Antioxidant Vitamins and Ageing

  • Irina MilisavEmail author
  • Samo Ribarič
  • Borut Poljsak
Part of the Subcellular Biochemistry book series (SCBI, volume 90)


The free radical theory of ageing (FRTA), presented by Denham Harman in 1950s, proposed that aerobic organisms age due to reactive oxygen species (ROS)/free radical induced damage that accumulates in cells over time. Since antioxidants can neutralize free radicals by electron donation, the most logical approach was to use them as supplements in order to prevent ageing. In this chapter, we will discuss the inability of antioxidant supplementation to improve health and longevity.

Although many antioxidants are efficient free radical quenchers in vitro, their in vivo effects are less clear. Recent evidence from human trials implies that antioxidant supplements do not increase lifespan and can even increase the incidence of diseases. Synthetic antioxidants were unable to consistently prevent ROS-induced damage in vivo, possibly as dietary antioxidants may not act only as ROS scavengers. Antioxidants can have dichotomous roles on ROS production. They are easily oxidized and can act as oxidants to induce damage when present in large concentrations. In appropriate amounts, they can modulate cellular metabolism by induction of cell stress responses and/or activate cell damage repair and maintenance systems. Therefore, the antioxidants’ beneficial role may be reversed/prevented by excessive amounts of antioxidant supplements. On the other hand, ROS are also involved in many important physiological processes in humans, such as induction of stress responses, pathogen defence, and systemic signalling. Thus, both “anti-oxidative or reductive stress” (the excess of antioxidants) as well as oxidative stress (the excess of ROS) can be damaging and contribute to the ageing processes.


Antioxidants Ageing ROS Dietary supplements Longevity 



The authors acknowledge the financial support from the Slovenian Research Agency (research core funding No. P3-0019 and P3-0171). This work was also partially supported by the H2020-MSCA-ITN:721236 TREATMENT project.


  1. Alam MT, Zelezniak A, Muelleder M, Shliaha P, Schwarz R, Capuano F et al (2016) The metabolic background is a global player in Saccharomyces gene expression epistasis. Nat Microbiol 1:15030CrossRefPubMedPubMedCentralGoogle Scholar
  2. Allen CL, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4:461–470CrossRefPubMedGoogle Scholar
  3. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994) The effects of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330(15):1029–1035CrossRefGoogle Scholar
  4. Ames BN (2001) DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res 475(1–2):7–20CrossRefPubMedGoogle Scholar
  5. Ames BN (2004) Dealying the mitochondrial decay ageing. Ann N Y Acad Sci 1019:406–411CrossRefPubMedGoogle Scholar
  6. Ames BN (2005) Increasing longevity by tuning up metabolism: to maximize human health and lifespan, scientist must abandon outdated models of micronutrients. EMBO Rep 6:S20–S24CrossRefPubMedPubMedCentralGoogle Scholar
  7. Ames BN (2006) Low micronutrient intake may accelerate the degenerative diseases of ageing through allocation of scarce micronutrient by triage. Proc Natl Acad Sci U S A 103(47):17589–17,594CrossRefPubMedPubMedCentralGoogle Scholar
  8. Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of ageing. Proc Natl Acad Sci U S A 90(17):7915–7922CrossRefPubMedPubMedCentralGoogle Scholar
  9. Anisimov VN, Bakeeva LE, Egormin PA et al (2008) Mitochondrial-targeted plastoquinone derivatives as tools to interrupt execution of the ageing program. 5. SkQl prolongs lifespan and prevents development of traits of senescence. Biochemistry 73(12):1329–1342PubMedGoogle Scholar
  10. Argüelles S, Gomez A, Machado A, Ayala A (2007) A preliminary analysis of within-subject variation in human serum oxidative stress parameters as a function of time. Rejuvenation Res 10(4):621–636CrossRefPubMedGoogle Scholar
  11. Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008) Remarkable longevity and stress resistance of nematode PI3K-null mutants. Ageing Cell 7(1):13–22CrossRefGoogle Scholar
