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Cited by 926Genetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and SenescenceDNA Repair Mechanisms

The central role of DNA damage in the ageing process

Open access
Schumacher, Björn, Pothof, Joris, Vijg, Jan, Hoeijmakers, Jan H. J.·2021·Nature
DOI 10.1038/s41586-021-03307-7PMC PMC9844150
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Abstract

Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level-for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.

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Crossref · 10.1038/s41586-021-03307-7

Cites

127 of 127 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 64 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    A single DNA double-strand break is sufficient to cause full cell cycle blockade.

    “Even a single DSB suffices to cause full-blown cell cycle blockade13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Abdallah, P. et al. A two-step model for senescence triggered by a single critically short telomere. Nat. Cell Biol. 11, 988–993 (2009). source

      Not checked in the free run.

  • Interpretationreasoning

    Some age-related physiological alterations increase genome instability, thereby amplifying the deterioration of homeostasis during ageing.

    “Some of the physiological alterations in turn boost genome instability thus amplifying the deterioration of homeostasis during ageing.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Genetic defects in telomere maintenance cause human telomeropathies with multiple progeroid features.

    “Genetic defects in telomere maintenance cause human telomeropathies, including dyskeratosis congenita, aplastic anemia, and pulmonary and liver disease exhibiting multiple progeroid features15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Martínez, P. & Blasco, M. A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol. 216, 875–887 (2017). source

      Not checked in the free run.

  • Premisecitation

    During normal ageing, DNA damage occurs continuously on a massive scale because of many exogenous and endogenous genotoxins.

    “During normal ageing, DNA damage occurs continuously on a massive scale, due to numerous exogenous and endogenous genotoxins.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Lubberts, S., Meijer, C., Demaria, M. & Gietema, J. A. Early ageing after cytotoxic treatment for testicular cancer and cellular senescence: time to act. Crit. Rev. Oncol. Hematol. 151, 102963 (2020). source

      Not checked in the free run.

    • cites [8] Gonzalo, S., Kreienkamp, R. & Askjaer, P. Hutchinson–Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Res. Rev. 33, 18–29 (2017). source

      Not checked in the free run.

  • Interpretationcitation

    DNA damage is a major driver of age-associated epigenetic changes.

    “Increasing evidence suggests that DNA damage is a major driver of age-associated epigenetic changes.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Mortusewicz, O., Schermelleh, L., Walter, J., Cardoso, M. C. & Leonhardt, H. Recruitment of DNA methyltransferase I to DNA repair sites. Proc. Natl Acad. Sci. USA 102, 8905–8909 (2005). source

      Not checked in the free run.

    • cites [24] Wang, S., Meyer, D. H. D. H. & Schumacher, B. H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage. Nat. Struct. Mol. Biol. 27, 1165–1177 (2020). S. Wang and colleagues revealed that, after the repair of DNA lesions, the epigenetic mark H3K4me2 is deposited to restore protein homeostasis and thus antagonize DNA damage-driven ageing. source

      Not checked in the free run.

    • cites [25] Ito, T., Teo, Y. V., Evans, S. A., Neretti, N. & Sedivy, J. M. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22, 3480–3492 (2018). source

      Not checked in the free run.

  • May combine two claims. 25
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Interpretationreasoning

    DNA damage affects most if not all features of the ageing phenotype and is the most likely unifying cause of ageing.

    “Here, we synthesize accumulating evidence that DNA damage affects most if not all aspects of the ageing phenotype making it a most likely unifying cause of ageing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Senolytic agents that selectively eliminate senescent cells confirm that senescent cells contribute to ageing in atherosclerotic plaques and osteoarthritic lesions.

    “Application of ‘senolytic’ agents that selectively eliminate senescent cells confirm that they contribute to ageing e.g. in atherosclerotic plaques66 and osteoarthritic lesions67.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). source

      Not checked in the free run.

    • cites [67] Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The main features of the ageing phenotype converge causally and mechanistically on DNA damage, making it a strong candidate for the primary cause of ageing.

    “In this perspective we show how the main features of the ageing phenotype, causally and mechanistically, converge onto one factor: DNA damage (Figure 1), rendering this a strong candidate as the primary cause of ageing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Continuous DNA damage induction and repair leaves epigenetic marks and contributes to intercellular epigenetic heterogeneity in ageing.

