An updated version of the mitochondrial free radical theory of aging (MFRTA) and longevity is reviewed. Key aspects of the theory are emphasized. Another main focus concerns common misconceptions that can mislead investigators from other specialties, even to wrongly discard the theory. Those different issues include (i) the main reactive oxygen species (ROS)-generating site in the respiratory chain in relation to aging and longevity: complex I; (ii) the close vicinity or even contact between that site and the mitochondrial DNA, in relation to the lack of local efficacy of antioxidants and to sub-cellular compartmentation; (iii) the relationship between mitochondrial ROS production and oxygen consumption; (iv) recent criticisms on the MFRTA; (v) the widespread assumption that ROS are simple “by-products” of the mitochondrial respiratory chain; (vi) the unnecessary postulation of “vicious cycle” hypotheses of mitochondrial ROS generation which are not central to the free radical theory of aging; and (vii) the role of DNA repair concerning endogenous versus exogenous damage. After considering the large body of data already available, two general characteristics responsible for the high maintenance degree of long-lived animals emerge: (i) a low generation rate of endogenous damage: and (ii) the possession of tissue macromolecules that are highly resistant to oxidative modification. Antioxid. Redox Signal. 19, 1420–1445.
AndziakB, BuffensteinR. Disparate patterns of age-related changes in lipid peroxidation in long-lived naked mole-rats and shorter-lived mice. Aging Cell, 5:525–532. 2006.
2.
AndziakB, O'ConnorTP, BuffensteinR. Antioxidants do not explain the disparate longevity between mice and the longest-living rodent, the naked mole-rat. Mech Ageing Dev, 126:1206–1212. 2005.
3.
AndziakB, O'ConnorTP, QiW, DeWaalEM, PierceA, ChaudhuriAR, Van RemmenH, BuffensteinR. High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging Cell, 5:463–471. 2006.
4.
BackP, BraeckmanBP, MatthijssensF. ROS in aging Caenorhabditis elegans: damage or signaling?Oxid Med Cell Longev, 608478. 2012.
5.
BarjaG. Oxygen radicals, a failure or a success of evolution?Free Rad Res, 18:63–70. 1993.
6.
BarjaG. The flux of free radical attack through mitochondrial DNA is related to aging rate. Aging (Milano), 12:342–355. 2000.
7.
BarjaG. The quantitative measurement of H2O2 generation in isolated mitochondria. J Bioenerg Biomembr, 34:227–233. 2002.
8.
BarjaG. Aging in vertebrates and the effect of caloric restriction: a mitochondrial free radical production-DNA damage mechanism?Biol Rev, 79:235–251. 2004.
9.
BarjaG. Free radicals and aging. Trends Neurosci, 27:595–600. 2004.
10.
BarjaG. Mitochondrial oxygen consumption and ROS production are independently modulated. Implications for aging studies. Rejuvenation Res, 10:215–223. 2007.
11.
BarjaG. The gene cluster hypothesis of aging and longevity. Biogerontology, 9:57–66. 2008.
12.
BarjaG. Longevity and Evolution. New York: Nova Science Publishers, Inc., 2011; 1–194.
13.
BarjaG, CadenasS, RojasC, López-TorresM, Pérez-CampoR. A decrease of free radical production near critical sites as the main cause of maximum longevity in animals. Comp Biochem Physiol, 108B:501–512. 1994.
14.
BarjaG, CadenasS, RojasC, Pérez-CampoR, López-TorresM. Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high metabolic rates in birds. Free Radic Res, 21:317–328. 1994.
15.
BarjaG, HerreroA. Localization at complex I and mechanism of the higher free radical production of brain non-synaptic mitochondria in the short-lived rat than in the longevous pigeon. J Bioenerg Biomembr, 30:235–243. 1998.
16.
BarjaG, HerreroA. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J, 14:312–318. 2000.
17.
BenderA, KishnanK, MorrisMC, TaylorGA, ReeveAK, PerryRH, JarosE, HershesonJS, BettsJ, KlopstockT, TaylorRW, TurnbullDM. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genet, 38:515–517. 2006.
18.
BergBN. Study of vitamin E supplements in relation to muscular dystrophy and other diseases in aging rats. J Gerontol, 14:174–180. 1959.
19.
BoverisA, CadenasE. Mitochondrial production of hydrogen peroxide regulation by nitric oxide and the role of ubisemiquinone. IUBMB Life, 50:245–250. 2000.