  12. Barja G (1998) Mitochondrial free radical production and ageing in mammals and birds. Ann N Y Acad Sci 854:224–238CrossRefPubMedGoogle Scholar
  13. Barja G (2002) Rate of generation of oxidative stress-related damage and animal longevity. Free Radic Biol Med 33(9):1167–1172CrossRefPubMedGoogle Scholar
  14. Barja G (2012) Evolution and longevity. Nova Science Publisher, New YorkGoogle Scholar
  15. Bases R, Franklin WA, Moy T, Mendez F (1992) Enhanced expression repair activity in mammalian cells after ionizing radiation. Int J Radiat Biol 62(4):427–441CrossRefPubMedGoogle Scholar
  16. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A et al (2006) Resveratrol improves health and survival of mice on high-caloric diet. Nature 444:337–342CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bautista DM, Movahed P, Hinman A, Axelsson HE, Sterner O, Högestätt ED et al (2005) Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci U S A 102:12248–12,252CrossRefPubMedPubMedCentralGoogle Scholar
  18. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313CrossRefPubMedGoogle Scholar
  19. Bellavia A, Larsson SC, Bottai M, Wolk A, Orsini N (2013) Fruit and vegetable consumption and all-cause mortality: a dose-response analysis. Am J Clin Nutr 98(2):454–459CrossRefPubMedGoogle Scholar
  20. Bhuiyan MN, Mitsuhashi S, Sigetomi K, Ubukata M (2017) Quercetin inhibits advanced glycation end product formation via chelating metal ions, trapping methylglyoxal, and trapping reactive oxygen species. Biosci Biotechnol Biochem 81(5):882–890CrossRefPubMedGoogle Scholar
  21. Bieganowski P, Brenner C (2004) Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 117:495–502CrossRefPubMedGoogle Scholar
  22. Birringer M (2011) Hormetics: dietary triggers of an adaptive stress response. Pharm Res 28(11):2680–2694CrossRefPubMedGoogle Scholar
  23. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C (2004) Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 364(9441):1219–1228CrossRefPubMedGoogle Scholar
  24. 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. J Am Med Assoc 297(8):842–857CrossRefGoogle Scholar
  25. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev 2.
  26. Bogan KL, Brenner C (2008) Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr 28:115–130CrossRefPubMedGoogle Scholar
  27. Bokov A, Chaudhuri A, Richardson A (2004) The role of oxidative damage and stress in ageing. Mech Ageing Dev 125(10–11):811–826CrossRefPubMedGoogle Scholar
  28. Bonawitz ND, Rodeheffer MS, Shadel GS (2006) Defective mitochondrial gene expression results in reactive oxygen species-mediated inhibition of respiration and reduction of yeast life span. Mol Cell Biol 26:4818–4829CrossRefPubMedPubMedCentralGoogle Scholar
  29. Bravo L (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 56:317–333CrossRefPubMedGoogle Scholar
  30. Brunk UT, Jones CB, Sohal RS (1992) A novel hypothesis of lipofuscinogenesis and cellular ageing based on interaction between oxidative stress and autophagocitosis. Mutat Res 275:395–403CrossRefGoogle Scholar
  31. Bürkle A, Brabeck C, Diefenbach J, Beneke S (2005) The emerging role of poly (ADP-ribose) polymerase-1 in longevity. Int J Biochem Cell Biol 37(5):1043–1053CrossRefGoogle Scholar
  32. Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y et al (2012) The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15(6):838–847CrossRefPubMedPubMedCentralGoogle Scholar
  33. Caraballoso M, Sacristan M, Serra C, Bonfill X (2003) Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev 2:CD002141Google Scholar
  34. Cheeseman KH, Slater TF (1993) An introduction to free radical biochemistry. Br Med Bull 49:481–493, Chem Biol Interact 160(1):1–40CrossRefGoogle Scholar
  35. Cherubini A, Vigna G, Zuliani G, Ruggiero C, Senin U, Fellin R (2005) Role of antioxidants in atherosclerosis: epidemiological and clinical update. Curr Pharm Des 11(16):2017–2032CrossRefGoogle Scholar
  36. Congdon JD, Nagle RD, Kinney OM, van Loben Sels RC (2001) Hypotheses of ageing in a long-lived vertebrate, Blanding’s turtle (Emydoidea blandingii). Exp Gerontol 36(4–6):813–827CrossRefGoogle Scholar
