects of aging, especially
158:, and limit oxidative damage to biological structures by
1296:"Oxidative Stress, Mitochondrial Dysfunction, and Aging"
1828:
1826:
1824:
50:
1736:
Biochimica et Biophysica Acta (BBA) - General Subjects
892:
Biochimica et Biophysica Acta (BBA) - General Subjects
2288:
2205:
1885:Brink TC, Demetrius L, Lehrach H, Adjaye J (2009).
251:'s observation that hyperbaric oxygen toxicity and
831:"Extending Healthy Life Span—From Yeast to Humans"
238:The free radical theory of aging was conceived by
1280:
1278:
1040:
1038:
1036:
553:Oxidative stress may promote life expectancy of
385:, cell death and ultimately tissue dysfunction.
2356:Strategies for engineered negligible senescence
2090:The Journal of the American Medical Association
1732:"Is the oxidative stress theory of aging dead?"
888:"Is the oxidative stress theory of aging dead?"
354:electron off the next molecule, and a chemical
1392:
1390:
49:Please review the contents of the article and
2182:
2122:
2120:
1672:Conte D, Narindrasorasak S, Sarkar B (1996).
1345:Crean C, Geacintov NE, Shafirovich V (2008).
990:
988:
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8:
695:
693:
640:
638:
2189:
2175:
2167:
1587:, Exp Gerontol, 15, 1980, pp. 575–591
1417:Annals of the New York Academy of Sciences
1241:Gruber J, Schaffer S, Halliwell B (2008).
788:Journal of the American Geriatrics Society
2270:Reliability theory of aging and longevity
1951:
1910:
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1294:Cui Hang; Kong Yahui; Zhang Hong (2011).
1258:
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1016:
966:
956:
911:
862:
762:
717:
395:. Other cross-linking can occur between
1582:Miquel J, Economos AC, Fleming J, et al.
469:
2397:Proximate theories of biological ageing
625:
492:processes in the mitochondria like the
359:molecule often becomes dysfunctional).
483:ROS, mitochondrial components such as
604:List of life extension-related topics
369:Oxidative free radicals, such as the
256:functionality, and ultimately death.
7:
342:normally exist in pairs in specific
1686:The Journal of Biological Chemistry
1363:10.1016/j.freeradbiomed.2008.07.008
1161:10.1016/j.freeradbiomed.2010.12.037
545:maintaining normal cell functions.
2215:Antagonistic pleiotropy hypothesis
800:10.1111/j.1532-5415.1972.tb00787.x
585:live about five times longer than
14:
1351:Free Radical Biology and Medicine
1149:Free Radical Biology and Medicine
202:In some model organisms, such as
2336:List of longest-living organisms
1779:Yee C, Yang W, Hekimi S (2014).
1585:Mitochondrial role in cell aging
719:10.1111/j.1753-4887.2012.00476.x
524:Epigenetic oxidative redox shift
452:, thus being a major reason for
115:
23:
500:, or via an indirect route the
298:(ROS) that are produced in the
1300:Journal of Signal Transduction
614:Mitochondrial theory of ageing
466:Mitochondrial theory of ageing
65:"Free-radical theory of aging"
51:add the appropriate references
1:
2392:Theories of biological ageing
2024:10.1016/S0891-5849(02)00856-0
1989:10.1016/S0891-5849(02)00886-9
1437:C. Richter, JW Park, BN Ames
2235:Free-radical theory of aging
1748:10.1016/j.bbagen.2009.06.003
1640:10.1371/journal.pcbi.1000572
958:10.1371/journal.pgen.1000361
904:10.1016/j.bbagen.2009.06.003
128:free radical theory of aging
2141:10.1016/j.exger.2011.11.006
1851:10.1016/j.exger.2009.11.007
1209:10.1016/j.exger.2008.12.006
444:Modifications of the theory
302:, causes damage to certain
36:reliable medical references
2413:
2225:DNA damage theory of aging
1953:10.1016/j.cmet.2007.08.011
1797:10.1016/j.cell.2014.02.055
1619:PLOS Computational Biology
463:
2280:Stem cell theory of aging
2059:10.1080/10715760600911303
1903:10.1007/s10522-008-9197-8
1468:10.1007/s10522-005-2626-z
1059:10.1007/s10522-009-9234-2
676:10.1016/j.saa.2007.09.030
162:them from free radicals.
