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Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians

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Abstract

Oxidative stress is an important factor in age-associated neurodegeneration. Accordingly, mitochondrial dysfunction and genomic instability have been considered as key hallmarks of aging and have important roles in age-associated cognitive decline and neurodegenerative disorders. In order to evaluate whether maintenance of cognitive abilities at very old age is associated with key hallmarks of aging, we measured mitochondrial bioenergetics, mitochondrial DNA copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians in a Danish 1915 birth cohort (n = 120). Also, the circulating levels of brain-derived neurotrophic factor, NAD+ /NADH and carbonylated proteins were measured in plasma of the centenarians and correlated to cognitive capacity. Mitochondrial respiration was well preserved in the centenarian cohort when compared to young individuals (21–35 years of age, n = 33). When correlating cognitive performance of the centenarians with mitochondrial function such as basal respiration, ATP production, reserve capacity and maximal respiration, no overall correlations were observed, but when stratifying by sex, inverse associations were observed in the males (p < 0.05). Centenarians with the most severe cognitive impairment displayed the lowest activity of the central DNA repair enzyme, APE1 (p < 0.05). A positive correlation between cognitive capacity and levels of NAD+ /NADH was observed (p < 0.05), which may be because NAD+ /NADH consuming enzyme activities strive to reduce the oxidative DNA damage load. Also, circulating protein carbonylation was lowest in centenarians with highest cognitive capacity (p < 0.05). An opposite trend was observed for levels of brain-derived neurotrophic factor (p = 0.17). Our results suggest that maintenance of cognitive capacity at very old age may be associated with cellular mechanisms related to oxidative stress and DNA metabolism.

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References

  1. Bartus RT. Drugs to treat age-related neurodegenerative problems. The final frontier of medical science? J Am Geriatr Soc. 1990;38:680–95.

    Article  CAS  PubMed  Google Scholar 

  2. Kluger A, Gianutsos JG, Golomb J, Ferris SH, George AE, Franssen E, Reisberg B. Patterns of motor impairement in normal aging, mild cognitive decline, and early Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci. 1997;52B:P28-39.

    Article  CAS  PubMed  Google Scholar 

  3. Albert M, Duffy FH, Naeser M. Nonlinear changes in cognition with age and their neuropsychologic correlates. Can J Psychol. 1987;41:141–57.

    CAS  PubMed  Google Scholar 

  4. Wisdom NM, Mignogna J, Collins RL. Variability in Wechsler Adult Intelligence Scale-IV subtest performance across age. Arch Clin Neuropsychol. 2012;27:389–97.

    Article  PubMed  Google Scholar 

  5. Alles B, Samieri C, Feart C, Jutand MA, Laurin D, Barberger-Gateau P. Dietary patterns: a novel approach to examine the link between nutrition and cognitive function in older individuals. Nutr Res Rev. 2012;25:207–22.

    Article  CAS  PubMed  Google Scholar 

  6. Gow AJ, Pattie A, Deary IJ. Lifecourse activity participation from early, mid, and later adulthood as determinants of cognitive aging: the Lothian birth cohort 1921. J Gerontol B Psychol Sci Soc Sci. 2017;72:25–37.

    Article  PubMed  Google Scholar 

  7. McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA, Plomin R. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science. 1997;276:1560–3.

    Article  CAS  PubMed  Google Scholar 

  8. McGue M, Christensen K. The heritability of level and rate-of-change in cognitive functioning in Danish twins aged 70 years and older. Exp Aging Res. 2002;28:435–51.

    Article  PubMed  Google Scholar 

  9. Schonfeld P, Reiser G. Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain. J Cereb Blood Flow Metab. 2013;33:1493–9.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61:654–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tavallaie M, Voshtani R, Deng X, Qiao Y, Jiang F, Collman JP, Fu L. Moderation of mitochondrial respiration mitigates metabolic syndrome of aging. Proc Natl Acad Sci U S A. 2020;117:9840–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jeng JY, Yeh TS, Lee JW, Lin SH, Fong TH, Hsieh RH. Maintenance of mitochondrial DNA copy number and expression are essential for preservation of mitochondrial function and cell growth. J Cell Biochem. 2008;103:347–57.