  37. Congdon JD, Nagle RD, Kinney OM, van Loben Sels RC, Quinter T, Tinkle DW (2003) Testing hypotheses of ageing in long-lived painted turtles (Chrysemys picta). Exp Gerontol 38(7):765–772CrossRefGoogle Scholar
  38. Deguillaume L, Leriche M, Chaumerliac N (2005) Impact of radical versus non-radical pathway in the Fenton chemistry on the iron redox cycle in clouds. Chemosphere 60:718–724CrossRefGoogle Scholar
  39. Di Filippo C, Cuzzocrea S, Rossi F, Marfella R, D’Amico M (2006) Oxidative stress as the leading cause of acute myocardial infarction in diabetics. Cardiovasc Drug Rev 24:77–87CrossRefGoogle Scholar
  40. Donato A, Uberoi A, Bailey D, Wray W, Richardson R (2010) Exercise-induced brachial artery vasodilation: effects of antioxidants and exercise training in elderly men. Am J Physiol Heart Circ Physiol 298:H671–H678CrossRefGoogle Scholar
  41. Doonan R, McElwee JJ, Matthijssens F et al (2008) Against the oxidative damage theory of ageing: superoxide dismutase protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22(23):3236–3241CrossRefPubMedPubMedCentralGoogle Scholar
  42. Emanuel P, Scheinfeld N (2007) A review of DNA repair and possible DNA-repair adjuvants and selected natural anti-oxidants. Dermatol Online J 13(3):10PubMedGoogle Scholar
  43. Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C (2007) Chronic inflammation and oxidative stress in human carcinogenesis. Int J Cancer 121:2381–2386CrossRefGoogle Scholar
  44. Fiaschi T, Chiarugi P (2012) Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison. Int J Cell Biol 2012:762825CrossRefPubMedPubMedCentralGoogle Scholar
  45. Finch CE (1990) Longevity, senescence and the genome. University of Chicago Press, ChicagoGoogle Scholar
  46. Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247CrossRefPubMedPubMedCentralGoogle Scholar
  47. Forman HJ, Daves KJ, Ursini F (2014) How do nutritional antioxidants really work: nucleophilic tone para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med 66:24–35CrossRefGoogle Scholar
  48. Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN (1990) Oxidative damage to DNA during ageing: 8-hydroxy-2-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A 87:4533–4537CrossRefPubMedPubMedCentralGoogle Scholar
  49. Frescas D, Valenti L, Accili D (2005) Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280:20589–20,595CrossRefGoogle Scholar
  50. Fulgencio JP, Kohl C, Girard J, Pegorier JP (2001) Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and specific gene expression in cultured hepatocytes. Biochem Pharma 62(4):439–446CrossRefGoogle Scholar
  51. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y et al (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761CrossRefPubMedPubMedCentralGoogle Scholar
  52. Gems D, Doonan R (2009) Antioxidant defense and ageing in C. elegans: is the oxidative damage theory of ageing wrong? Cell Cycle 8(11):1681–1687CrossRefGoogle Scholar
  53. Girondot M, Garcia J (1999) Senescence and longevity in turtles: what telomeres tell us. In: Miaud C, Guyetant R (eds) Proceedings of the 9th extraordinary meeting of the Europea Societas Herpetologica. Chambery, France, pp 25–29Google Scholar
  54. Gliemann L, Schmidt JF, Olsen J, Biensø RS, Peronard SL, Grandjean SU et al (2013) Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol 591(20):5047–5059CrossRefPubMedPubMedCentralGoogle Scholar
  55. Gomez Cabrera MC, Domenech E, Romagnoli M, Arduini A, Borras C, Pallardo FV et al (2008) Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adapations in endurance performance. Am J Clin Nutr 87(1):142–149CrossRefGoogle Scholar
  56. Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA (2000) Mechanisms and implications of the age-associated decrease in DNA repair capacity. FASEB J 14(10):1325–1334CrossRefGoogle Scholar
  57. Gratão PL, Polle A, Lea PJ, Azevedo RA (2005) Making the life of heavy metal-stressed plants a little easier. Funct Plant Biol 32:481–494CrossRefGoogle Scholar
  58. Gredilla R, Barja G (2003) Mitochodrial oxidative stress and caloric restriction. Advances in cell ageing and gerontology 14:105–122CrossRefGoogle Scholar
  59. Grube K, Bürkle A (1992) Poly (ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc Natl Acad Sci U S A 89(24):11759–11,763CrossRefPubMedPubMedCentralGoogle Scholar