20.
BoverisA, CadenasE, StoppaniAOM. Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem J, 156:435–444. 1976.
21.
BoverisA, ChanceB. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J, 134:707–716. 1973.
22.
BoversA, OshinoN, ChanceB. The cellular production of hydrogen peroxide. Biochem J, 128:617–630. 1972.
23.
Brunet-RossinniAK. Reduced free-radical production and extreme longevity in the little brown bat (Myotis lucifugus) versus two non-flying mammals. Mech Ageing Dev, 125:11–20. 2004.
24.
BuffensteinR, EdreyYH, YangT, MeleJ. The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms. Age, 30:99–109. 2008.
25.
BurchHB, LowryOH, BradleyME, MaxPFJr. Hepatic metabolites and cofactors in riboflavin deficiency and calorie restriction. Am J Physiol, 219:409–415. 1970.
26.
CaroP, GómezJ, ArduiniA, González-SánchezM, González-GarcíaM, BorrásC, ViñaJ, PuertasMJ, SastreJ, BarjaG. Mitochondrial DNA sequences are present inside nuclear DNA in rat tissues and increase with age. Mitochondrion, 10:479–486. 2010.
27.
CaroP, GómezJ, López-TorresM, SánchezI, NaudíA, JoveM, PamplonaR, BarjaG. Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver. Biogerontology, 9:183–196. 2008.
28.
CaroP, GomezJ, SanchezI, GarciaR, López-TorresM, NaudíA, Portero-OtinM, PamplonaR, BarjaG. Effect of 40% restriction of dietary amino acids -except methionine- on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver. Biogerontology, 10:579–592. 2009.
29.
ChaudharyAK, NokuboM, ReddyGR, YeolaSN, MorrowJD, BlairIA, MarnettLJ. Detection of endogenous malondialdehyde-deoxyguanosine adducts in human liver. Science, 265:1580–1582. 1994.
30.
ClappNK, SatterfieldLC, BowlesND. Effects of the antioxidant butylated hydroxytoluene (BHT) on mortality in BALB/c mice. J Gerontol, 34:497–501. 1979.
31.
CocheméHM, QuinC, McQuakerSJ, CabreiroF, LoganA, PrimeTA, AbakumovaI, PatelJV, FearnleyIM, JamesAM, PorteousCM, SmithRA, SaeedS, CarréJE, SingerM, GemsD, HartleyRC, PartridgeL, MurphyMP. Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab, 13:340–350. 2011.
ComfortA, Youhotsky-GoreI, PathmanathanK. Effect of ethoxyquin on the longevity of C3H mice. Nature, 229:254–255. 1971.
34.
CortopassiGA, WangE. There is substantial agreement among interspecies estimates of DNA repair activity. Mech Ageing Dev, 91:211–218. 1996.
35.
CsiszarA, PodlutskyA, PodlutskayaN, SonntagWE, MerlinSZ, PhilippEE, DoyleK, DavilaA, RecchiaFA, BallabhP, PintoJT, UngvariZ. Testing the oxidative stress hypothesis of aging in primate fibroblasts: is there a correlation between species longevity and cellular ROS production?J Gerontol A, 67:841–852. 2012.
36.
DaniD, ShimokawaI, KomatsuT, HigamiY, WarnkenU, SchokraieE, SchnölzerM, KrauseF, SugawaMD, DencherNA. Modulation of oxidative phosphorylation machinery signifies a prime mode of anti-ageing mechanism of calorie restriction in male rat liver mitochondria. Biogerontology, 11:321–334. 2010.
37.
DeAK, ChipalkattiS, AiyarAS. Some biochemical parameters of ageing in relation to dietary protein. Mech Ageing Dev, 21:37–48. 1983.
38.
DlaskováA, HlavatáL, JezekP. Oxidative stress caused by blocking of mitochondrial complex I H(+) pumping as a link in aging/disease vicious cycle. Int J Biochem Cell Biol, 40:1792–1805. 2008.
39.
DoonanR, McElweeJJ, MatthijssensF, WalkerGA, HouthoofdK, BackP, MatscheskiA, VanfleterenJR, GemsD. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev, 22:3236–3241. 2008.
40.
DufourE, BoulayJ, RinchevalV, Sainsard-ChanetA. A causal link between respiration and senescence in Podospora anserina. PNAS, 97:4138–4143. 2000.