    “It is thus plausible that continuous DNA damage induction and repair for tens of thousands of lesions daily leave epigenetic marks and thereby contribute to intercellular epigenetic heterogeneity in ageing”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Somatic cells do not need to function indefinitely, and epigenetic memory is erased in the germline at the start of each generation.

  • May combine two claims.

    Premisecitation

    An unprotected telomere resembles a persistent DNA double-strand break and triggers chronic DNA damage response activation, resulting in replicative senescence.

    “An unprotected telomere resembles a persistent DNA double strand break (DSB) triggering chronic DDR activation resulting in replicative senescence12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inherited defects in DNA repair and DNA damage response systems predispose to cancer and cause numerous segmental forms of premature ageing in humans, indicating a link between genome integrity, cancer and ageing.

    “Inherited defects in these maintenance systems not only predispose to cancer but also underlie numerous, segmental forms of premature ageing in humans, indicating a tight link between genome integrity, cancer and ageing6 (Box 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Niedernhofer, L. J. et al. Nuclear genomic instability and aging. Annu. Rev. Biochem. 87, 295–322 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cellular senescence appears to be a bona fide part of the DNA damage response or, as in mitochondrial-dysfunction-associated senescence, indirectly attributable to DNA damage.

    “Hence, cellular senescence appears a bona fide part of the DDR or, as in MiDAS, can be attributed indirectly to DNA damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Senescent cells acquire a senescence-associated secretory phenotype, secreting factors that disrupt microenvironments and compromise tissue structure and function, contributing to ageing pathologies and cancer.

    “However, senescent cells acquire a “senescence-associated secretory phenotype” (SASP), secreting many pro-inflammatory cytokines, proteases, and growth and angiogenesis factors that can disrupt microenvironments and compromise tissue structure and function thereby contributing to local and systemic ageing-associated pathologies47 and promote cancer64.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). This study established that senescent cells release cytokines and thus elicit non-cell-autonomous effects such as inflammatory responses. source

      Not checked in the free run.

    • cites [64] Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The DNA damage response is likely a primary cause of epigenetic changes that deteriorate gene expression control, contributing to somatic heterogeneity and functional decline.

    “Hence, the DDR likely is a primary cause of epigenetic changes that lead to deterioration of control of gene expression, which in turn contributes to somatic heterogeneity and time-dependent overall functional decline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Time-dependent accumulation of stochastic DNA damage hampers stem cell functionality, increases mutations during human HSC ageing, impairs functional properties, promotes clonal expansion and loss of clonal diversity, and raises oncogenic potential.

    “Thus, time-dependent accumulation of stochastic DNA damage severely hampers stem cell functionality, increasing mutations during human HSC ageing80, impairing functional properties, promoting clonal expansion of positively selected somatic mutations resulting in loss of clonal diversity81 or raising the potential for oncogenic transformation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [80] Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018). source

      Not checked in the free run.

    • cites [81] Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    DNA-damage-driven mechanisms explain the decoupling of transcription and protein expression and the loss of protein complex stoichiometry during ageing.

    “These DNA-damage-driven mechanisms would explain the decoupling of transcription and protein expression44 and loss of stoichiometry of protein complexes noted during ageing in different species45, thus creating proteotoxic stress and protein aggregates.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Wei, Y. N. et al. Transcript and protein expression decoupling reveals RNA binding proteins and miRNAs as potential modulators of human aging. Genome Biol. 16, 41 (2015).

      Not checked in the free run.

    • cites [45] Kelmer Sacramento, E. et al. Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation. Mol. Syst. Biol. 16, e9596 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    DNA injuries inevitably accumulate over time, making genome instability a true hallmark of ageing.

    “In time, DNA injuries inevitably accumulate9 making genome instability a true hallmark of ageing (Figure 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Vijg, J. Aging of the Genome (Oxford Univ. Press, 2007). source

      Not checked in the free run.

    • Rests on an assumption: Most DNA lesions are efficiently removed, but some escape detection, are irreparable, are repaired too late, or are repaired erroneously.

  • May combine two claims.

    Premisecitation

    Up to 10^5 DNA lesions occur daily in an active mammalian cell, with spontaneous hydrolysis alone causing about 10^4 abasic sites.

    “It is estimated that up to 105 DNA lesions occur in an active mammalian cell on a daily basis, with spontaneous hydrolysis alone causing ~104 abasic (mostly apurinic) sites5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Accumulating DNA damage interferes with gene expression and replication, causing replication and transcription stress, senescence, functional decline and cell death, which are main drivers of ageing.