    Article  CAS  PubMed  Google Scholar 

  14. Hartmann N, Reichwald K, Wittig I, Drose S, Schmeisser S, Luck C, Hahn C, Graf M, Gausmann U, Terzibasi E, Cellerino A, Ristow M, Brandt U, Platzer M, Englert C. Mitochondrial DNA copy number and function decrease with age in the short-lived fish Nothobranchius furzeri. Aging Cell. 2011;10:824–31.

    Article  CAS  PubMed  Google Scholar 

  15. Mengel-From J, Thinggaard M, Dalgard C, Kyvik KO, Christensen K, Christiansen L. Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly. Hum Genet. 2014;133:1149–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ashar FN, Moes A, Moore AZ, Grove ML, Chaves PHM, Coresh J, Newman AB, Matteini AM, Bandeen-Roche K, Boerwinkle E, Walston JD, Arking DE. Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med (Berl). 2015;93:177–86.

    Article  CAS  Google Scholar 

  17. Takahashi PY, Jenkins GD, Welkie BP, McDonnell SK, Evans JM, Cerhan JR, Olson JE, Thibodeau SN, Cicek MS, Ryu E. Association of mitochondrial DNA copy number with self-rated health status, Appl. Clin Genet. 2018;11:121–7.

    Article  CAS  Google Scholar 

  18. Lee JW, Park KD, Im JA, Kim MY, Lee DC. Mitochondrial DNA copy number in peripheral blood is associated with cognitive function in apparently healthy elderly women. Clin Chim Acta. 2010;411:592–6.

    Article  CAS  PubMed  Google Scholar 

  19. Yang SY, Castellani CA, Longchamps RJ, Pillalamarri VK, O’Rourke B, Guallar E, Arking DE. Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease. Genome Res. 2021;31:349–58.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB. Mitochondrial dysfunction during brain aging: role of oxidative stress and modulation by antioxidant supplementation. Aging Dis. 2011;2:242–56.

    PubMed  PubMed Central  Google Scholar 

  21. Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. 2012;342:619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Glade MJ. Oxidative stress and cognitive longevity. Nutrition. 2010;26:595–603.

    Article  CAS  PubMed  Google Scholar 

  23. Grimm A, Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view. J Neurochem. 2017;143:418–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jeppesen DK, Bohr VA, Stevnsner T. DNA repair deficiency in neurodegeneration. Prog Neurobiol. 2011;94:166–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Canugovi C, Misiak M, Ferrarelli LK, Croteau DL, Bohr VA. The role of DNA repair in brain related disease pathology. DNA Repair. 2013;12:578–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Akbari M, Morevati M, Croteau D, Bohr VA. The role of DNA base excision repair in brain homeostasis and disease. DNA Repair (Amst). 2015;32:172–9.

    Article  CAS  Google Scholar 

  27. Sykora P, Wilson DM 3rd, Bohr VA. Base excision repair in the mammalian brain: implication for age related neurodegeneration. Mech Ageing Dev. 2013;134:440–8.

    Article  CAS  PubMed  Google Scholar 

  28. Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, Beal MF. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol. 1993;34:609–16.

    Article  CAS  PubMed  Google Scholar 

  29. Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer’s disease. J Neurochem. 1997;68:2061–9.

    Article  CAS  PubMed  Google Scholar 

  30. Weissman L, Jo DG, Sorensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP, Bohr VA. Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res. 2007;35:5545–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lillenes MS, Rabano A, Stoen M, Riaz T, Misaghian D, Mollersen L, Esbensen Y, Gunther CC, Selnes P, Stenset VT, Fladby T, Tonjum T. Altered DNA base excision repair profile in brain tissue and blood in Alzheimer’s disease. Mol Brain. 2016;9:61.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wang J, Markesbery WR, Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J Neurochem. 2006;96:825–32.

    Article  CAS  PubMed  Google Scholar 

  33. Cabelof DC, Raffoul JJ, Yanamadala S, Ganir C, Guo Z, Heydari AR. Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice. Mutat Res. 2002;500:135–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Imam SZ, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA. Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol Aging. 2006;27:1129–36.