41.
DrewB, PhaneufS, DirksA, SelmanC, GredillaR, LezzaA, BarjaG, LeeuwenburghC. Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart. Am J Physiol, 284:R474–R480. 2003.
42.
DuttonPL, MoserCC, SledVD, DaldalF, OhnishiT. A reductant-induced oxidation mechanism for complex I. Biochim Biophys Acta, 1364:245–257. 1998.
43.
FlemingJE, MiquelJ, CottrellSF, YengoyanLS, EconomosAC. Is cell aging caused by respiration-dependent injury to the mitochondrial genome?Gerontology, 28:44–53. 1982.
44.
FontanaL, PartridgeL, LongoVD. Extending healthy life span—from yeast to humans. Science, 328:321–326. 2010.
45.
GenovaML, VenturaB, GiulianoG, BovinaC, FormigginiG, Parenti CastelliG, LenazG. The state of production of superoxide radical in mitochondrial complex I is not a bound semiquinone but presumably iron-sulphur cluster N2. FEBS Lett, 505:364–368. 2001.
46.
GoodrickCL. Effects of long-term voluntary wheel exercise on male and female Wistar rats. I. Longevity, body weight, and metabolic rate. Gerontology, 26:22–33. 1980.
47.
GrandisonRC, PiperMD, PartridgeL. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature, 462:1061–1064. 2009.
48.
GredillaR, BarjaG. The role of oxidative stress in relation to caloric restriction and longevity. Endocrinology, 146:3713–3717. 2005.
49.
GredillaR, BarjaG, López-TorresM. Effect of short-term caloric restriction on H2O2 production and oxidative DNA damage in rat liver mitochondria and location of the free radical source. J Bioenerg Biomembr, 33:279–287. 2001.
50.
GredillaR, SanzA, Lopez-TorresM, BarjaG. Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J, 15:1589–1591. 2001.
51.
HamiltonML, GuoZ, FullerCD, Van RemmenH, WardWF, AustadSN, TroyerDA, ThompsonI, RichardsonA. A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. Nucleic Acids Res, 29:2117–2126. 2001.
52.
HarmanD. Aging: a theory based on free radical and radiation chemistry. J Gerontol, 11:298–300. 1956.
53.
HarmanD. Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice. J Gerontol, 23:476–482. 1968.
54.
HarmanD. The biological clock: the mitochondria?J Am Geriatr Soc, 20:145–147. 1972.
55.
HarrisSB, WeindruchR, SmithGS, MickeyMR, WalfordRL. Dietary restriction alone and in combination with oral ethoxyquine/2-mercaptoethylamine in mice. J Gerontol, 45:B141–B147. 1990.
56.
HashizumeO, ShimizuA, YokotaM, SugiyamaA, NakadaK, MiyoshiH, ItamiM, OhiraM, NagaseH, TakenagaK, HayashiJ-I. Specific mitochondrial DNA mutation in mice regulates diabetes and linfoma development. Proc Natl Acad Sci U S A, 109:10528–10533. 2012.
57.
HayflickL. Theories of biological aging. Exp Gerontol, 20:145–159. 1985.
58.
HeidrickML, HendircksLC, CookDE. Effect of dietary 2-mercaptoethanol on the life span, immune system, tumor incidence and lipid peroxidation damage in spleen lymphocytes of aging BC3F1 mice. Mech Aging Dev, 27:341–358. 1984.
59.
HerreroA, BarjaG. Sites and mechanisms responsible for the low rate of free radical production of heart mitochondria in the long-lived pigeon. Mech Ageing Dev, 98:95–111. 1997.
60.
HerreroA. and Barja G. ADP regulation of mitochondrial free radical production is different with complex I- or complex II-linked substrates: implications for the exercise paradox and brain hypermetabolism. J Bioenerg Biomembr, 29:241–249. 1997.
61.
HerreroA, BarjaG. H2O2 production of heart mitochondria and aging rate are slower in canaries and parakeets than in mice: sites of free radical generation and mechanisms involved. Mech Ageing Dev, 103:133–146. 1998.
62.
HerreroA, BarjaG. 8-oxodeoxyguanosine levels in heart and brain mitochondrial and nuclear DNA of two mammals and three birds in relation to their different rates of aging. Aging Clin Exp Res, 11:294–300. 1999.