    “However, besides causing mutations, accumulating DNA damage also interferes with gene expression and replication causing replication and transcription stress, senescence, functional decline and cell death, all main drivers of ageing (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mechanical stress to tissues can cause genome instability and may contribute to accelerated ageing in Hutchinson-Gilford Progeria.

    “Even mechanical stress to tissues can cause genome instability and may contribute to the accelerated ageing in Hutchinson-Gilford Progeria, where mechanical resilience of the nucleus is compromised by a mutation affecting the scaffold protein lamin A8.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Gonzalo, S., Kreienkamp, R. & Askjaer, P. Hutchinson–Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Res. Rev. 33, 18–29 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High levels of nuclear DNA damage lead to prolonged PARP1 activation, which consumes large amounts of NAD+.

    “High levels of nuclear DNA damage, e.g. in cells from aged organisms or DNA repair mutants, lead to prolonged activation of PARP1, a DNA break sensor that upon activation consumes large amounts of NAD+60.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Hoch, N. C. et al. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541, 87–91 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calorie restriction dramatically delays premature ageing in DNA repair mutant mice, likely by decreasing ROS and other reactive compounds and thereby reducing DNA damage.

    “CR dramatically delays premature ageing in DNA repair mutant mice likely by decreased levels of ROS and other reactive compounds leading to reduced DNA damage levels43.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Vermeij, W. P. et al. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature 537, 427–431 (2016). W. P. Vermeij and colleagues showed that premature ageing in DNA repair-deficient mice could be alleviated by dietary restriction, suggesting that DNA repair is capable of reducing DNA damage infliction and promoting genome stability. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It remains unknown whether the frequency of accumulating mutations is high enough to account for loss of tissue function and increased disease risk at old age.

    “Nevertheless, while there is no doubt that accumulating mutations cause cancer and, possibly, increased cancer risk with age, it is –as yet– unknown if their frequency is high enough to account for the loss of tissue function and increased disease risk at old age.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Reliable quantification of spontaneous DNA damage in animal or human tissues is technically extremely difficult.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Master regulators of DNA repair affecting multiple DNA repair systems have thus far remained elusive.

    “Master regulators of DNA repair affecting multiple DNA repair systems have thus far remained elusive but might await discovery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    All three arguments against a major role of DNA damage in ageing are unconvincing, though not invalid.

    “Hence, while not invalid, all three arguments against a major role of DNA damage in ageing are unconvincing in view of the sheer complexity of DNA repair processes and the abundant evidence that only DNA repair dysfunction, not defects in proteostasis, antioxidant defense, immune response or any other physiological defense system, is associated with systemic premature ageing.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Only DNA repair dysfunction, not defects in proteostasis, antioxidant defense, immune response or any other physiological defense system, is associated with systemic premature ageing.

  • May combine two claims.

    Interpretationreasoning

    DNA damage affects key signaling mechanisms, including IIS, Sirtuins, AMPK and mTOR, that regulate lifespan and elicit anti-ageing effects of calorie restriction in model organisms.

    “In summary, abundant evidence indicates that DNA damage affects key signaling mechanisms –by impinging on IIS, Sirtuins, AMPK and mTOR– that regulate lifespan and elicit anti-ageing effects of CR in model organisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Age of natural menopause is strongly linked with cardiovascular disease, type II diabetes, osteoporosis, and longevity.

    “Age of natural menopause is strongly linked with a wide variety of ageing-pathologies, including cardio-vascular disease, type II diabetes and osteoporosis, and importantly with longevity113.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] Laven, J. S. E., Visser, J. A., Uitterlinden, A. G., Vermeij, W. P. & Hoeijmakers, J. H. J. Menopause: Genome stability as new paradigm. Maturitas 92, 15–23 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Non-cell-autonomous DNA damage response can compromise the stem cell niche and promote stem cell exhaustion.

    “Also the non-cell-autonomous DDR can compromise the stem cell niche and promote stem cell exhaustion.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Ju, Z. et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat. Med. 13, 742–747 (2007). source

      Not checked in the free run.

    • cites [85] Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006). source

      Not checked in the free run.