    Article  CAS  PubMed  Google Scholar 

  35. Gredilla R, Garm C, Holm R, Bohr VA, Stevnsner T. Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions. Neurobiol Aging. 2010;31:993–1002.

    Article  CAS  PubMed  Google Scholar 

  36. Wilson DM 3rd, Barsky D. The major human abasic endonuclease: formation, consequences and repair of abasic lesions in DNA. Mutat Res. 2001;485:283–307.

    Article  CAS  PubMed  Google Scholar 

  37. Chen DS, Herman T, Demple B. Two distinct human DNA diesterases that hydrolyze 3′-blocking deoxyribose fragments from oxidized DNA. Nucleic Acids Res. 1991;19:5907–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang JL, Chen WY, Mukda S, Yang YR, Sun SF, Chen SD. Oxidative DNA damage is concurrently repaired by base excision repair (BER) and apyrimidinic endonuclease 1 (APE1)-initiated nonhomologous end joining (NHEJ) in cortical neurons. Neuropathol Appl Neurobiol. 2020;46:375–90.

    Article  CAS  PubMed  Google Scholar 

  39. Thakur S, Dhiman M, Tell G, Mantha AK. A review on protein-protein interaction network of APE1/Ref-1 and its associated biological functions. Cell Biochem Funct. 2015;33:101–12.

    Article  CAS  PubMed  Google Scholar 

  40. Dyrkheeva NS, Lebedeva NA, Lavrik OI. AP endonuclease 1 as a key enzyme in repair of apurinic/apyrimidinic sites. Biochemistry Biokhimiia. 2016;81:951–67.

    Article  CAS  PubMed  Google Scholar 

  41. Li M, Wilson DM 3rd. Human apurinic/apyrimidinic endonuclease 1. Antioxid Redox Signal. 2014;20:678–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Leak RK, Li P, Zhang F, Sulaiman HH, Weng Z, Wang G, Stetler RA, Shi Y, Cao G, Gao Y, Chen J. Apurinic/apyrimidinic endonuclease 1 upregulation reduces oxidative DNA damage and protects hippocampal neurons from ischemic injury. Antioxid Redox Signal. 2015;22:135–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ramana CV, Boldogh I, Izumi T, Mitra S. Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proc Natl Acad Sci U S A. 1998;95:5061–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tell G, Quadrifoglio F, Tiribelli C, Kelley MR. The many functions of APE1/Ref-1: not only a DNA repair enzyme. Antioxid Redox Signal. 2009;11:601–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Thakur S, Sarkar B, Cholia RP, Gautam N, Dhiman M, Mantha AK. APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions. Exp Mol Med. 2014:46:e106.

  46. Lillenes MS, Espeseth T, Stoen M, Lundervold AJ, Frye SA, Rootwelt H, Reinvang I, Tonjum T. DNA base excision repair gene polymorphisms modulate human cognitive performance and decline during normal life span. Mech Ageing Dev. 2011;132:449–58.

    Article  CAS  PubMed  Google Scholar 

  47. Lillenes MS, Stoen M, Gunther CC, Selnes P, Stenset VT, Espeseth T, Reinvang I, Fladby T, Tonjum T. Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance. Neurosci Lett. 2017;645:46–52.

    Article  CAS  PubMed  Google Scholar 

  48. Maynard S, Hejl AM, Dinh TS, Keijzers G, Hansen AM, Desler C, Moreno-Villanueva M, Burkle A, Rasmussen LJ, Waldemar G, Bohr VA. Defective mitochondrial respiration, altered dNTP pools and reduced AP endonuclease 1 activity in peripheral blood mononuclear cells of Alzheimer’s disease patients. Aging (Albany NY). 2015;7:793–815.

    Article  CAS  Google Scholar 

  49. Koch-Nolte F, Fischer S, Haag F, Ziegler M. Compartmentation of NAD+-dependent signalling. FEBS Lett. 2011;585:1651–6.

    Article  CAS  PubMed  Google Scholar 

  50. Goody MF, Henry CA. A need for NAD+ in muscle development, homeostasis, and aging. Skelet Muscle. 2018;8:9.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Xie X, Gao Y, Zeng M, Wang Y, Wei TF, Lu YB, Zhang WP. Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice. Metab Brain Dis. 2019;34:353-366.