63.
HerreroA, BarjaG. Localization of the site of oxygen radical generation inside the Complex I of heart and non-synaptic brain mammalian mitochondria. J Bioenerg Biomembr, 32:609–615. 2000.
64.
HoffmanDL, SalterJD, BrooksPS. The response of mitochondrial reactive oxygen species generation to steady-state oxygen tension: implications for hypoxic cell signalling. Am J Physiol, 291:H101–H108. 2007.
65.
HolloszyJO, SmithEK, ViningM, AdamsSA. Effect of voluntary exercise on longevity in rats. J Appl Physiol, 59:826–831. 1985.
66.
HoutfoodK, BraeckmanBP, LenaertsI, BrysK, De VreeseA, Van EygenS, VanfleterenJR. No reduction of metabolic rate in food restricted Caenorhabditis elegans. Exp Gerontol, 37:1359–1369. 2002.
67.
HulbertT, PamplonaR, BuffensteinR, ButtemerWA. Life and death: metabolic rate, membrane composition and lifespan of animals. Physiol Rev, 87:1175–1213. 2007.
68.
HulbertAJ. The links between membrane composition, metabolic rate and lifespan. Comp Biochem Physiol A, 150:196–203. 2008.
69.
HütterE, SkobroM, LenerB, PratsC, RabolR, DelaF, Jansen-DürrP. Oxidative stress and mitochondrial impairment can be separated from lipofuscin accumulation in aged skeletal muscle. Aging Cell, 6:245–256. 2007.
70.
JudgeS, JangYM, SmithA, HagenT, LeeuwenburghC. Age-associated increases in oxidative stress and antioxidant enzyme activities in cardiac interfibrillar mitochondria: implications for the mitochondrial theory of aging. FASEB J, 19:419–421. 2005.
71.
JudgeS, JangYM, SmithA, SelmanC, PhillipsT, SpeakmanJR, HagenT, LeeuwenburghC. Exercise by long-life voluntary running reduces subsarcolemmal and interfibrilar hydrogen peroxide production in the rat heart. Am J Physiol, 89:R1564–R1572. 2005.
72.
KeaneyM, GemsD. No increase in lifespan in Caenorhabditis elegans upon treatment with the superoxide dismutase mimetic EUK-8. Free Radic Biol Med, 34:277–282. 2003.
73.
KirkwoodTBL. A systematic look to an old problem: as life expectancy increases, a systems-biology approach is needed to ensure that we have a healthy old age. Nature, 451:644–647. 2008.
74.
KohnRR. Effect of antioxidants on life-span of C57BL mice. J Gerontol, 26:378–380. 1971.
75.
KraytsbergY, KudryavtsevaE, McKeeAC, GeulaC, KowallNW, KhrapkoK. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet, 38:518–520. 2006.
76.
KregelKC, ZhangHJ. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol, 292:R18–R36. 2007.
77.
KuHH, BrunkUT, SohalRS. Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med, 15:621–627. 1993.
78.
KudinAP, MalinskaD, KunzWS. Sites of generation of reactive oxygen species in homogenates of brain tissue determined with the use of respiratory substrates and inhibitors. Biochim Biophys Acta, 1777:689–695. 2008.
79.
KujothGC, HionaA, PughTD, SomeyaS, PanzerK, WohlgemuthSE, HoferT, SeoAY, SullivanR, JoblingWA, MorrowJD, Van RemmenH, SedivyJM, YamasobaT, TanokuraM, WeindruchR, LeeuwenburghC, ProllaTA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science, 309:481–484. 2005.
80.
KushnarevaY, MurphyA, AndreyevA. Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P+) oxidation-reduction state. Biochem J, 368:545–553. 2002.
81.
LambertA, BrandM. Inhibitors of the quinine-binding site allow rapid superoxide production from mitochondrial NADH:ubiquinone oxidoreductase (complex I)J Biol Chem, 279:39414–39420. 2004.
82.
LambertA, BoysenH, BuckinghamJA, YangT, PodlutskyA, AustadSN, KunzTH, BuffensteinR, BrandD. Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms. Aging Cell, 6:607–618. 2007.
83.
LambertAJ, Portero-OtinM, PamplonaR, MerryBJ. Effect of ageing and caloric restriction on specific markers of protein oxidative damage and membrane peroxidizability in rat liver mitochondria. Mech Ageing Dev, 125:529–538. 2004.