134:because cells accumulate
42:or relies too heavily on
16:Free-radical aging theory
1839:Experimental Gerontology
1197:Experimental Gerontology
494:Electron transport chain
2255:Network theory of aging
1247:Frontiers in Bioscience
1018:2027/mdp.39015086547422
1009:10.1093/geronj/11.3.298
855:10.1126/science.1172539
764:2027/mdp.39015086547422
755:10.1093/geronj/11.3.298
476:reactive oxygen species
296:reactive oxygen species
171:reactive oxygen species
2346:Regeneration (biology)
2306:Biological immortality
2102:10.1001/jama.297.8.842
1699:10.1074/jbc.271.9.5125
1105:10.1002/bies.201000132
939:Caenorhabditis elegans
743:Journal of Gerontology
556:Caenorhabditis elegans
506:positive feedback loop
479:
335:
219:Caenorhabditis elegans
130:states that organisms
2265:Programmed cell death
2250:Negligible senescence
473:
329:
287:and in extreme cases
245:rate of living theory
2351:Rejuvenation (aging)
1502:Afanas'ev I (2010).
1419:2005;1043(1) 529-32.
700:Halliwell B (2012).
224:superoxide dismutase
2326:Indefinite lifespan
2230:Evolution of ageing
2200:(biology of ageing)
2012:Free Radic Biol Med
1977:Free Radic Biol Med
1631:2009PLSCB...5E0572P
1600:Scientific American
1313:10.1155/2012/646354
847:2010Sci...328..321F
668:2008AcSpA..69.1429H
540:Metabolic stability
454:cellular senescence
377:radical, can cause
277:Alzheimer's disease
199:production of ROS.
144:chemically reactive
2387:Theories of ageing
1833:Brewer GJ (2010).
498:superoxide radical
480:
336:
253:radiation toxicity
226:has been shown to
2364:
2363:
2341:Maximum life span
2296:Adaptive mutation
1508:Aging and Disease
841:(5976): 321–326.
706:Nutrition Reviews
478:in living systems
474:Major sources of
389:DNA cross-linking
175:hydrogen peroxide
124:
123:
100:
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2275:Selection shadow
2260:Plant senescence
2245:Immunosenescence
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502:hydroxyl radical
417:chronic diseases
371:hydroxyl radical
330:In chemistry, a
249:Rebeca Gerschman
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2008:
2004:
1974:
1973:
1969:
1940:Cell Metabolism
1933:
1932:
1928:
1884:
1883:
1876:
1832:
1831:
1822:
1778:
1777:
1773:
1742:(10): 1005–14.
1729:
1728:
1724:
1719:
1715:
1671:
1670:
1666:
1612:
1611:
1607:
1597:
1596:
1592:
1583:
1581:
1577:
1569:
1563:
1561:
1557:
1549:
1543:
1541:
1537:
1501:
1500:
1491:
1453:
1452:
1445:
1436:
1432:
1427:
1423:
1414:
1410:
1405:
1401:
1395:
1388:
1344:
1343:
1339:
1293:
1292:
1288:
1283:
1276:
1253:(13): 6554–79.
1240:
1239:
1232:
1194:
1193:
1186:
1142:
1141:
1137:
1132:
1128:
1090:
1089:
1082:
1044:
1043:
1034:
994:
993:
984:
951:(2): e1000361.
934:
933:
929:
898:(10): 1005–14.
885:
884:
880:
828:
827:
823:
785:
784:
780:
740:
739:
735:
699:
698:
691:
653:
652:
648:
643:
636:
631:
627:
622:
595:
579:
574:
561:epidemiological
551:
542:
526:
468:
462:
446:
383:gene expression
324:
315:aging process.
