Mitochondria and Ageing

Chapter

Abstract

Mitochondria are the major sites of oxygen utilisation for energy production in cells. Indeed, all the reactions of the Krebs’ Cycle take place in mitochondria and they produce NADH and succinate, which are then oxidised in the respiratory chain. Experiments dating back to the early part of the twentieth century seemed to indicate that at a high rate of oxygen consumption (referred to gram of body weight) was normally associated with a low maximum lifespan. Thus, it was thought that it was the rate of oxygen utilisation that was related to “the rate of living”. However, more recent data pointed out that birds are unique because they combine high rates of oxygen consumption with a high maximum lifespan. It would later be pointed out that the maximal lifespan is more correlated with the rate of free radical production by mitochondria rather than the rate of oxygen utilisation. These experiments were performed under the general scheme of the free radical theory of ageing. Still, more than 300 theories have been postulated to explain ageing and this can indicate that none of them is completely satisfactory to explain a complex phenomenon such as ageing. We postulate in this chapter that the free radical theory of ageing could be revisited and that it is the age-associated derangement of the free radical signalling network that is central to understand ageing.

Keywords

Free radicals Oxidants Longevity Antioxidants Frailty 

References

  1. Ali SS, Xiong C et al (2006) Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress. Aging Cell 5(6):565–574CrossRefPubMedGoogle Scholar
  2. Ames BN, Shigenaga MK et al (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 90:7915–7922CrossRefPubMedPubMedCentralGoogle Scholar
  3. Ames BN, Shigenaga MK et al (1995) Mitochondrial decay in aging. Biochim Biophys Acta 1271(1):165–170CrossRefPubMedGoogle Scholar
  4. Anson RM, Hudson E et al (2000) Mitochondrial endogenous oxidative damage has been overestimated. FASEB J 14(2):355–360CrossRefPubMedGoogle Scholar
  5. Asunción JG, Millan A et al (1996) Mitochondrial glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA. FASEB J 10:333CrossRefPubMedGoogle Scholar
  6. de la Asuncion JG, del Olmo ML et al (1998) AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins. J Clin Invest 102(1):4–9CrossRefPubMedPubMedCentralGoogle Scholar
  7. Atamna H, Frey WH 2nd (2004) A role for heme in Alzheimer’s disease: heme binds amyloid beta and has altered metabolism. Proc Natl Acad Sci U S A 101(30):11153–11158CrossRefPubMedPubMedCentralGoogle Scholar
  8. Barja G (1998) Mitochondrial free radical production and aging in mammals and birds. Ann N Y Acad Sci 854:224–238CrossRefPubMedGoogle Scholar
  9. Barja de Quiroga C (1999) Mitochondrial oxygen radical generation and leak: sites of produccion in states 4 an 3, organ specificity and relation to aging and longevity. J Bioenerg Biomembr 31(4):347–366CrossRefGoogle Scholar
  10. Barja G, Herrero A (2000) Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J 14(2):312–318CrossRefPubMedGoogle Scholar
  11. Barja G, Cadenas S et al (1994) Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds. Free Radic Res 21(5):317–327CrossRefPubMedGoogle Scholar
  12. Borras C, Sastre J et al (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med 34(5):546–552CrossRefPubMedGoogle Scholar
  13. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134(3):707–716CrossRefPubMedPubMedCentralGoogle Scholar
  14. Calleja M, Pena P et al (1993) Mitochondrial DNA remains intact during Drosophila aging, but the levels of mitochondrial transcripts are significantly reduced. J Biol Chem 268(25):18891–18897PubMedGoogle Scholar
  15. Caro P, Gomez J et al (2010) Mitochondrial DNA sequences are present inside nuclear DNA in rat tissues and increase with age. Mitochondrion 10(5):479–486CrossRefPubMedGoogle Scholar
  16. Corral-Debrinski M, Shoffner JM et al (1992) Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 275(3-6):169–180CrossRefPubMedGoogle Scholar
  17. Cortopassi GA, Shibata D et al (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci U S A 89(16):7370–7374CrossRefPubMedPubMedCentralGoogle Scholar
  18. Croteau DL, Stierum RH et al (1999) Mitochondrial DNA repair pathways. Mutat Res 434(3):137–148CrossRefPubMedGoogle Scholar
  19. Davies KJ, Ermak G et al (2007) Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J 21(12):3023–3028CrossRefPubMedGoogle Scholar
  20. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82(1):47–95CrossRefPubMedGoogle Scholar
  21. Gadaleta MN, Petruzzella V et al (1990) Reduced transcription of mitochondrial DNA in the senescent rat. Tissue dependence and effect of L-carnitine. Eur J Biochem 187(3):501–506CrossRefPubMedGoogle Scholar
  22. Gadaleta MN, Rainaldi G et al (1992) Mitochondrial DNA copy number and mitochondrial DNA deletion in adult and senescent rats. Mutat Res 275(3-6):181–193CrossRefPubMedGoogle Scholar
  23. García de la Asunción J, Millan A et al (1996) Mitochondiral glutathione oxidation correlates with age-associated oxidative damage to mitochondrial DNA. FASEB J 10:333–338CrossRefGoogle Scholar
  24. Gershman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO (1954) Oxygen poisoning and X irradiation: a mechanism in common. Science 119:623–626CrossRefGoogle Scholar