84.
LawrenceA, BurkRF. Species, tissue and subcellular distribution of non-Se dependent glutathione peroxidasa activity. J Nutr, 108:211–215. 1978.
85.
LedvinaM, HodánováM. The effect of simultaneous administration of tocopherol and sunflower oil on the life-span of female mice. Exp Gerontol, 15:67–71. 1980.
86.
LeeIM, SiehCCH, PaffenbargerRS. Exercise intensity and longevity in men. The Harvard Alumni Health Study. JAMA, 273:1179–1184. 1995.
87.
LeeKP, SimpsonSJ, ClissoldFJ, BrooksR, BallardJW, TaylorPW, SoranN, RaubenheimerD. Lifespan and reproduction in Drosophila: new insights from nutritional geometry. PNAS, 105:2498–2503. 2008.
88.
LeeYS, ChoiJY, ParkMK, ChoiEM, KasaiH, ChungMH. Induction of oh8Gua glycosylase in rat kidneys by potassium bromate (KBrO3), a renal carcinogen. Mutat Res, 364:227–233. 1996.
89.
LehningerAL. Principles of Biochemistry. New York: Freeman and Co., 2005.
90.
LiangS, MeleJ, WuY, BuffensteinR, HornsbyPJ. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber)Aging Cell, 9:626–635. 2010.
LinnaneAW, KiosMM, VittetaL. Healthy aging: regulation of the metabolome by cellular redox modulation and prooxidant signalling systems: the essential roles of superoxide anion and hydrogen peroxide. Biogerontology, 8:445–467. 2007.
93.
LiuY, FiskumG, SchubertD. Generation of reactive oxygen species by the electron transport chain. J Neurochem, 80:780–787. 2002.
López-TorresM, BarjaG. Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction. Possible implications for humans. Biochim Biophys Acta, 1780:1337–1347. 2008.
96.
López-TorresM, GredillaR, SanzA, BarjaG. Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria. Free Radic Biol Med, 32:882–889. 2002.
97.
López-TorresM, Pérez-CampoR, RojasC, CadenasS, BarjaG. Maximum life span in vertebrates: correlation with liver antioxidant enzymes, glutathione system, ascorbate, urate, sensitivity to peroxidation, true malondialdehyde, in vivo H2O2, and basal and maximum aerobic capacity. Mech Ageing Dev, 70:177–199. 1993.
98.
López-TorresM, Pérez-CampoR, RojasC, CadenasS, Barja de QuirogaG. Simultaneous induction of superoxide dismutase, glutathione reductase, GSH and ascorbate in liver and kidney correlates with survival throughout the life span. Free Radic Biol Med, 15:133–142. 1993.
99.
MagalhãesJP, ChurchGM. Cells discover fire: employing reactive oxygen species in development and consequences for aging. Exp Gerontol, 41:1–10. 2006.
100.
MattisonJA, RothGS, BeasleyTM, TilmontEM, HandyAM, HerbertRL, LongoDL, AllisonDB, YoungJE, BryantM, BarnardD, WardWF, QiW, IngramD. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature, 489:318–321. 2012.
101.
McCarterR, MasoroEJ, YuBP. Does food restriction retard aging by reducing metabolic rate?Am J Physiol, 248:E488–E490. 1985.
102.
MelovS, RavenscroftJ, MalikS, GillMS, WalkerDW, ClaytonPE, WallaceDC, MalfroyB, DoctrowSR, LithgowGJ. Extension of life-span with superoxide dismutase/catalase mimetics. Science, 289:1567–1569. 2000.
MilgramNW, RacineRJ, NellisP, MendoncaA, IvyGO. Maintenance on l-deprenyl prolongs life in aged male rats. Life Sci, 47:415–420. 1990.
105.
MillerRA, BuehnerG, ChangY, HarperJM, SiglerR, Smith-WheelockM. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell, 4:119–125. 2005.
106.
MullerF. The nature and mechanism of superoxide production by the electron transport chain: its relevance to aging. J Am Aging Assoc, 23:227–253. 2000.
MullerFL, SongW, JangYC, LiuY, SabiaM, RichardsonA, Van RemmenH. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am J Physiol, 293:R1159–R1168. 2007.
109.
MunroD, BlierPU. The extreme longevity of Arctica islandica is associated with increased peroxidation resistance in mitochondrial membranes. Aging Cell, 11:845–855. 2012.
