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Molecular damage in aging

Nature Aging volume 1, pages 1096–1106 (2021)Cite this article

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Abstract

Cellular metabolism and environmental interactions generate molecular damage affecting all levels of biological organization. Accumulation of this damage over time is thought to have a central role in the aging process. Insufficient attention has been paid to the role of molecular damage in aging-related phenotypes, particularly in humans, in part because of the difficulty in measuring its various forms. Recently, omics approaches have been developed that begin to address this challenge, because they can assess a sizable proportion of age-related damage at the level of small molecules, proteins, RNA, DNA, organelles and cells. This Review describes the concept of molecular damage in aging and discusses its diverse aspects from theoretical models to experimental approaches. Measurement of multiple types of damage enables studies of the role of damage in aging and lays a foundation for testing interventions that reduce the burden of molecular damage, thereby targeting aging.

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Fig. 1: Molecular damage is a central element of aging concepts.
Fig. 2: The burden of damage expands with age and affects cellular biomolecules at all levels of biological hierarchy.
Fig. 3: A prototypic example of damage in the form of amino acid residues.

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References

  1. Kirkwood, T. B. & Austad, S. N. Why do we age? Nature 408, 233–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stadtman, E. R. Protein oxidation and aging. Science 257, 1220–1224 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. Rando, T. A. & Wyss-Coray, T. Asynchronous, contagious and digital aging. Nat. Aging 1, 29–35 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kinzina, E. D., Podolskiy, D. I., Dmitriev, S. E. & Gladyshev, V. N. Patterns of aging biomarkers, mortality, and damaging mutations illuminate the beginning of aging and causes of early-life mortality. Cell Rep. 29, 4276–4284 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Shindyapina, A. V. et al. Germline burden of rare damaging variants negatively affects human healthspan and lifespan. eLife 9, e53449 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ogrodnik, M., Salmonowicz, H. & Gladyshev, V. N. Integrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells. Aging Cell 18, e12841 (2019).

    Article  PubMed  Google Scholar 

  8. Takasugi, M. Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell 17, e12734 (2018).

    Article  PubMed Central  Google Scholar 

  9. Kerepesi, C., Zhang, B., Lee, S. G., Trapp, A. & Gladyshev, V. N. Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. Sci. Adv. 7, eabg6082 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Golubev, A. G. [The other side of metabolism]. Biokhimiia 61, 2018–2039 (1996).

    CAS  PubMed  Google Scholar 

  11. Golubev, A., Hanson, A. D. & Gladyshev, V. N. A tale of two concepts: harmonizing the free radical and antagonistic pleiotropy theories of aging. Antioxid. Redox Signal. 29, 1003–1017 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Golubev, A., Hanson, A. D. & Gladyshev, V. N. Non-enzymatic molecular damage as a prototypic driver of aging. J. Biol. Chem. 292, 6029–6038 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Avanesov, A. S. et al. Age- and diet-associated metabolome remodeling characterizes the aging process driven by damage accumulation. eLife 3, e02077 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee, S. G. et al. Age-associated molecular changes are deleterious and may modulate life span through diet. Sci. Adv. 3, e1601833 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hughes, A. L. & Gottschling, D. E. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261–265 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles–a cause of aging in yeast. Cell 91, 1033–1042 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. King, G. A. et al. Meiotic cellular rejuvenation is coupled to nuclear remodeling in budding yeast. eLife 8, e47156 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaya, A., Lobanov, A. V. & Gladyshev, V. N. Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae. Aging Cell 14, 366–371 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

    Article  CAS  PubMed  Google Scholar 

  20. Gladyshev, V. N. The free radical theory of aging is dead. Long live the damage theory! Antioxid. Redox Signal. 20, 727–731 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stamatoyannopoulos, J. A. et al. Human mutation rate associated with DNA replication timing. Nat. Genet. 41, 393–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lodato, M. A. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350, 94–98 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    Article  CAS  PubMed  Google Scholar 