273:atherosclerosis
236:
184:
180:
168:
156:reducing agents
120:
116:
111:
105:
102:
59:
48:
44:primary sources
28:
24:
17:
12:
11:
5:
2410:
2408:
2400:
2399:
2394:
2389:
2384:
2379:
2369:
2368:
2362:
2361:
2359:
2358:
2353:
2348:
2343:
2338:
2333:
2331:Life extension
2328:
2323:
2318:
2313:
2308:
2303:
2298:
2292:
2290:
2289:Related topics
2286:
2285:
2283:
2282:
2277:
2272:
2267:
2262:
2257:
2252:
2247:
2242:
2240:Hayflick limit
2237:
2232:
2227:
2222:
2217:
2211:
2209:
2203:
2202:
2196:
2194:
2193:
2186:
2179:
2171:
2163:
2162:
2116:
2080:
2053:(12): 1230–8.
2047:Free Radic Res
2037:
2002:
1967:
1926:
1891:Biogerontology
1874:
1820:
1791:(4): 897–909.
1771:
1722:
1713:
1692:(9): 5125–30.
1664:
1605:
1590:
1575:
1555:
1535:
1489:
1456:Biogerontology
1443:
1430:
1421:
1408:
1399:
1386:
1357:(8): 1125–34.
1337:
1286:
1274:
1230:
1184:
1135:
1126:
1080:
1047:Biogerontology
1032:
1003:(3): 298–300.
982:
927:
878:
821:
794:(4): 145–147.
778:
749:(3): 298–300.
733:
689:
662:(5): 1429–35.
646:
634:
624:
623:
621:
618:
617:
616:
611:
606:
601:
599:Life extension
594:
591:
578:
575:
573:
570:
550:
547:
541:
538:
525:
522:
464:Main article:
461:
458:
445:
442:
356:chain reaction
323:
320:
304:macromolecules
235:
232:
182:
178:
173:(ROS) such as
166:
122:
121:
114:
112:
31:
29:
22:
15:
13:
10:
9:
6:
4:
3:
2:
2409:
2398:
2395:
2393:
2390:
2388:
2385:
2383:
2382:Free radicals
2380:
2378:
2375:
2374:
2372:
2357:
2354:
2352:
2349:
2347:
2344:
2342:
2339:
2337:
2334:
2332:
2329:
2327:
2324:
2322:
2319:
2317:
2314:
2312:
2309:
2307:
2304:
2302:
2299:
2297:
2294:
2293:
2291:
2287:
2281:
2278:
2276:
2273:
2271:
2268:
2266:
2263:
2261:
2258:
2256:
2253:
2251:
2248:
2246:
2243:
2241:
2238:
2236:
2233:
2231:
2228:
2226:
2223:
2221:
2218:
2216:
2213:
2212:
2210:
2208:
2204:
2199:
2192:
2187:
2185:
2180:
2178:
2173:
2172:
2169:
2158:
2154:
2150:
2146:
2142:
2138:
2135:(3): 203–10.
2134:
2130:
2129:Exp. Gerontol
2123:
2121:
2117:
2111:
2107:
2103:
2099:
2096:(8): 842–57.
2095:
2091:
2084:
2081:
2076:
2072:
2068:
2064:
2060:
2056:
2052:
2048:
2041:
2038:
2033:
2029:
2025:
2021:
2017:
2013:
2006:
2003:
1998:
1994:
1990:
1986:
1983:(5): 575–86.
1982:
1978:
1971:
1968:
1963:
1959:
1954:
1949:
1946:(4): 280–93.
1945:
1941:
1937:
1930:
1927:
1922:
1918:
1913:
1908:
1904:
1900:
1897:(5): 549–64.