  52. Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, Bohr VA. NAD(+) in aging: molecular mechanisms and translational implications. Trends Mol Med. 2017;23:899–916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010;459:277–89.

    Article  CAS  PubMed  Google Scholar 

  54. Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol. 2010;5:297–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016;17:679–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hu Y, Russek SJ. BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 2008;105:1–17.

    Article  CAS  PubMed  Google Scholar 

  57. Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow JC. The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging. 2005;26:115–23.

    Article  CAS  PubMed  Google Scholar 

  58. Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009;5:311–22.

    Article  CAS  PubMed  Google Scholar 

  59. Yang JL, Lin YT, Chuang PC, Bohr VA, Mattson MP. BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1. Neuromolecular Med. 2014;16:161–74.

    Article  CAS  PubMed  Google Scholar 

  60. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB. The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull. 2006;53:441–9.

    PubMed  Google Scholar 

  61. Rasmussen SH, Andersen-Ranberg K, Thinggaard M, Jeune B, Skytthe A, Christiansen L, Vaupel JW, McGue M, Christensen K, Cohort Profile: The,. 1905, 1910 and 1915 Danish birth cohort studies—secular trends in the health and functioning of the very old. Int J Epidemiol. 1895;46(2017):1746–1746j.

    Google Scholar 

  62. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.

    Article  CAS  PubMed  Google Scholar 

  63. Engberg H, Jeune B, Andersen-Ranberg K, Martinussen T, Vaupel JW, Christensen K. Optimism and survival: does an optimistic outlook predict better survival at advanced ages? A twelve-year follow-up of Danish nonagenarians. Aging Clin Exp Res. 2013;25:517–25.

    Article  PubMed  Google Scholar 

  64. Engberg H, Christensen K, Andersen-Ranberg K, Jeune B. Cohort changes in cognitive function among Danish centenarians. A comparative study of 2 birth cohorts born in 1895 and 1905. Dement Geriatr Cogn Disord. 2008;26:153–60.

    Article  PubMed  Google Scholar 

  65. Maynard S, Keijzers G, Gram M, Desler C, Bendix L, Budtz-Jorgensen E, Molbo D, Croteau DL, Osler M, Stevnsner T, Rasmussen LJ, Dela F, Avlund K, Bohr VA. Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells. Aging (Albany NY). 2013;5:850–64.

    Article  CAS  Google Scholar 

  66. Ferrick DA, Neilson A, Beeson C. Advances in measuring cellular bioenergetics using extracellular flux. Drug Discov Today. 2008;13:268–74.

    Article  CAS  PubMed  Google Scholar 

  67. Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435:297–312.

    Article  CAS  PubMed  Google Scholar 

  68. Hartman ML, Shirihai OS, Holbrook M, Xu G, Kocherla M, Shah A, Fetterman JL, Kluge MA, Frame AA, Hamburg NM, Vita JA. Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus. Vasc Med. 2014;19:67–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Leuner K, Schulz K, Schutt T, Pantel J, Prvulovic D, Rhein V, Savaskan E, Czech C, Eckert A, Muller WE. Peripheral mitochondrial dysfunction in Alzheimer’s disease: focus on lymphocytes. Mol Neurobiol. 2012;46:194–204.

    Article  CAS  PubMed  Google Scholar 

  70. Perl A, Hanczko R, Doherty E. Assessment of mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus. Methods Mol Biol. 2012;900:61–89.

    Article  CAS  PubMed  Google Scholar 

  71. Tyrrell DJ, Bharadwaj MS, Van Horn CG, Marsh AP, Nicklas BJ, Molina AJ. Blood-cell bioenergetics are associated with physical function and inflammation in overweight/obese older adults. Exp Gerontol. 2015;70:84–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kramer PA, Chacko BK, Ravi S, Johnson MS, Mitchell T, Darley-Usmar VM. Bioenergetics and the oxidative burst: protocols for the isolation and evaluation of human leukocytes and platelets. J Vis Exp. 2014;27:51301

  73. Ruas JS, Siqueira-Santos ES, Amigo I, Rodrigues-Silva E, Kowaltowski AJ, Castilho RF. Underestimation of the maximal capacity of the mitochondrial electron transport system in oligomycin-treated cells. PLoS One. 2016;11:e0150967.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Liu CS, Tsai CS, Kuo CL, Chen HW, Lii CK, Ma YS, Wei YH. Oxidative stress-related alteration of the copy number of mitochondrial DNA in human leukocytes. Free Radic Res. 2003;37:1307–17.