  25. Giulivi C, Boveris A et al (1995) Hydroxyl radical generation during mitochondrial electron transfer and the formation of 8-hydroxydesoxyguanosine in mitochondrial DNA. Arch Biochem Biophys 316(2):909–916CrossRefPubMedGoogle Scholar
  26. Hagen TM, Yowe DL, Bartholomew JC, Wehr CM, Do KL, Park JY, Ames BN (1997) Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci U S A 94(7):3064–3069CrossRefPubMedPubMedCentralGoogle Scholar
  27. Halliwell B, Auroma OI (1991) DNA damage by oxygen derived species. Its mechanism of action and measurement in mammalian systems. FEBS Lett 281:9–19CrossRefPubMedGoogle Scholar
  28. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 2:298–300CrossRefGoogle Scholar
  29. Harman D (1972) The biological clock: The mitocondria. J Am Geriatr Soc 20(4):145–147CrossRefPubMedGoogle Scholar
  30. Jang YM, Kendaiah S et al (2004) Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. FEBS Lett 577(3):483–490CrossRefPubMedGoogle Scholar
  31. Johns DR (1995) Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease. N Engl J Med 333(10):638–644CrossRefPubMedGoogle Scholar
  32. Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342(3):619–630CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kristal BS, Chen J et al (1994) Sensitivity of mitochondrial transcription to different free radical species. Free Radic Biol Med 16(3):323–329CrossRefPubMedGoogle Scholar
  34. Lee CM, Weindruch R et al (1997) Age-associated alterations of the mitochondrial genome. Free Radic Biol Med 22(7):1259–1269CrossRefPubMedGoogle Scholar
  35. Lezza AM, Boffoli D et al (1994) Correlation between mitochondrial DNA 4977-bp deletion and respiratory chain enzyme activities in aging human skeletal muscles. Biochem Biophys Res Commun 205(1):772–779CrossRefPubMedGoogle Scholar
  36. Lezza AM, Mecocci P et al (1999) Mitochondrial DNA 4977 bp deletion and OH8dG levels correlate in the brain of aged subjects but not Alzheimer’s disease patients. FASEB J 13(9):1083–1088CrossRefPubMedGoogle Scholar
  37. Lloret A, Badia MC et al (2008) Gender and age-dependent differences in the mitochondrial apoptogenic pathway in Alzheimer’s disease. Free Radic Biol Med 44(12):2019–2025CrossRefPubMedGoogle Scholar
  38. Lloret A, Fuchsberger T et al (2015) Molecular mechanisms linking amyloid beta toxicity and Tau hyperphosphorylation in Alzheimers disease. Free Radic Biol Med 83:186–191CrossRefPubMedGoogle Scholar
  39. Martin JA, Sastre J et al (2001) Hepatic gamma-cystathionase deficiency in patients with AIDS. JAMA 285(11):1444–1445CrossRefPubMedGoogle Scholar
  40. Miquel J (1992) An update on the mitochondrial-DNA mutation hypothesis of cell aging. Mutat Res 275(3-6):209–216CrossRefPubMedGoogle Scholar
  41. Miquel J, Economos AC et al (1980) Mitochondrial role in cell aging. Exp Gerontol 15(6):575–591CrossRefPubMedGoogle Scholar
  42. Navarro A, Gomez C et al (2004) Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 286(3):R505–R511CrossRefPubMedGoogle Scholar
  43. Pearl R (1928) The rate of living. University of London Press, LondonGoogle Scholar
  44. Pereira C, Santos MS et al (1998) Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 9(8):1749–1755CrossRefPubMedGoogle Scholar
  45. Perry G, Castellani RJ et al (1998) Reactive oxygen species mediate cellular damage in Alzheimer disease. J Alzheimers Dis 1(1):45–55CrossRefPubMedGoogle Scholar
  46. Richter C, Park JW et al (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A 85:6465–6467CrossRefPubMedPubMedCentralGoogle Scholar
  47. Sanz A, Hiona A et al (2007) Evaluation of sex differences on mitochondrial bioenergetics and apoptosis in mice. Exp Gerontol 42(3):173–182CrossRefPubMedGoogle Scholar
  48. Sastre J, Pallardo FV et al (1996) Aging of the liver: age-associated mitochondrial damage in intact hepatocytes. Hepatology 24(5):1199–1205CrossRefPubMedGoogle Scholar
  49. Sastre J, Millan A et al (1998) A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress. Free Radic Biol Med 24(2):298–304CrossRefPubMedGoogle Scholar
  50. Schapira AH (2006) Mitochondrial disease. Lancet 368(9529):70–82CrossRefPubMedGoogle Scholar
  51. Selkoe DJ (1991) Amyloid protein and Alzheimer's disease. Sci Am 265(5):68–71. 74-6, 78CrossRefPubMedGoogle Scholar
  52. Shen CC, Wertelecki W et al (1995) Repair of mitochondrial DNA damage induced by bleomycin in human cells. Mutat Res 337(1):19–23CrossRefPubMedGoogle Scholar
  53. Shigenaga MK, Hagen TM et al (1994) Oxidative damage and mitochondrial decay in aging. Proc Natl Acad Sci U S A 91:10771–10778CrossRefPubMedPubMedCentralGoogle Scholar
  54. Suter M, Richter C (1999) Fragmented mitochondrial DNA is the predominant carrier of oxidized DNA bases. Biochemistry 38(1):459–464CrossRefPubMedGoogle Scholar
  55. Vina J, Borras C et al (2007) Theories of ageing. IUBMB Life 59(4-5):249–254CrossRefPubMedGoogle Scholar
  56. Vina J, Borras C et al (2013) The free radical theory of aging revisited: the cell signaling disruption theory of aging. Antioxid Redox Signal 19(8):779–787CrossRefPubMedPubMedCentralGoogle Scholar
  57. Yin F, Sancheti H et al (2004) Mitochondrial function in ageing: coordination with signalling and transcriptional pathways. J Physiol 594(8):2025–2042CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of Medicine and DentistryUniversity of ValenciaValenciaSpain
  2. 2.Center for Biomedical Network Research on Frailty and Healthy Aging (CIBERFES), CIBER-ISCIIIValenciaSpain

Personalised recommendations