1896:
1892:
1888:
1881:
1879:
1875:
1870:
1866:
1861:
1856:
1852:
1848:
1844:
1840:
1836:
1829:
1827:
1825:
1821:
1816:
1812:
1807:
1802:
1798:
1794:
1790:
1786:
1782:
1775:
1772:
1767:
1763:
1758:
1753:
1749:
1745:
1741:
1737:
1733:
1726:
1723:
1717:
1714:
1709:
1705:
1700:
1695:
1691:
1687:
1683:
1681:
1677:
1668:
1665:
1660:
1656:
1651:
1646:
1641:
1636:
1632:
1628:
1624:
1620:
1616:
1609:
1606:
1601:
1594:
1591:
1586:
1579:
1576:
1568:
1567:
1562:Lobachev A.N.
1559:
1556:
1548:
1547:
1542:Lobachev A.N.
1539:
1536:
1531:
1527:
1522:
1517:
1513:
1509:
1505:
1498:
1496:
1494:
1490:
1485:
1481:
1477:
1473:
1469:
1465:
1462:(4): 283–90.
1461:
1457:
1450:
1448:
1444:
1441:"PNAS", 1988.
1440:
1434:
1431:
1425:
1422:
1418:
1412:
1409:
1403:
1400:
1393:
1391:
1387:
1382:
1378:
1373:
1368:
1364:
1360:
1356:
1352:
1348:
1341:
1338:
1333:
1329:
1324:
1319:
1314:
1309:
1305:
1301:
1297:
1290:
1287:
1281:
1279:
1275:
1270:
1266:
1261:
1256:
1252:
1248:
1244:
1237:
1235:
1231:
1226:
1222:
1218:
1214:
1210:
1206:
1203:(4): 256–60.
1202:
1198:
1191:
1189:
1185:
1180:
1176:
1171:
1166:
1162:
1158:
1155:(8): 988–99.
1154:
1150:
1146:
1139:
1136:
1130:
1127:
1122:
1118:
1114:
1110:
1106:
1102:
1098:
1094:
1087:
1085:
1081:
1076:
1072:
1068:
1064:
1060:
1056:
1053:(6): 773–81.
1052:
1048:
1041:
1039:
1037:
1033:
1028:
1024:
1019:
1014:
1010:
1006:
1002:
998:
991:
989:
987:
983:
978:
974:
969:
964:
959:
954:
950:
946:
945:PLOS Genetics
942:
940:
931:
928:
923:
919:
914:
909:
905:
901:
897:
893:
889:
882:
879:
874:
870:
865:
860:
856:
852:
848:
844:
840:
836:
832:
825:
822:
817:
813:
809:
805:
801:
797:
793:
789:
782:
779:
774:
770:
765:
760:
756:
752:
748:
744:
737:
734:
729:
725:
720:
715:
712:(5): 257–65.
711:
707:
703:
696:
694:
690:
685:
681:
677:
673:
669:
665:
661:
657:
650:
647:
641:
639:
635:
629:
626:
619:
615:
612:
610:
607:
605:
602:
600:
597:
596:
592:
590:
588:
584:
581:Among birds,
576:
571:
569:
566:
562:
558:
557:
548:
546:
539:
537:
535:
531:
523:
521:
517:
513:
509:
507:
503:
499:
495:
491:
486:
477:
472:
467:
459:
457:
455:
451:
443:
441:
439:
435:
431:
429:
425:
420:
418:
414:
410:
409:heart disease
406:
402:
398:
394:
390:
386:
384:
380:
376:
372:
367:
365:
360:
357:
351:
348:
345:
341:
333:
328:
321:
319:
316:
313:
309:
305:
301:
297:
292:
290:
286:
282:
278:
274:
270:
266:
262:
257:
254:
250:
246:
241:
240:Denham Harman
233:
231:
229:
225:
221:
220:
215:
211:
210:
205:
200:
198:
197:mitochondrial
194:
193:Denham Harman
190:
188:
187:peroxynitrite
176:
172:
163:
161:
157:
153:
149:
145:
141:
137:
133:
129:
113:
109:
98:
95:
91:
88:
84:
81:
77:
74:
70:
67: –
66:
62:
61:Find sources:
56:
52:
46:
45:
41:
37:
32:This article
30:
21:
20:
2311:CGK733 fraud
2234:
2132:
2128:
2093:
2089:
2083:
2050:
2046:
2040:
2018:(1): 37–44.