  60. Halliwel B, Gutteridge JMC (2005) Free radicals in biology and medicine, 4rth edn. Oxford University Press, OxfordGoogle Scholar
  61. Halliwell B (1999) Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic Res 31(4):261–272CrossRefGoogle Scholar
  62. Halliwell B (2007) Biochemistry of oxidative stress. Biochem Soc Trans 35(Pt 5):1147–1150Google Scholar
  63. Halliwell B (2011) Free radicals and antioxidants – quo vadis? Trends Pharmacol Sci 32(3):125–130CrossRefGoogle Scholar
  64. Halliwell B, Gutteridge JMC (1984) Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem J 219:1–14CrossRefPubMedPubMedCentralGoogle Scholar
  65. Halliwell B, Gutteridge J (2015) Free radicals in biology and medicine, 5th edn. Clarendon Press, OxfordCrossRefGoogle Scholar
  66. Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K et al (2001) Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 98:10469–10474CrossRefPubMedPubMedCentralGoogle Scholar
  67. Hanson RW, Hakimi P (2008) Born to run; the story of the PEPCK-Cmus mouse. Biochimie 90:838–842CrossRefPubMedPubMedCentralGoogle Scholar
  68. Hart RW, Setlow RB (1974) Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc Natl Acad Sci U S A 71(6):2169–2173CrossRefPubMedPubMedCentralGoogle Scholar
  69. He C, Tsuchiyama SK, Nguyen QT, Plyusnina EN, Terrill SR, Sahibzada S, Patel B, Faulkner AR, Shaposhnikov MV, Tian R, Tsuchiya M, Kaeberlein M, Moskalev AA, Kennedy BK, Polymenis M (2014) Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import. PLoS Genet 10(12):e1004860CrossRefPubMedPubMedCentralGoogle Scholar
  70. Hipkiss AR (2008) Energy metabolism, altered proteins, sirtuins and ageing: converging mechanisms? Biogerontology 9(1):49–55CrossRefGoogle Scholar
  71. Houtkooper RH, Canto C, Wanders RJ, Auwerx J (2010) The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev 31(2):194–223CrossRefPubMedGoogle Scholar
  72. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196CrossRefGoogle Scholar
  73. Hulbert AJ (2008) Explaining longevity of different animals: is membrane fatty acid composition the missing link? Age 30(2–3):89–97CrossRefPubMedPubMedCentralGoogle Scholar
  74. Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA (2007) Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev 87(4):1175–1213CrossRefPubMedGoogle Scholar
  75. Imai S (2010) The NAD World: a new systemic regulatory network for metabolism and ageing—Sirt1, systemic NAD biosyntesis, and their importance. Cell Biochem Biophys 53(2):65–74CrossRefGoogle Scholar
  76. Imlay JA (2003) Pathways of oxidative damage. Annuv Rev Microbiol 57:395–418CrossRefGoogle Scholar
  77. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS et al (2006) Caloric restriction mimetics: an emerging research field. Ageing Cell 5(2):97–108CrossRefGoogle Scholar
  78. Jee J, Lim S, Park J, Kim C (2006) Stabilization of all-trans retinol by loading lipophilic antioxidants in solid lipid nanoparticles. Eur J Pharm Biopharm 63:134–139CrossRefPubMedPubMedCentralGoogle Scholar
  79. Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(3):26–36. CrossRefGoogle Scholar
  80. Kaiser J (2012) Will an aspirin a day keep the cancer away? Science 337(6101):1471–1473CrossRefGoogle Scholar
  81. Kand’ar R, Zakova P, Muzakova V (2006) Monitoring of antioxidant properties of uric acid in humans for a consideration measuring of levels of allantoin in plasma by liquid chromatography. Clin Chim Acta 365:249–256CrossRefPubMedGoogle Scholar
  82. Kenyon C (2005) The plasticity of ageing: insights from long-lived mutants. Cell 120:449–460CrossRefPubMedPubMedCentralGoogle Scholar
  83. Khan JA, Forouhar F, Tao X, Tong L (2007) Nicotinamide adenine dinucleotide metabolism as an attractive target for drug discovery. Expert Opin Ther Targets 11:695–705CrossRefPubMedGoogle Scholar
  84. Khlebnikov AI, Schepetkin IA, Domina NG, Kirpotina LN, Quinn MT (2007) Improved quantative structure-activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems. Bioorg Med Chem 15:1749–1770CrossRefPubMedGoogle Scholar