    Article  CAS  PubMed  Google Scholar 

  75. Paz-Elizur T, Krupsky M, Blumenstein S, Elinger D, Schechtman E, Livneh Z. DNA repair activity for oxidative damage and risk of lung cancer. J Natl Cancer Inst. 2003;95:1312–9.

    Article  CAS  PubMed  Google Scholar 

  76. Paz-Elizur T, Elinger D, Leitner-Dagan Y, Blumenstein S, Krupsky M, Berrebi A, Schechtman E, Livneh Z. Development of an enzymatic DNA repair assay for molecular epidemiology studies: distribution of OGG activity in healthy individuals. DNA Repair. 2007;6:45–60.

    Article  CAS  PubMed  Google Scholar 

  77. Sevilya Z, Leitner-Dagan Y, Pinchev M, Kremer R, Elinger D, Lejbkowicz F, Rennert HS, Freedman LS, Rennert G, Paz-Elizur T, Livneh Z. Development of APE1 enzymatic DNA repair assays: low APE1 activity is associated with increase lung cancer risk. Carcinogenesis. 2015;36:982–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Silaidos C, Pilatus U, Grewal R, Matura S, Lienerth B, Pantel J, Eckert GP. Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain. Biol Sex Differ. 2018;9:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sgarbi G, Matarrese P, Pinti M, Lanzarini C, Ascione B, Gibellini L, Dika E, Patrizi A, Tommasino C, Capri M, Cossarizza A, Baracca A, Lenaz G, Solaini G, Franceschi C, Malorni W, Salvioli S. Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. Aging (Albany NY). 2014;6:296–310.

    Article  Google Scholar 

  80. Greco M, Villani G, Mazzucchelli F, Bresolin N, Papa S, Attardi G. Marked aging-related decline in efficiency of oxidative phosphorylation in human skin fibroblasts. FASEB J. 2003;17:1706–8.

    Article  CAS  PubMed  Google Scholar 

  81. Goyal MS, Blazey TM, Su Y, Couture LE, Durbin TJ, Bateman RJ, Benzinger TL, Morris JC, Raichle ME, Vlassenko AG. Persistent metabolic youth in the aging female brain. Proc Natl Acad Sci U S A. 2019;116:3251-3255

  82. Demarest TG, Varma VR, Estrada D, Babbar M, Basu S, Mahajan UV, Moaddel R, Croteau DL, Thambisetty M, Mattson MP, Bohr VA. Biological sex and DNA repair deficiency drive Alzheimer’s disease via systemic metabolic remodeling and brain mitochondrial dysfunction. Acta Neuropathol. 2020;140:25–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sjovall F, Ehinger JK, Marelsson SE, Morota S, Frostner EA, Uchino H, Lundgren J, Arnbjornsson E, Hansson MJ, Fellman V, Elmer E. Mitochondrial respiration in human viable platelets—methodology and influence of gender, age and storage. Mitochondrion. 2013;13:7–14.

    Article  PubMed  Google Scholar 

  84. Desler C, Frederiksen JH, Angleys M, Maynard S, Keijzers G, Fagerlund B, Mortensen EL, Osler M, Lauritzen M, Bohr VA, Rasmussen LJ. Increased deoxythymidine triphosphate levels is a feature of relative cognitive decline. Mitochondrion. 2015;25:34–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Apaijai N, Sriwichaiin S, Phrommintikul A, Jaiwongkam T, Kerdphoo S, Chansirikarnjana S, Thongmung N, Mahantassanapong U, Vathesatogkit P, Kitiyakara C, Sritara P, Chattipakorn N, Chattipakorn SC. Cognitive impairment is associated with mitochondrial dysfunction in peripheral blood mononuclear cells of elderly population. Sci Rep. 2020;10:21400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Loesch DZ, Annesley SJ, Trost N, Bui MQ, Lay ST, Storey E, De Piazza SW, Sanislav O, Francione LM, Hammersley EM, Tassone F, Francis D, Fisher PR. Novel blood biomarkers are associated with white matter lesions in fragile X-associated tremor/ataxia syndrome. Neurodegener Dis. 2017;17:22–30.