2015:
2011:
2005:
1980:
1976:
1970:
1943:
1939:
1929:
1894:
1890:
1845:(3): 173–9.
1842:
1838:
1788:
1784:
1774:
1739:
1735:
1725:
1716:
1689:
1685:
1679:
1675:
1667:
1622:
1618:
1608:
1599:
1593:
1584:
1578:
1565:
1558:
1545:
1538:
1514:(2): 75–88.
1511:
1507:
1459:
1455:
1433:
1424:
1416:
1411:
1402:
1354:
1350:
1340:
1303:
1299:
1289:
1260:10.2741/3174
1250:
1246:
1200:
1196:
1152:
1148:
1138:
1129:
1099:(4): 255–9.
1096:
1092:
1050:
1046:
1000:
996:
948:
944:
938:
930:
895:
891:
881:
838:
834:
824:
791:
787:
781:
746:
742:
736:
709:
705:
659:
655:
649:
628:
580:
554:
552:
549:Mitohormesis
543:
527:
518:
514:
510:
481:
460:Mitochondria
450:biomolecules
447:
434:Antioxidants
432:
428:nitric oxide
421:
387:
368:
361:
352:
349:
337:
332:free radical
317:
300:mitochondria
293:
260:
258:
237:
227:
217:
207:
201:
191:
164:
152:Antioxidants
136:free radical
127:
125:
103:
93:
86:
79:
72:
60:
40:verification
33:
379:DNA damages
160:passivating
34:needs more
2377:Senescence
2371:Categories
2321:DNA repair
2220:Catabiosis
2207:Senescence
2198:Senescence
1306:: 646354.
997:J Gerontol
620:References
609:Senescence
572:Challenges
565:prevalence
424:superoxide
375:superoxide
306:including
234:Background
214:roundworms
209:Drosophila
76:newspapers
1093:BioEssays
516:CuZnSOD.
490:metabolic
438:Vitamin C
364:base pair
340:Electrons
322:Processes
285:apoptosis
269:arthritis
148:oxidative
2149:22123429
2110:17327526
2075:11125090
2067:17090411
2032:12086680
1997:12208343
1962:17908557
1921:19031007
1869:19945522
1815:24813612
1766:19524016
1680:in vitro
1659:19936024
1602:: 49–52.
1530:22396858
1476:16333762
1381:18692567
1332:21977319
1269:18508680
1225:19815246
1217:19171187
1179:21215311
1121:13720843
1113:21290398
1075:13512659
1067:19466577
1027:13332224
977:19197346
922:19524016
873:20395504
773:13332224
728:22537212
684:17988942
593:See also
373:and the
344:orbitals
312:proteins
289:necrosis
281:diabetes
228:increase
189:(OONO).
150:damage.