  24. Lodato, M. A. & Walsh, C. A. Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms. Hum. Mol. Genet. 28, R197–R206 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Podolskiy, D. I., Lobanov, A. V., Kryukov, G. V. & Gladyshev, V. N. Analysis of cancer genomes reveals basic features of human aging and its role in cancer development. Nat. Commun. 7, 12157 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brazhnik, K. et al. Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver. Sci. Adv. 6, eaax2659 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hollstein, M., Alexandrov, L. B., Wild, C. P., Ardin, M. & Zavadil, J. Base changes in tumour DNA have the power to reveal the causes and evolution of cancer. Oncogene 36, 158–167 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Alexandrov, L. B. & Stratton, M. R. Mutational signatures: the patterns of somatic mutations hidden in cancer genomes. Curr. Opin. Genet. Dev. 24, 52–60 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Freitas, A. A. & de Magalhaes, J. P. A review and appraisal of the DNA damage theory of ageing. Mutat. Res. 728, 12–22 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Niedernhofer, L. J. et al. Nuclear genomic instability and aging. Annu. Rev. Biochem. 87, 295–322 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jacob, K. D., Noren Hooten, N., Trzeciak, A. R. & Evans, M. K. Markers of oxidant stress that are clinically relevant in aging and age-related disease. Mech. Ageing Dev. 134, 139–157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang, J., Clauson, C. L., Robbins, P. D., Niedernhofer, L. J. & Wang, Y. The oxidative DNA lesions 8,5ʹ-cyclopurines accumulate with aging in a tissue-specific manner. Aging Cell 11, 714–716 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Beerman, I. Accumulation of DNA damage in the aged hematopoietic stem cell compartment. Semin. Hematol. 54, 12–18 (2017).

    Article  PubMed  Google Scholar 

  36. Robinson, A. R. et al. Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol. 17, 259–273 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cui, H., Kong, Y. & Zhang, H. Oxidative stress, mitochondrial dysfunction, and aging. J. Signal Transduct. 2012, 646354 (2012).

    Article  PubMed  Google Scholar 

  38. Pfohl-Leszkowicz, A. in Advances in Molecular Toxicology Vol. 2 (ed. Fishbein, J. C.) 183–239 (Elsevier, 2008).

  39. Ioannidou, A., Goulielmaki, E. & Garinis, G. A. DNA damage: from chronic inflammation to age-related deterioration. Front. Genet. 7, 187 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Roos, W. P. & Kaina, B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 332, 237–248 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  42. von Zglinicki, T., Saretzki, G., Ladhoff, J., d’Adda di Fagagna, F. & Jackson, S. P. Human cell senescence as a DNA damage response. Mech. Ageing Dev. 126, 111–117 (2005).

    Article  Google Scholar 

  43. Takahashi, A. et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat. Commun. 8, 15287 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Teo, Y. V. et al. Cell-free DNA as a biomarker of aging. Aging Cell 18, e12890 (2019).

    Article  PubMed  Google Scholar 

  45. Kananen, L. et al. Circulating cell-free DNA level predicts all-cause mortality independent of other predictors in the Health 2000 survey. Sci. Rep. 10, 13809 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Farmer, P. B. et al. DNA adducts: mass spectrometry methods and future prospects. Toxicol. Appl. Pharmacol. 207, 293–301 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Guthrie, O. W. Localization and distribution of neurons that co-express xeroderma pigmentosum-A and epidermal growth factor receptor within Rosenthal’s canal. Acta Histochem. 117, 688–695 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Carra, A. et al. Targeted high resolution LC/MS(3) adductomics method for the characterization of endogenous DNA damage. Front. Chem. 7, 658 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pinto, M. & Moraes, C. T. Mechanisms linking mtDNA damage and aging. Free Radic. Biol. Med. 85, 250–258 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Carelli, V. & Chan, D. C. Mitochondrial DNA: impacting central and peripheral nervous systems. Neuron 84, 1126–1142 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tranah, G. J. et al. Mitochondrial DNA heteroplasmy associations with neurosensory and mobility function in elderly adults. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 70, 1418–1424 (2015).

    Article  CAS  Google Scholar 

  52. Tranah, G. J. et al. Mitochondrial DNA m.3243A > G heteroplasmy affects multiple aging phenotypes and risk of mortality. Sci. Rep. 8, 11887 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl Acad. Sci. USA 102, 17993–17998 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Booth, L. N. & Brunet, A. The aging epigenome. Mol. Cell 62, 728–744 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sinclair, D. A. & Oberdoerffer, P. The ageing epigenome: damaged beyond repair? Ageing Res. Rev. 8, 189–198 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gladyshev, V. N. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15, 594–602 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sziraki, A., Tyshkovskiy, A. & Gladyshev, V. N. Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 17, e12738 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Johnson, A. A. et al. The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation Res. 15, 483–494 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49, 359–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10, 573–591 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Belsky, D. W. et al. Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm. eLife 9, e54870 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bell, C. G. et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 20, 249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Petkovich, D. A. et al. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. 25, 954–960 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Meer, M. V., Podolskiy, D. I., Tyshkovskiy, A. & Gladyshev, V. N. A whole lifespan mouse multi-tissue DNA methylation clock. eLife 7, e40675 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Stubbs, T. M. et al. Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18, 68 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Thompson, M. J. et al. A multi-tissue full lifespan epigenetic clock for mice. Aging 10, 2832–2854 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, T. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Lu, A. T. et al. Universal DNA methylation age across mammalian tissues. Preprint at https://doi.org/10.1101/2021.01.18.426733 (2021).