    Article  CAS  PubMed  Google Scholar 

  87. Scheibye-Knudsen M, Ramamoorthy M, Sykora P, Maynard S, Lin PC, Minor RK, Wilson DM 3rd, Cooper M, Spencer R, de Cabo R, Croteau DL, Bohr VA. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. J Exp Med. 2012;209:855–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Arciero PJ, Goran MI, Poehlman ET. Resting metabolic rate is lower in women than in men. J Appl Physiol. 1985;75(1993):2514–20.

    Google Scholar 

  89. Vina J, Sastre J, Pallardo F, Borras C. Mitochondrial theory of aging: importance to explain why females live longer than males. Antioxid Redox Signal. 2003;5:549–56.

    Article  CAS  PubMed  Google Scholar 

  90. Morales RC, Bahnson ES, Havelka GE, Cantu-Medellin N, Kelley EE, Kibbe MR. Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide. Redox Biol. 2015;4:226–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Proteggente AR, England TG, Rehman A, Rice-Evans CA, Halliwell B. Gender differences in steady-state levels of oxidative damage to DNA in healthy individuals. Free Radic Res. 2002;36:157–62.

    Article  CAS  PubMed  Google Scholar 

  92. Berchtold NC, Cribbs DH, Coleman PD, Rogers J, Head E, Kim R, Beach T, Miller C, Troncoso J, Trojanowski JQ, Zielke HR, Cotman CW. Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci U S A. 2008;105:15605–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fischer AG, Danielmeier C, Villringer A, Klein TA, Ullsperger M. Gender influences on brain responses to errors and post-error adjustments. Sci Rep. 2016;6:24435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Austad SN, Fischer KE. Sex differences in lifespan. Cell Metab. 2016;23:1022–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014;24:R453-462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ristow M, Zarse K. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol. 2010;45:410–8.

    Article  CAS  PubMed  Google Scholar 

  97. Berquist BR, McNeill DR, Wilson DM 3rd. Characterization of abasic endonuclease activity of human Ape1 on alternative substrates, as well as effects of ATP and sequence context on AP site incision. J Mol Biol. 2008;379:17–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kong Q, Lin CL. Oxidative damage to RNA: mechanisms, consequences, and diseases. Cell Mol Life Sci. 2010;67:1817–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dumitrache LC, Shimada M, Downing SM, Kwak YD, Li Y, Illuzzi JL, Russell HR, Wilson DM 3rd, McKinnon PJ. Apurinic endonuclease-1 preserves neural genome integrity to maintain homeostasis and thermoregulation and prevent brain tumors. Proc Natl Acad Sci U S A. 2018;115:E12285–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Misiak M, Vergara Greeno R, Baptiste BA, Sykora P, Liu D, Cordonnier S, Fang EF, Croteau DL, Mattson MP, Bohr VA. DNA polymerase beta decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer’s disease. Aging Cell. 2017;16:162–72.

    Article  CAS  PubMed  Google Scholar 

  101. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012;7:e42357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A. 2015;112:2876–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155:1624–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Clement J, Wong M, Poljak A, Sachdev P, Braidy N. The plasma NAD(+) metabolome is dysregulated in “normal” aging. Rejuvenation Res. 2019;22:121-130

  105. Elhassan YS, Philp AA, Lavery GG. Targeting NAD+ in metabolic disease: new insights into an old molecule. J Endocr Soc. 2017;1:816–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Aman Y, Qiu Y, Tao J, Fang EF. Therapeutic potential of boosting NAD+ in aging and age-related diseases. Transl Med Aging. 2018;2:30e37.