142:are not
106:May 2015
1912:2730443
1860:2826600
1806:4454526
1757:2789432
1708:8617792
1676:In vivo
1650:2771766
1627:Bibcode
1521:3295029
1484:7661778
1372:2577587
1323:3184498
1170:3051032
968:2628729
913:2789432
864:3607354
843:Bibcode
835:Science
808:5016631
664:Bibcode
583:parrots
530:insulin
401:protein
140:melanin
90:scholar
55:removed
2301:Ageing
2157:984298
2155:
2147:
2108:
2073:
2065:
2030:
1995:
1960:
1919:
1909:
1867:
1857:
1813:
1803:
1764:
1754:
1706:
1657:
1647:
1528:
1518:
1482:
1474:
1379:
1369:
1330:
1320:
1267:
1223:
1215:
1177:
1167:
1119:
1111:
1073:
1065:
1025:
975:
965:
920:
910:
871:
861:
816:396830
814:
806:
771:
726:
682:
413:stroke
393:cancer
308:lipids
279:, and
265:cancer
261:per se
185:), or
92:
85:
78:
71:
63:
2316:Death
2153:S2CID
2071:S2CID
1570:(PDF)
1550:(PDF)
1480:S2CID
1221:S2CID
1117:S2CID
1071:S2CID
812:S2CID
587:quail
577:Birds
534:redox
485:mtDNA
204:yeast
97:JSTOR
83:books
2145:PMID
2106:PMID
2063:PMID
2028:PMID
1993:PMID
1958:PMID
1917:PMID
1865:PMID
1811:PMID
1785:Cell
1762:PMID
1740:1790
1704:PMID
1678:and
1655:PMID
1526:PMID
1472:PMID
1397:York
1377:PMID
1328:PMID
1304:2012
1265:PMID
1213:PMID
1175:PMID
1109:PMID
1063:PMID
1023:PMID
973:PMID
918:PMID
896:1790
869:PMID
804:PMID
769:PMID
724:PMID
680:PMID
426:and
411:and
399:and
206:and
154:are
126:The
69:news
38:for
2137:doi
2098:doi
2094:297
2055:doi
2020:doi
1985:doi
1948:doi
1907:PMC
1899:doi
1855:PMC
1847:doi
1801:PMC
1793:doi
1789:157
1752:PMC
1744:doi
1694:doi
1690:271
1645:PMC
1635:doi
1516:PMC
1464:doi
1367:PMC
1359:doi
1318:PMC
1308:doi
1255:doi
1205:doi
1165:PMC
1157:doi
1101:doi
1055:doi
1013:hdl
1005:doi
963:PMC
953:doi
908:PMC
900:doi
859:PMC
851:doi
839:328
796:doi
759:hdl
751:doi
714:doi
672:doi
405:LDL
397:fat
132:age
2373::
2151:.
2143:.
2133:47
2131:.
2119:^
2104:.
2092:.
2069:.
2061:.
2051:40
2049:.
2026:.
2016:33
2014:.
1991:.
1981:33
1979:.
1956:.
1942:.
1938:.
1915:.
1905:.
1895:10
1893:.
1889:.
1877:^
1863:.
1853:.
1843:45
1841:.
1837:.
1823:^
1809:.
1799:.
1787:.
1783:.
1760:.
1750:.
1738:.
1734:.
1702:.
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1524:.
1510:.
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1492:^
1478:.
1470:.
1458:.
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1389:^
1375:.
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1349:.
1326:.
1316:.
1302:.
1298:.
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1219:.
1211:.
1201:44
1199:.
1187:^
1173:.
1163:.
1153:50
1151:.
1147:.
1115:.
1107:.
1097:33
1095:.
1083:^
1069:.
1061:.
1051:10
1049:.
1035:^
1021:.
1011:.
1001:11
999:.
985:^
971:.
961:.
947:.
943:.
916:.
906:.
894:.
890:.
867:.
857:.
849:.
837:.
833:.
810:.
802:.
792:20
790:.
767:.
757:.
747:11
745:.
722:.
710:70
708:.
704:.
692:^
678:.
670:.
660:69
658:.
637:^
419:.
310:,
291:.
275:,
271:,
267:,
177:(H
57:.
2190:e
2183:t
2176:v
2159:.
2139::
2114:.
2112:.
2100::
2077:.
2057::
2034:.
2022::
1999:.
1987::
1964:.
1950::
1944:6
1923:.
1901::
1871:.
1849::
1817:.
1795::
1768:.
1746::
1710:.
1696::
1674:"
1661:.
1637::
1629::
1623:5
1532:.
1512:1
1486:.
1466::
1460:6
1383:.
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1334:.
1310::
1271:.
1257::
1227:.
1207::
1181:.
1159::
1123:.
1103::
1077:.
1057::
1029:.
1015::
1007::
979:.
955::
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924:.
902::
875:.
853::
845::
818:.
798::
775:.
761::
753::
730:.
716::
686:.
674::
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216:(
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47:.
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