  72. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Olova, N., Simpson, D. J., Marioni, R. E. & Chandra, T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell 18, e12877 (2019).

    Article  PubMed  Google Scholar 

  74. Fahy, G. M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18, e13028 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Horvath, S. et al. Reversing age: dual species measurement of epigenetic age with a single clock. Preprint at https://doi.org/10.1101/2020.05.07.082917 (2020).

  76. Bhadra, M., Howell, P., Dutta, S., Heintz, C. & Mair, W. B. Alternative splicing in aging and longevity. Hum. Genet. 139, 357–369 (2020).

    Article  PubMed  Google Scholar 

  77. Wang, K. et al. Comprehensive map of age-associated splicing changes across human tissues and their contributions to age-associated diseases. Sci. Rep. 8, 10929 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Heintz, C. et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102–106 (2017).

    Article  CAS  PubMed  Google Scholar 

  79. Kurosaki, T., Popp, M. W. & Maquat, L. E. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat. Rev. Mol. Cell Biol. 20, 406–420 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu, C. C., Peterson, A., Zinshteyn, B., Regot, S. & Green, R. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wood, S. H., Craig, T., Li, Y., Merry, B. & de Magalhaes, J. P. Whole transcriptome sequencing of the aging rat brain reveals dynamic RNA changes in the dark matter of the genome. Age 35, 763–776 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. de Magalhaes, J. P., Curado, J. & Church, G. M. Meta-analysis of age-related gene expression profiles identifies common signatures of aging. Bioinformatics 25, 875–881 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Palmer, D., Fabris, F., Doherty, A., Freitas, A. A. & de Magalhaes, J. P. Ageing transcriptome meta-analysis reveals similarities and differences between key mammalian tissues. Aging 13, 3313–3341 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Consortium, G. T. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

    Article  Google Scholar 

  85. Tabula Muris, C. et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018).

    Article  Google Scholar 

  86. Grassi, L. & Cabrele, C. Susceptibility of protein therapeutics to spontaneous chemical modifications by oxidation, cyclization, and elimination reactions. Amino Acids 51, 1409–1431 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Levine, R. L. & Stadtman, E. R. Oxidative modification of proteins during aging. Exp. Gerontol. 36, 1495–1502 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Lourenco Dos Santos, S., Petropoulos, I. & Friguet, B. The oxidized protein repair enzymes methionine sulfoxide reductases and their roles in protecting against oxidative stress, in ageing and in regulating protein function. Antioxidants 7, 191 (2018).

    Article  PubMed Central  Google Scholar 

  89. Mishra, P. K. K. & Mahawar, M. PIMT-mediated protein repair: mechanism and implications. Biochemistry 84, 453–463 (2019).

    CAS  PubMed  Google Scholar 

  90. Weinert, B. T., Moustafa, T., Iesmantavicius, V., Zechner, R. & Choudhary, C. Analysis of acetylation stoichiometry suggests that SIRT3 repairs nonenzymatic acetylation lesions. EMBO J. 34, 2620–2632 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Van Schaftingen, E., Collard, F., Wiame, E. & Veiga-da-Cunha, M. Enzymatic repair of Amadori products. Amino Acids 42, 1143–1150 (2012).