  85. Kim KM, Kim PK, Kwon YG, Bai SK, Nam WD, Kim YM (2002) Regulation of apoptosis by nitrosative stress. J Biochem Mol Biol 35:127–133PubMedGoogle Scholar
  86. Kupferschmidt K (2012) Uncertain verdict as vitamin D goes on trial. Science 337(6101):1476–1478CrossRefPubMedGoogle Scholar
  87. Lamming DW, Wood JG, Sinclair DA (2004) Small molecules that regulate lifespan: evidence for xenohormesis. Mol Microbiol 53(4):1003–1009CrossRefPubMedGoogle Scholar
  88. Lane MA, Roth GS, Ingram DK (2007) Caloric restriction mimetics: a novel approach for biogerontology. Methods Mol Biol 371:143–149CrossRefPubMedGoogle Scholar
  89. Lanza IR, Short DK, Skort KR, Raghavakaimal S, Basu R, Joyner MJ et al (2008) Endurance exercise as a countermeasure for ageing. Diabetes 57:2933–2942CrossRefPubMedPubMedCentralGoogle Scholar
  90. Lee JS, Surh YJ (2005) Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 224:171–184CrossRefPubMedGoogle Scholar
  91. Lewis KN, Andziak B, Yang T, Buffestein R (2013) The naked mole-rat response to oxidative stress: just deal with it. Antioxid Redox Signal 19(12):1388–1399CrossRefPubMedPubMedCentralGoogle Scholar
  92. Little JB (1976) Relationship between DNA repair capacity and cellular ageing. Gerontology 22(1–2):28–55CrossRefPubMedGoogle Scholar
  93. Liu Y, Long J, Liu J (2014) Mitochondrial free radical theory of ageing: who moved my premise? Geriatr Gerontol Int 14(4):740–749CrossRefPubMedGoogle Scholar
  94. Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP et al. (2004) Molecular biology of the cell, 5 WH Freeman, New York.Google Scholar
  95. Lotito SB, Frei B (2006) Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon. Free Radic Biol Med 41(12):1727–1746CrossRefPubMedGoogle Scholar
  96. Lutz PL, Prentice HM, Milton SL (2003) Is turtle longevity linked to enhanced mechanisms for surviving brain anoxia and reoxygenation? Exp Gerontol 38(7):797–800CrossRefPubMedGoogle Scholar
  97. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147CrossRefPubMedGoogle Scholar
  98. Mattson MP (2008a) Dietary factors, hormesis and health. Ageing Res Rev 7(1):43–48CrossRefPubMedGoogle Scholar
  99. Mattson MP (2008b) Hormesis defined. Ageing Res Rev 7(1):1–7CrossRefPubMedGoogle Scholar
  100. Milisav I, Poljsak B, Suput D (2012) Adaptive response, evidence of cross-resistance and its potential clinical use. Int J Mol Sci 13(9):10771–10,806CrossRefPubMedPubMedCentralGoogle Scholar
  101. Miller ER, Pastor Barriuso R, Dalal D, Riemersma R, Appel LJ, Guallar E (2005a) High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37–46CrossRefPubMedGoogle Scholar
  102. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma A, Appel LJ, Guallar E (2005b) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142(1):37–46CrossRefPubMedGoogle Scholar
  103. Mills KF, Yoshida S, Stein LR, Groziol A, Kubota S, Sasaki Y et al (2016) Long-term administration of Nicotinamide Mononucleotide Mitigates age-associated physiological decline in mice. Cell Metab 24:1–12CrossRefGoogle Scholar
  104. Mira L, Fernandez MT, Santos M, Rocha R, Florencio MH, Jennings KR (2002) Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res 36(11):1199–1208CrossRefPubMedGoogle Scholar
  105. Mockett RJ, Sohal RS, Orr WC (1999) Overexpression of glutathione reductase extends survival in transgenic Drosophila melanogaster under hyperoxia but not normoxia. FASEB J 13(13):1733–1742CrossRefPubMedGoogle Scholar
  106. Morris KC, Lin HW, Thompson JW, Perez Pinzon MA (2011) Pathways for ischemic cytoprotection: role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J Cereb Blood Flow Metab 31(4):1003–1019CrossRefPubMedPubMedCentralGoogle Scholar
  107. Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K et al (2010) Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis 1(1):e10CrossRefPubMedPubMedCentralGoogle Scholar
  108. Muiras ML, Müller M, Schächter F, Bürkle A (1998) Increased poly (ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians. J Mol Med (Berl) 76(5):346–354CrossRefPubMedGoogle Scholar
  109. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr (2011) Dietary supplements and mortality rate in older women: The iowa women’s health study. Arch Intern Med 171:1625–1633CrossRefPubMedPubMedCentralGoogle Scholar