110.
MurphyMP. How mitochondria produce reactive oxygen species. Biochem J, 417:1–13. 2009.
111.
NaudiA, JoveM, AyalaV, Portero-OtínM, BarjaG, PamplonaR. Regulation of membrane unsaturation as antioxidant adaptive mechanisms in long-lived animal species. Free Radic Antiox, 1:3–12. 2011.
112.
NichollsDG. Mitochondrial membrane potential and aging. Aging Cell, 3:35–40. 2004.
113.
NisoliE, TonelloC, CardileA, CozziV, BracaleR, TedescoL, FalconeS, ValerioA, CantoniO, ClementiE, MoncadaS, CarrubaMO. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science, 310:314–317. 2005.
114.
NohlH, HegnerD. Do mitochondria produce oxygen radicals in vivo?Eur J Biochem, 82:563–567. 1978.
115.
OeriuS, VochituE. The effect of the administration of compounds which contain sulfhydryl groups on the survival rates of mice, rats, and guinea pigs. J Gerontol, 20:417–419. 1965.
116.
PaffenbargerRS, HydeRT, WingAL, HsieC. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med, 314:605–613. 1986.
117.
PageMM, RichardsonJ, WiensBF, TiedtkeF, PetersCW, FaurePA, BurnessG, StuartJA. Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endothermic species. Age, 32:255–270. 2010.
118.
PageMM, StuartJA. Activities of DNA base excision repair enzymes in liver and brain correlate with body mass, but not with lifespan. Age (Dordr), 34:1195–1209. 2011.
119.
PamplonaR, BarjaG. Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection. Biochim Biophys Acta Bioenerg, 1757:496–508. 2006.
120.
PamplonaR, BarjaG. An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms. Biogerontology, 12:409–435. 2011.
121.
PamplonaR, BarjaG, Portero-OtínM. Membrane fatty acid unsaturation, protection against oxidative stress, and maximum life span: a homeoviscous-longevity adaptation. Ann N Y Acad Sci, 959:475–490. 2002.
122.
PamplonaR, ConstantiniD. Molecular and structural antioxidant defenses against oxidative stress in animals. Am J Physiol, 301:R843–R863. 2011.
123.
PamplonaR, Portero-OtínM, RequenaJ, GredillaR, BarjaG. Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after four months of caloric restriction than in age-matched controls. Mech Ageing Dev, 123:1437–1446. 2002.
124.
PamplonaR, Portero-OtínM, RuizC, GredillaR, HerreroA, BarjaG. Double bond content of phospholipids and lipid peroxidation negatively correlate with maximum longevity in the heart of mammals. Mech Ageing Dev, 112:169–183. 1999.
125.
PamplonaR, Portero-OtínM, RuizC, PratJ, BellmuntMJ, BarjaG. Mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals. J Lipid Res, 39:1989–1994. 1998.
126.
PamplonaR, PratJ, CadenasS, RojasC, Pérez-CampoR, López-TorresM, BarjaG. Low fatty acid unsaturation protects against lipid peroxidation in liver mitochondria from longevous species: the pigeon and human case. Mech Ageing Dev, 86:53–66. 1996.
127.
PearlR. The Rate of Living. London: University of London Press, 1928.
128.
PerezVI, BokovA, Van RemmenH, MeleJ, RanQ, IkenoY, RichardsonA. Is the oxidative stress theory of aging dead?Biochim Biophys Acta, 1790:1005–1014. 2009.
129.
PérezVI, BuffensteinR, MasamsettiV, LeonardS, SalmonAB, MeleJ, AndziakB, YangT, EdreyY, FriguetB, WardW, RichardsonA, ChaudhuriA. Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. PNAS, 106:3059–3064. 2009.
130.
Pérez-CampoR, López-TorresM, CadenasS, RojasC, BarjaG. The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach. J Comp Physiol B, 168:149–158. 1998.
131.
Pérez-CampoR, López-TorresM, RojasC, CadenasS, BarjaG. Longevity and antioxidant enzymes, non-enzymatic antioxidants, oxidative stress, malondialdehyde, and in vivo H2O2 levels in the vertebrate lung: a comparative study. J Comp Physiol, 163:682–689. 1994.
132.