    Article  Google Scholar 

  107. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun. 2018;9:1286.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, Guarente L. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008;22:1753–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Canto C, Jiang LQ, Deshmukh AS, Mataki C, Coste A, Lagouge M, Zierath JR, Auwerx J. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 2010;11:213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14:528–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Frederick DW, Loro E, Liu L, Davila A Jr, Chellappa K, Silverman IM, Quinn WJ 3rd, Gosai SJ, Tichy ED, Davis JG, Mourkioti F, Gregory BD, Dellinger RW, Redpath P, Migaud ME, Nakamaru-Ogiso E, Rabinowitz JD, Khurana TS, Baur JA. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab. 2016;24:269–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24:795–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, Zhang Y, Moritoh K, O’Connell JF, Baptiste BA, Stevnsner TV, Mattson MP, Bohr VA. NAD(+) supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A. 2018;115:E1876–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Maciejczyk M, Zalewska A, Ladny JR. Salivary antioxidant barrier, redox status, and oxidative damage to proteins and lipids in healthy children, adults, and the elderly. Oxid Med Cell Longev. 2019;2019:4393460.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Paniz C, Bairros A, Valentini J, Charao M, Bulcao R, Moro A, Grune T, Garcia SC. The influence of the serum vitamin C levels on oxidative stress biomarkers in elderly women. Clin Biochem. 2007;40:1367–72.

    Article  CAS  PubMed  Google Scholar 

  116. Baierle M, Nascimento SN, Moro AM, Brucker N, Freitas F, Gauer B, Durgante J, Bordignon S, Zibetti M, Trentini CM, Duarte MM, Grune T, Breusing N, Garcia SC. Relationship between inflammation and oxidative stress and cognitive decline in the institutionalized elderly. Oxid Med Cell Longev. 2015;2015:804198.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Wang Z, Wang Y, Liu H, Che Y, Xu Y, Lingling E. Age-related variations of protein carbonyls in human saliva and plasma: is saliva protein carbonyls an alternative biomarker of aging? Age (Dordr). 2015;37:9781.

    Article  Google Scholar 

  118. Abdul Sani NF, Ahmad Damanhuri MH, Amir Hamzah AIZ, Abu Bakar ZH, Tan JK, Nor Aripin KN, Mohd Rani MD, Noh NA, Shamaan NA, Razali R, Mohd Yusof YA, Mazlan M, Makpol S, Wan Ngah WZ. DNA damage and protein oxidation associated with ageing correlate with cognitive dysfunction in a Malaysian population. Free Radic Res. 2018;52:1000–9.

    Article  CAS  PubMed  Google Scholar 

  119. Perrotte M, Le Page A, Fournet M, Le Sayec M, Rassart E, Fulop T, Ramassamy C. Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer’s disease patients. Free Radic Biol Med. 2019;130:499–511.

    Article  CAS  PubMed  Google Scholar 

  120. Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butterfield DA, Markesbery WR. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology. 2005;64:1152–6.

    Article  CAS  PubMed  Google Scholar 

  121. Sayre LM, Smith MA, Perry G. Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem. 2001;8:721–38.

    Article  CAS  PubMed  Google Scholar 

  122. Aksenov MY, Aksenova MV, Butterfield DA, Geddes JW, Markesbery WR. Protein oxidation in the brain in Alzheimer’s disease. Neuroscience. 2001;103:373–83.

    Article  CAS  PubMed  Google Scholar 

  123. Di Domenico F, Pupo G, Giraldo E, Badia MC, Monllor P, Lloret A, Schinina ME, Giorgi A, Cini C, Tramutola A, Butterfield DA, Vina J, Perluigi M. Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients. Free Radic Biol Med. 2016;91:1–9.

    Article  PubMed  Google Scholar 

  124. Sultana R, Perluigi M, Butterfield DA. Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: insights into mechanism of neurodegeneration from redox proteomics. Antioxid Redox Signal. 2006;8:2021–37.

    Article  CAS  PubMed  Google Scholar 

  125. Webster MJ, Herman MM, Kleinman JE, Shannon Weickert C. BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan. Gene Expr Patterns. 2006;6:941–51.

    Article  CAS  PubMed  Google Scholar 

  126. Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 2011;13:217–22.