    Article  PubMed  Google Scholar 

  92. Gorisse, L. et al. Protein carbamylation is a hallmark of aging. Proc. Natl Acad. Sci. USA 113, 1191–1196 (2016).

    Article  CAS  PubMed  Google Scholar 

  93. Khoury, G. A., Baliban, R. C. & Floudas, C. A. Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database. Sci. Rep. 1, 90 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  94. Lee, B. C. et al. MsrB1 and MICALs regulate actin assembly and macrophage function via reversible stereoselective methionine oxidation. Mol. Cell 51, 397–404 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Fedorova, M., Kuleva, N. & Hoffmann, R. Identification of cysteine, methionine and tryptophan residues of actin oxidized in vivo during oxidative stress. J. Proteome Res. 9, 1598–1609 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Rankin, N. J. et al. High-throughput quantification of carboxymethyl lysine in serum and plasma using high-resolution accurate mass Orbitrap mass spectrometry. Ann. Clin. Biochem. 56, 397–407 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Fu, M. X. et al. The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J. Biol. Chem. 271, 9982–9986 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Wang, R. et al. Affinity purification of methyllysine proteome by site-specific covalent conjugation. Anal. Chem. 90, 13876–13881 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Huseby, C. J. et al. Quantification of tau protein lysine methylation in aging and Alzheimer’s disease. J. Alzheimers Dis. 71, 979–991 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lesnefsky, E. J. & Hoppel, C. L. Oxidative phosphorylation and aging. Ageing Res. Rev. 5, 402–433 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Akimov, V. et al. UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites. Nat. Struct. Mol. Biol. 25, 631–640 (2018).

    Article  CAS  PubMed  Google Scholar 

  102. Hoopmann, M. R. et al. Kojak: efficient analysis of chemically cross-linked protein complexes. J. Proteome Res. 14, 2190–2198 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kim, E., Lowenson, J. D., MacLaren, D. C., Clarke, S. & Young, S. G. Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice. Proc. Natl Acad. Sci. USA 94, 6132–6137 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nat. Med. 21, 1406–1415 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Hohn, A. & Grune, T. Lipofuscin: formation, effects and role of macroautophagy. Redox Biol. 1, 140–144 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Gan, J., Leestemaker, Y., Sapmaz, A. & Ovaa, H. Highlighting the proteasome: using fluorescence to visualize proteasome activity and distribution. Front. Mol. Biosci. 6, 14 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Juste, Y. R. & Cuervo, A. M. Analysis of chaperone-mediated autophagy. Methods Mol. Biol. 1880, 703–727 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Raz, Y. et al. Activation-induced autophagy is preserved in CD4+ T-cells in familial longevity. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 72, 1201–1206 (2017).

    Article  CAS  Google Scholar 

  110. Lerma-Ortiz, C. et al. ‘Nothing of chemistry disappears in biology’: the top 30 damage-prone endogenous metabolites. Biochem. Soc. Trans. 44, 961–971 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Chen, L., Ducker, G. S., Lu, W., Teng, X. & Rabinowitz, J. D. An LC–MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate. Anal. Bioanal. Chem. 409, 5955–5964 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhang, J. et al. Determination of the cytosolic NADPH/NADP ratio in Saccharomyces cerevisiae using shikimate dehydrogenase as sensor reaction. Sci. Rep. 5, 12846 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Niehaus, T. D. et al. Plants utilize a highly conserved system for repair of NADH and NADPH hydrates. Plant Physiol. 165, 52–61 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Tawfik, D. S. Enzyme promiscuity and evolution in light of cellular metabolism. FEBS J. 287, 1260–1261 (2020).

    Article  CAS  PubMed  Google Scholar 

  115. Linster, C. L., Van Schaftingen, E. & Hanson, A. D. Metabolite damage and its repair or pre-emption. Nat. Chem. Biol. 9, 72–80 (2013).

    Article  CAS  PubMed  Google Scholar 

  116. Bommer, G. T., Van Schaftingen, E. & Veiga-da-Cunha, M. Metabolite repair enzymes control metabolic damage in glycolysis. Trends Biochem. Sci. 45, 228–243 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. Piedrafita, G., Keller, M. A. & Ralser, M. The impact of non-enzymatic reactions and enzyme promiscuity on cellular metabolism during (oxidative) stress conditions. Biomolecules 5, 2101–2122 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kuiper, H. C., Miranda, C. L., Sowell, J. D. & Stevens, J. F. Mercapturic acid conjugates of 4-hydroxy-2-nonenal and 4-oxo-2-nonenal metabolites are in vivo markers of oxidative stress. J. Biol. Chem. 283, 17131–17138 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Marnett, L. J. & Plastaras, J. P. Endogenous DNA damage and mutation. Trends Genet. 17, 214–221 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Rockwood, K. & Mitnitski, A. Frailty in relation to the accumulation of deficits. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 62, 722–727 (2007).

    Article  Google Scholar 

  121. Longo, V. D., Mitteldorf, J. & Skulachev, V. P. Programmed and altruistic ageing. Nat. Rev. Genet. 6, 866–872 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (1957).