PortaEA, JounNS, NittaRT. Effects of the type of dietary fat at two levels of vitamin E in Wistar male rats during development and aging. I. Life span, serum biochemical parameters and pathological changes. Mech Aging Dev, 13:1–39. 1980.
133.
RattanS. Targeting the age-related occurrence, removal, and accumulation of molecular damage by hormesis. Ann N Y Acad Sci, 1197:28–32. 2010.
134.
RichieJPJr., LeutzingerY, ParthasarathyS, MalloyV, OrentreichN, ZimmermanJA. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J, 8:1302–1307. 1994.
135.
RistowM, ZarseK. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis)Exp Gerontol, 45:410–418. 2010.
136.
RobinsonBH. Human complex I deficiency: clinical spectrum and involvement of oxygen free radicals in the pathogenicity of the defect. Biochim Biophys Acta, 1364:271–286. 1998.
137.
RuizMC, AyalaV, Portero-OtínM, RequenaJR, BarjaG, PamplonaR. Protein methionine content and MDA-lysine protein adducts are inversely related to maximum life span in the heart of mammals. Mech Ageing Dev, 126:1106–1114. 2005.
138.
SalwayKD, PageMM, FaurePA, BurnessG, StuartJA. Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species. Age (Dordrecht), 33:33–47. 2011.
139.
Sanchez-RomanI, GomezA, GomezJ, SuarezH, SanchezC, NaudiA, AyalaV, Portero-OtinM, Lopez-TorresM, PamplonaR, BarjaG. Forty percent methionine restriction lowers DNA methylation, complex I ROS generation, and oxidative damage to mtDNA and mitochondrial proteins in rat heart. J Bioenerg Biomembr, 43:699–708. 2011.
140.
Sanchez-RomanI, GomezJ, NaudiA, AyalaV, Portero-OtínM, Lopez-TorresM, PamplonaR, BarjaG. The β-blocker atenolol lowers the longevity-related degree of fatty acid unsaturation, decreases protein oxidative damage and increases ERK signaling in the heart of C57BL/6 mice. Rejuvenation Res, 13:683–693. 2010.
141.
Sanchez-RomanI, GómezA, PérezI, SanchezC, SuarezH, NaudíA, JovéM, Lopez-TorresM, PamplonaR, BarjaG. Effects of aging and methionine restriction applied at old age on ROS generation and oxidative damage in rat liver mitochondria. Biogerontology, 13:399–411. 2012.
SanzA, CaroP, AyalaV, Portero-OtinM, PamplonaR, BarjaG. Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins. FASEB J, 20:1064–1073. 2006.
144.
SanzA, CaroP, BarjaG. Protein restriction without strong caloric restriction decreases mitochondrial oxygen radical production and oxidative DNA damage in rat liver. J Bioenerg Biomembr, 36:545–552. 2004.
145.
SanzA, CaroP, GómezJ, BarjaG. Testing the vicious cycle theory of mitochondrial ROS production: effects of H2O2 and cumene hydroperoxide treatment on heart mitochondria. J Bioenerg Biomembr, 38:121–127. 2006.
146.
SanzA, CaroP, IbáñezJ, GómezJ, GredillaR, BarjaG. Dietary restriction at old age lowers mitochondrial oxygen radical production and leak at complex I and oxidative DNA damage in rat brain. J Bioenerg Biomembr, 37:83–90. 2005.
147.
SanzA, PamplonaR, BarjaG. Is the mitochondrial free radical theory of aging intact?Antiox Redox Signal, 8:582–599. 2006.
148.
SanzA, StefanatosRKA. The mitochondrial free radical theory of aging: a critical view. Curr Aging Sci, 1:10–21. 2008.
149.
SeluanovA, HineC, AzpuruaJ, FeigensonM, BozzellaM, MaoZ, CataniaKC, GorbunovaV. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. PNAS, 106:19352–19357. 2009.
150.
SchrinerSE, LinfordNJ, MartinGM, TreutingP, OgburnCE, EmondM, CoskunPE, LadigesW, WolfN, Van RemmenH, WallaceDC, RabinovitchPS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science, 308:1909–1911. 2005.
151.
SkulachevVP. Aging is a specific biological function rather than a result of a disorder in complex living systems: evidence in support of the Weismann's hypothesis. Biochemistry (Moscow), 62:1191–1195. 1997.
152.