    Article  CAS  PubMed  Google Scholar 

  127. Forlenza OV, Miranda AS, Guimar I, Talib LL, Diniz BS, Gattaz WF, Teixeira AL. Decreased neurotrophic support is associated with cognitive decline in non-demented subjects. J Alzheimers Dis. 2015;46:423–9.

    Article  CAS  PubMed  Google Scholar 

  128. Buchman AS, Yu L, Boyle PA, Schneider JA, De Jager PL, Bennett DA. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology. 2016;86:735–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, McAuley E, Kramer AF. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci. 2010;30:5368–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Laske C, Stellos K, Hoffmann N, Stransky E, Straten G, Eschweiler GW, Leyhe T. Higher BDNF serum levels predict slower cognitive decline in Alzheimer’s disease patients. Int J Neuropsychopharmacol. 2011;14:399–404.

    Article  CAS  PubMed  Google Scholar 

  131. Michalski B, Corrada MM, Kawas CH, Fahnestock M. Brain-derived neurotrophic factor and TrkB expression in the “oldest-old”, the 90+ study: correlation with cognitive status and levels of soluble amyloid-beta. Neurobiol Aging. 2015;36:3130–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Clare L, Wu YT, Teale JC, MacLeod C, Matthews F, Brayne C, Woods B. Potentially modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: a cross-sectional study. PLoS Med. 2017;14:e1002259.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Lahav O, Katz N. Independent older adult’s IADL and executive function according to cognitive performance. OTJR (Thorofare N J). 2020;40:183–9.

    Google Scholar 

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Acknowledgements

We thank the participants who collaborated in this work. A special thank you goes to Ulla Birk Henriksen, Dorthe Caroline Rishøj and Majken Boris Hojgaard for their excellent technical support.

Funding

The work was supported by the Novo Nordisk Foundation; the Faculty of Health Sciences, University of Southern Denmark; The Health Foundation (Helsefonden) (Grant nr.16-B-0271); the Danish Interdisciplinary Research Council and the Intramural Program of the National Institute on Aging, NIH, USA. The Danish Aging Research Center is supported by a grant from the Velux Foundation.

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Author notes

  1. Ines Sanchez-Roman

    Present address: Department of Genetics, Physiology and Microbiology, Faculty of Biological Sciences (Animal Physiology Unit), School of Biology, Complutense University of Madrid, Madrid, Spain

  2. Signe Høi Rasmussen

    Present address: Department of Geriatrics, Odense University Hospital, Svendborg, Denmark

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

    Ines Sanchez-Roman, Beatriz Ferrando, Camilla Myrup Holst & Tinna Stevnsner

  2. Danish Aging Research Center, Aarhus, Denmark

    Ines Sanchez-Roman, Beatriz Ferrando, Camilla Myrup Holst, Jonas Mengel-From, Signe Høi Rasmussen, Mikael Thinggaard, Vilhelm A. Bohr, Kaare Christensen & Tinna Stevnsner

  3. Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark

    Jonas Mengel-From, Signe Høi Rasmussen, Mikael Thinggaard & Kaare Christensen

  4. National Institute On Aging, NIH, Baltimore, MD, USA

    Vilhelm A. Bohr

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  1. Ines Sanchez-Roman
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Highlights

- Mitochondrial function is preserved in peripheral blood mononuclear cells (PBMCs) of centenarians when compared to young individuals, whereas AP-endonuclease 1 (APE1) activity is lower and level of brain-derived neurotrophic factor (BDNF) and protein carbonylation is higher in centenarians.

- Cognitive scores (CCS and MMSE) correlate negatively with mitochondrial respiration in centenarian males.

- Cognitive capacity correlates positively with APE1 protein level and APE1 incision activity in PBMCs in centenarians.

- Centenarians with high cognitive scores have the highest plasma levels of NAD + /NADH.

- Oxidative stress, measured as protein carbonylation, is highest in plasma from centenarians with low cognitive scores.

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Sanchez-Roman, I., Ferrando, B., Holst, C.M. et al. Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians. GeroScience 44, 103–125 (2022). https://doi.org/10.1007/s11357-021-00502-2

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