  110. Nordberg J, Arner ESJ (2001) Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 31(11):1287–1312CrossRefPubMedGoogle Scholar
  111. Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER (1987) Age-related changes in oxidized proteins. J Biol Chem 262:5488–5491PubMedGoogle Scholar
  112. Orr WC, Sohal RS (1993) Effects of Cu-Zn superoxide dismutase overexpression of life span and resistance to oxidative stress in transgenic Drosophila melanogaster. Arch Biochem Biophys 301(1):34–40CrossRefPubMedGoogle Scholar
  113. Ozbek E (2012) Induction of oxidative stress in kidney. Int J Nephrol 2012:465897CrossRefPubMedPubMedCentralGoogle Scholar
  114. Perez VI, Bokov A, Van Remmen H, Mele J, Ran Q, Ikeno Y et al (2009a) Is the oxidative stress theory of ageing dead? Biochimica et Biophysica Acta 1790(10):1005–1014CrossRefPubMedPubMedCentralGoogle Scholar
  115. Perez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J et al (2009b) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci U S A 106(9):3059–3064. CrossRefPubMedPubMedCentralGoogle Scholar
  116. Perez-Campo R, Lopez-Torres M, Cadenas S, Rojas C, Barja G (1998) The rate of free radical production as a determinant of the rate of ageing: evidence from the comparative approach. J Comp Physiol 168(3):149–158CrossRefGoogle Scholar
  117. Piotrowska A, Bartnik E (2014) The role of reactive oxygen species and mitochondria in ageing. Postepy Biochem 60(2):240–247PubMedPubMedCentralGoogle Scholar
  118. Poljsak B (2011) Strategies for reducing or preventing the generation of oxidative stress. Oxid Med Cell Longev 2011:194586PubMedPubMedCentralGoogle Scholar
  119. Poljsak B (2017) NAMPT-mediated nad biosyntesis as the internal timing mechanism: in NAD+ world, time is running in its own way. Rejuvenation Res.
  120. Poljsak B, Fink R (2014) The protective role of antioxidants in the defence against ROS/RNS-mediated environmental pollution. Oxid Med Cell Longev 2014:671539CrossRefPubMedPubMedCentralGoogle Scholar
  121. Poljsak B, Milisav I (2012) The neglected significance of “antioxidative stress”. Oxid Med Cell Longev 2012:480895CrossRefPubMedPubMedCentralGoogle Scholar
  122. Poljsak B, Milisav I (2014) What doesn’t kill us makes us stronger. Nova Science Publisher, New YorkGoogle Scholar
  123. Poljsak B, Milisav I (2016) NAD+ as the link between oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity, and health span. Rejuvenation Res 19(5):406–413CrossRefGoogle Scholar
  124. Poljsak B, Raspor P (2008) The antioxidant and pro-oxidant activity of vitamin C and trolox in vitro: a comparative study. J Appl Toxicol 28(2):183–188CrossRefPubMedGoogle Scholar
  125. Poljsak B, Gazdag Z, Pesti M, Jenko Brinovec S, Belagy J, Plesničar S et al (2006) Pro-oxidative versus antioxidative reactions between Trolox and Cr(VI): The role of H(2)O(2). Environ Toxicol Pharmacol 22(1):15–19CrossRefPubMedGoogle Scholar
  126. Poljsak B, Milislav I, Lampe T, Ostan I (2011) Reproductive benefit of oxidative damage: an oxidative stress “malevolence”? Oxid Med Cell Longev 2011:760978. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Pryor W (1994) Free radicals and lipid peroxidation: what they are and how they got that way. In: Frei B (ed) Natural antioxidants in human health and disease. Academic, San Diego, pp 1–19Google Scholar
  128. Rahman K (2007) Studies on free radicals, antioxidants and co-factors. Clin Interv Ageing 2:219–236Google Scholar
  129. Ralser M, Benjamin IJ (2008) Reductive stress on life span extension in C. elegans. BMC Res Notes 1:19CrossRefPubMedPubMedCentralGoogle Scholar
  130. Raskin I, Ribnicky DM, Komarnytsky S, Ilic N, Poulev A, Borisjuk A et al (2002) Plants and human health in twenty-first century. Trends Biotechnol 20:522–531CrossRefPubMedGoogle Scholar
  131. Reddy L, Odhav B, Bhoola KD (2003) Natural products for cancer prevention: a global perspective. Pharmacol Ther 99:1–13CrossRefPubMedGoogle Scholar
  132. Rhee SG (1999) Redox signaling: hydrogen peroxide as intracellular messenger. Exp Mol Med 31(2):53–59CrossRefGoogle Scholar
  133. Richardson R, Donato A, Uberoi A, Wray W, Lawrenson L, Nishiyama S, Bailey D (2007) Exercise-induced brachial artery vasodilation: role of free radicals. Am J Physiol Heart Circ Physiol 292(3):H1516–H1522CrossRefGoogle Scholar