    Article  Google Scholar 

  123. Medawar, P. B. An Unsolved Problem of Biology (University College London, 1952).

  124. Hamilton, W. D. The moulding of senescence by natural selection. J. Theor. Biol. 12, 12–45 (1966).

    Article  CAS  PubMed  Google Scholar 

  125. Ronce, O. & Promislow, D. Kin competition, natal dispersal and the moulding of senescence by natural selection. Proc. Biol. Sci. 277, 3659–3667 (2010).

    PubMed  PubMed Central  Google Scholar 

  126. de Magalhaes, J. P. Programmatic features of aging originating in development: aging mechanisms beyond molecular damage? FASEB J. 26, 4821–4826 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kirkwood, T. B. Evolution of ageing. Nature 270, 301–304 (1977).

    Article  CAS  PubMed  Google Scholar 

  128. Blagosklonny, M. V. Aging: ROS or TOR. Cell Cycle 7, 3344–3354 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Blagosklonny, M. V. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 5, 2087–2102 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Blagosklonny, M. V. Paradoxes of aging. Cell Cycle 6, 2997–3003 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Vina, J., Borras, C., Abdelaziz, K. M., Garcia-Valles, R. & Gomez-Cabrera, M. C. The free radical theory of aging revisited: the cell signaling disruption theory of aging. Antioxid. Redox Signal. 19, 779–787 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Miquel, J., Economos, A. C., Fleming, J. & Johnson, J. E. Jr. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1980).

    Article  CAS  PubMed  Google Scholar 

  133. Gladyshev, V. N. The origin of aging: imperfectness-driven non-random damage defines the aging process and control of lifespan. Trends Genet. 29, 506–512 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The review is based in part on a workshop, Biological Damage and Human Aging held in December 2019, sponsored by the Longevity Consortium with support from the National Institute of Aging. This work was supported by the National Institutes of Health (NIH) AG021332 (S.K.), NSF MCB-1714569, Life Extension Foundation and the Elizabeth and Thomas Plott Chair in Gerontology (S.G.C.), NIH AG064223, AG067782, AG065403 and AG047200 (V.N.G.), NIH HL121023 and AG032498 (G.T.) and NIA U19AG023122 (the Longevity Consortium).

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Authors and Affiliations

  1. Department of Medicine, Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Vadim N. Gladyshev & Bohan Zhang

  2. Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Stephen B. Kritchevsky

  3. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Steven G. Clarke

  4. Molecular Biology Institute, University of California, Los Angeles, CA, USA

    Steven G. Clarke

  5. Department of Development and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA

    Ana Maria Cuervo

  6. Institute for Aging Studies, Albert Einstein College of Medicine, New York, NY, USA

    Ana Maria Cuervo

  7. West Coast Metabolomics Center, University of California Davis, Davis, CA, USA

    Oliver Fiehn

  8. Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK

    João Pedro de Magalhães

  9. San Francisco Coordinating Center, California Pacific Medical Center, Research Institute, San Francisco, CA, USA

    Theresa Mau, Gregory J. Tranah & Steven R. Cummings

  10. Institute for Systems Biology, Seattle, WA, USA

    Michal Maes & Robert L. Moritz

  11. Institute of the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA

    Laura J. Niedernhofer

  12. De Duve Institute, Université Catholique de Louvain, Bruxelles, Belgium

    Emile Van Schaftingen

  13. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Université Catholique de Louvain, Bruxelles, Belgium

    Emile Van Schaftingen

  14. Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia-School of Medicine, Charlottesville, VA, USA

    Kenneth Walsh & Yoshimitsu Yura

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  1. Vadim N. Gladyshev
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Contributions

V.N.G. and S.B.K. were responsible for conception and design, drafting and substantial revisions. S.G.C., B.Z. and T.M. were responsible for drafting, creation of figures and substantial revision. A.M.C., O.F., J.P.M., M.M., R.M., E.V.S., G.T., K.W. and Y.Y. were responsible for drafting and substantial revisions. L.J.N. was responsible for drafting, creation of tables and substantial revisions. S.R.C. was responsible for conception, design, oversight, drafting and substantial revisions.

Corresponding author

Correspondence to Steven R. Cummings.

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The authors declare no competing interests.

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Peer review information Nature Aging thanks the anonymous reviewers for their contribution to the peer review of this work.

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Gladyshev, V.N., Kritchevsky, S.B., Clarke, S.G. et al. Molecular damage in aging. Nat Aging 1, 1096–1106 (2021). https://doi.org/10.1038/s43587-021-00150-3

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