SohalRS, FergusonM, SohalBH, ForsterMJ. Life span extension in mice by food restriction depends on an energy imbalance. J Nutr, 139:533–539. 2009.
153.
SohalRS, KuHH, AgarwalS, ForsterMJ, LalH. Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction. Mech Ageing Dev, 74:121–133. 1994.
154.
SohalRS, SohalBH, BrunkUT. Relationship between antioxidant defenses and longevity. Mech Ageing Dev, 53:217–227. 1990.
155.
SohalRS, SvenssonI, BrunkUT. Hydrogen peroxide production by liver mitochondria in different species. Mech Ageing Dev, 53:209–215. 1990.
156.
SohalRS, SvenssonI, SohalBH, BrunkUT. Superoxide anion radical production in different species. Mech Ageing Dev, 49:129–135. 1989.
SohalRS, OrrWC. The redox stress hypothesis of aging. Free Rad Biol Med, 52:539–555. 2012.
159.
SoltowQA, JonesDP, PromislowDE. A network perspective on metabolism and aging. Integr Comp Biol, 50:844–854. 2010.
160.
SomeyaS, YuW, HallowsWC, XuJ, VannJM, LeeuwenburghC, TanokuraM, DenuJM, ProllaTA. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell, 143:802–812. 2010.
161.
StrehlerB. Time, Cells and Aging. New York: Academic Press, 1962.
162.
StuartJA, KarahalilB, HogueBA, Souza-PintoNC, BohrVC. Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction. FASEB J, 18:595–597. 2004.
163.
SulimanHB, CarrawayMS, VelsorLW, DayBJ, GhioAJ, PinatadosiCA. Rapid mtDNA deletion by oxidants in rat liver mitochondria after hemin exposure. Free Radic Biol Med, 32:246–256. 2002.
164.
SunL, AmirA, AkhaS, MillarRA, HarperJ. Life-span extension in mice by preweaning food restriction and by methionine restriction in middle age. J Gerontol, 64A:711–722. 2009.
165.
TakeshigeK, MinakamiS. NADH- and NADPH-dependent formation of superoxide anions by bovine heart submitochondrial particles and NADH-ubiquinone reductase preparation. Biochem J, 180:129–135. 1979.
166.
TappelA, FletcherB, DeamerD. Effect of antioxidants and nutrients on lipid peroxidation fluorescent products and aging parameters in the mouse. J Gerontol, 28:415–424. 1973.
167.
TolmasoffJM, OnoT, CutlerRG. Superoxide dismutase: correlation with life span and specific metabolic rate in primate species. Proc Natl Acad Sci U S A, 77:2777–2781. 1980.
168.
TranahGJ. Mitochondrial-nuclear epistasis: implications for human aging and longevity. Ageing Res Rev, 10:238–252. 2011.
169.
TurrensJF, BoverisA. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J, 191:421–427. 1980.
170.
TylerDD. The Mitochondria in Health and Disease. New York: VCH, 1992.
171.
Van de BittnerGC, DubikovskayaEA, BertozziCR, ChangCJ. In vivo imaging of hydrogen peroxide production in a murine tumor model with a chemoselective bioluminescent reporter. PNAS U S A, 107:21316–21321. 2010.
172.
Van DiepeningenAD, MaasMF, HubertsDH, GoedbloedDJ, EngelmoerDJ, SlakhorstSM, KoopmanschapAB, KrauseF, DencherNA, SellemCH, Sainsard-ChanetA, HoekstraRF, DebetsAJ. Calorie restriction causes healthy life span extension in the filamentous fungus Podospora anserina. Mech Ageing Dev, 131:60–68. 2010.
173.
Van RaamsdonkJM, HekimiS. Reactive oxygen species and aging in Caenorhabditis elegans: causal or casual relationship?Antioxid Redox Signal, 13:1911–1953. 2010.
174.
Van RaamsdonkJM, HekimiS. Superoxide dismutase is dispensable for normal animal lifespan. PNAS, 109:5785–5790. 2012.
175.
VendittiP, MasulloP, Di MeoS. Effect of training on H2O2 release by mitochondria from rat skeletal muscle. Arch Biochem Biophys, 372:315–320. 1999.
176.
ZdanovS, RemacleJ, ToussaintO. Establishment of H2O2-induced premature senescence in human fibroblasts concomitant with increased cellular production of H2O2. Ann N Y Acad Sci, 1067:210–216. 2006.