  134. Richter C, Park JW, Ames BN (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A 85(17):6465–6467CrossRefPubMedPubMedCentralGoogle Scholar
  135. Riley PA (1994) Free radicals in biology: oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 65:27–33CrossRefGoogle Scholar
  136. Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radic Biol Med 51(2):327–336CrossRefGoogle Scholar
  137. Ristow M, Zarse K, Oberbach A, Kloeting N, Birringer M, Kiehntopf M et al (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106(21):8665–8670CrossRefPubMedPubMedCentralGoogle Scholar
  138. Roberts CK, Sindhu KK (2009) Oxidative stress and metabolic syndrome. Life Sci 84:705–712CrossRefGoogle Scholar
  139. Rocha M, Hernandez Mijares A, Garcia Malpartida K, Bañuls C, Bellod L, Victor VM (2010) Mitochondria-targeted antioxidant peptides. Curr Pharm Des 16(28):3124–3131CrossRefGoogle Scholar
  140. Salganik RI (2001) The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr 20(5):464S–472SCrossRefGoogle Scholar
  141. Sanz A, Stefanatos RK (2008) The mitochondrial free radical theory of ageing: a critical view. Curr Ageing Sci 1(1):10–21CrossRefGoogle Scholar
  142. Sastre J, Pallardo FV, Garcia De La Asuncion J, Vina J (2000) Mitochondria, oxidative stress and ageing. Free Radic Res 32(3):189–198CrossRefGoogle Scholar
  143. Sauve AA (2008) NAD+ and vitamin B3: from metabolism to therapies. J Pharmacol Exp Ther 324(3):883–893CrossRefGoogle Scholar
  144. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6(4):280–293CrossRefGoogle Scholar
  145. Schulz TJ, Westermann D, Isken F, Voigt A, Laube B, Thierbach R et al (2010) Activation of mitochondrial energy metabolism protects against cardiac failure. Ageing 2:843–853Google Scholar
  146. Seto NO, Hayashi S, Tener GM (1990) Overexpression of Cu-Zn superoxide dismutase in Drosophila does not affect life-span. Proc Natl Acad Sci U S A 87:4270–4274CrossRefPubMedPubMedCentralGoogle Scholar
  147. Sies H (1991) Oxidative stress II: oxidants and antioxidants. Academic, LondonGoogle Scholar
  148. Sinclair D, Howitz KT (2006) Dietary restriction, hormesis and small molecule mimetics. In: Masoro EJ, Austad SN (eds) Handbook of the biology of ageing, 6th edn. Academic, Amsterdam, pp 63–105Google Scholar
  149. Singh U, Jialal I (2006) Oxidative stress in atherosclerosis. Pathophysiology 13:129–142CrossRefGoogle Scholar
  150. Skulachev MV, Antonenko YN, Anisimov VN et al (2011) Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr Drug Targets 12(6):800–826CrossRefGoogle Scholar
  151. Sohal R, Weindruch R (1996) Oxidative stress, caloric restriction, and ageing. Science 273:59–63CrossRefPubMedPubMedCentralGoogle Scholar
  152. Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, LL ME (2013) Oxidative stress and cancer: an overview. Ageing Res Rev 12:376–390CrossRefGoogle Scholar
  153. Speakman JR, Selman C (2011) The free-radical damage theory: accumulating evidence against a simple link of oxidative stress to ageing and lifespan. Bioessays 33(4):255–259CrossRefGoogle Scholar
  154. Spindler SR (2012) Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span. Age 34(1):111–120CrossRefGoogle Scholar
  155. Spindler SR, Dhahbi JM, Mote PL, Kim HJ, Tshuchiya T (2003) Rapid identification of candidate CR mimetics using microarrays. Biogerontology 4(1):89Google Scholar
  156. Spindler SR, Mote PL, Flegal JM, Teter B (2013) Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice. Rejuvenation Res 16(2):143–151CrossRefGoogle Scholar
  157. Stanner SA, Hughes J, Kelly CNM, Buttriss J (2004) A review of the epidemiological evidence for the “antioxidant hypothesis”. Public Health Nutr 7(3):407–422CrossRefGoogle Scholar
  158. Strobel NA, Peake JM, Matsumoto A, Marsh SA, Coombes JS, Wadley GD (2011) Antioxidant supplementation reduces skeletal muscle mitochondrial biogenesis. Med Sci Sports Exerc 43(6):1017–1024CrossRefGoogle Scholar
  159. Tabassum A, Bristow RG, Venkateswaran V (2010) Ingestion of selenium and other antioxidants during prostate cancer radiotherapy: a good thing? Cancer Treat Rev 36:230–234CrossRefGoogle Scholar
  160. Terman A, Brunk UT (2006) Oxidative stress, accumulation of biological ‘garbage’, and ageing. Antioxid Redox Signal 8:197–204CrossRefGoogle Scholar
  161. Thierbach R, Schulz TJ, Isken F, Voigt A, Mietzner B, Drewes G et al (2005) Targeted disruption of hepatic fraxatin expression causes impaired mitochondrial function, decreased life span, and tumor growth in mice. Hum Mol Genet 14:3857–3864CrossRefGoogle Scholar
  162. Tijskens P (2004) Discovering the future: modelling quality matters. Wageningen University, WageningenGoogle Scholar
  163. Trammel SAJ, Weidemann J, Chadda A, Yorek MS, Holmes A, Coppey LJ et al (2016) Nicotinamide Riboside opposes Type 2 diabetes and neuropathy in mice. Sci Rep 6:26933CrossRefGoogle Scholar
  164. Tsutsui H, Kinugawa S, Matsushima S (2011) Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol 301:2181–2190CrossRefGoogle Scholar
  165. Turunen M, Olsson J, Dallner G (2004) Metabolism and function of coenzyme Q. Biochim Biophys Acta 1660:171–199CrossRefGoogle Scholar
  166. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human diseases. Int J Biochem Cell Biol 39:44–84CrossRefGoogle Scholar
  167. Van Remmen H et al (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate ageing. Physiol Genomics 16:29–37CrossRefGoogle Scholar
  168. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ (2003) Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 361(9374):2017–2023CrossRefGoogle Scholar
  169. Wallace DC (2005) A mitochondrial paradigm of metabolic and degenerative diseases, ageing, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 39:359–407CrossRefPubMedPubMedCentralGoogle Scholar
  170. Wani G, Milo GE, SM D’A (1998) Enhanced expression of 8-OHdG triphosphatase gene in human breast tumor cells. Cancer Lett 125(1–2):123–130CrossRefGoogle Scholar
  171. Warburton DE, Nicol CW, Bredin SS (2006) Health benefits of physical activity: the evidence. Can Med Assoc J 174:801–809CrossRefGoogle Scholar
  172. Williams KJ, Fisher EA (2005) Oxidation, lipoproteins, and atherosclerosis: which is wrong, the antioxidants or the theory? Curr Opin Clin Nutr Metab Care 8(2):139–146CrossRefGoogle Scholar
  173. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M et al (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430(7000):686–689CrossRefGoogle Scholar
  174. World Cancer Research Fund (2017) Accessed 4 Oct 2017
  175. World Health Organization (2017) Accessed 8 Oct 2017
  176. Yang YC, Remmen VH (2009) The mitochondrial theory of ageing: insight from transgenic and knockout mouse models. Exp Gerontol 44(4):256–260CrossRefGoogle Scholar
  177. Yang W, Li J, Hekimi S (2007) A measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics 177(4):2063–2074CrossRefPubMedPubMedCentralGoogle Scholar
  178. Ying W (2007) Therapeutic potential of NAD+ for neurological diseases. Future Neurol 2:129–132CrossRefGoogle Scholar
  179. Zarse K, Schulz TJ, Birringer M, Ristow M (2007) Impaired respiration is positively correlated with decreased life span in Caenorhabditis elegans models of Friedreich ataxia. FASEB J 21:1271–1275CrossRefPubMedGoogle Scholar
  180. Zhan J, Liu YJ, Cai LB, Xu FR, Xie T, He QQ (2017) Fruit and vegetable consumption and risk of cardiovascular disease: A meta-analysis of prospective cohort studies. Crit Rev Food Sci Nutr 57(8):1650–1663CrossRefPubMedGoogle Scholar
  181. Zhang YQ, Ikeno Y, Qi WB et al (2009) Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J Gerontol 64(12):1212–1220CrossRefGoogle Scholar
  182. Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P et al (2016a) NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352(6292):1436–1443. CrossRefGoogle Scholar
  183. Zhang W, Chen C, Shi H, Yang M, Liu Y, Ji P et al (2016b) Curcumin is a biologically active copper chelator with antitumor activity. Phytomedicine 23(1):1–8CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.University of Ljubljana, Faculty of Health SciencesUniversity of LjubljanaLjubljanaSlovenia
  2. 2.University of Ljubljana, Faculty of Medicine, Institue of PathophysiologyUniversity of LjubljanaLjubljanaSlovenia

Personalised recommendations