    • cites [86] Liu, L. et al. Impaired Notch signaling leads to a decrease in p53 activity and mitotic catastrophe in aged muscle stem cells. Cell Stem Cell 23, 544–556.e4 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Longevity-promoting changes in nutrient sensing pathways can stimulate DNA repair, suggesting that some health benefits in normal ageing could be due to improved genome maintenance.

    “Longevity-promoting changes in nutrient sensing pathways can also stimulate DNA repair itself, suggesting that some of the observed health benefits in normal ageing could be due to improved genome maintenance.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Dominick, G., Bowman, J., Li, X., Miller, R. A. & Garcia, G. G. mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell 16, 52–60 (2017). source

      Not checked in the free run.

    • cites [100] Alves-Fernandes, D. K. & Jasiulionis, M. G. The role of SIRT1 on DNA damage response and epigenetic alterations in cancer. Int. J. Mol. Sci. 20, 1–13 (2019). source

      Not checked in the free run.

    • cites [101] Wu, C. L. et al. Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene 32, 2682–2689 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA mutations can now be accurately determined and have been shown to accumulate with age in humans and mice in a tissue-specific manner.

    “However, DNA mutations, a consequence of erroneous DNA repair, can now be accurately determined and have been shown to accumulate with age in humans and mice in a tissue-specific manner42,107–110.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018). Using single-cell sequencing, this study revealed increasing somatic mutations in neurons during human ageing, indicating that even post-mitotic cell types accrue mutations that might trigger age-associated functional decline and degeneration. source

      Not checked in the free run.

    • cites [107] Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc. Natl Acad. Sci. USA 116, 9014–9019 (2019). Using single cell sequencing,  L. Zhang and colleagues show increased somatic mutations during normal human ageing occurring in genes and regulatory regions indicating their role in the age-dependent functional decline. source

      Not checked in the free run.

    • cites [108] 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). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Time-dependent accumulation of DNA damage from endogenous and exogenous sources and its consequences progressively impair cellular functionality and increase susceptibility to chronic diseases of ageing.

    “Time-dependent accumulation of DNA damage of endogenous and exogenous origin and its consequences progressively hamper cellular functionality and increase susceptibility to develop the chronic ailments of ageing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The first proposals that DNA damage was the main driver of ageing date from the 1960s.

    “the first proposals that DNA damage was the main driver of ageing stem from the 1960s115”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Alexander, P. The role of DNA lesions in the processes leading to aging in mice. Symp. Soc. Exp. Biol. 21, 29–50 (1967).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Initial proposals held that DNA damage was the main cause and DNA repair the main determinant of ageing.

    “Since the initial proposals that DNA damage was the main cause and DNA repair the main determinant of ageing117,118”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117] Hart, R. W. & Setlow, R. B. Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc. Natl Acad. Sci. USA 71, 2169–2173 (1974). source

      Not checked in the free run.

    • cites [118] Gensler, H. L. & Bernstein, H. DNA damage as the primary cause of aging. Q. Rev. Biol. 56, 279–303 (1981). source

      Not checked in the free run.

28 of 28

  • The paper relies on this without support.

    Most DNA lesions are efficiently removed, but some escape detection, are irreparable, are repaired too late, or are repaired erroneously.

    “Even though most of these lesions are efficiently removed, some escape detection, are irreparable, repaired too late, or repaired in an erroneous way.”

  • The paper relies on this without support.

    Somatic cells do not need to function indefinitely, and epigenetic memory is erased in the germline at the start of each generation.

    “particularly since somatic cells do not have to function forever and epigenetic memory is erased in the germline at the start of the next generation.”

  • The paper relies on this without support.

    Inflammatory signaling promotes a range of age-related pathologies.

    “In contrast, inflammatory signaling is thought to promote a range of age-related pathologies.”

  • The paper relies on this without support.

    DNA repair involves at least seven well-balanced multi-enzyme core pathways and many accessory processes encompassing hundreds of genes, many with other roles.

    “Instead DNA repair involves at least 7 well-balanced multi-enzyme core pathways and many more accessory processes that encompass hundreds of genes, many of which have other roles as well.”

  • The paper relies on this without support.

    DNA repair capacities evolved under selection conditions driven largely by environmental genotoxins such as UV or natural compounds.

    “DNA repair capacities have evolved under specific selection conditions largely driven by environmental genotoxins, such as high fluxes of UV or natural compounds.”

  • The paper relies on this without support.

    Reliable quantification of spontaneous DNA damage in animal or human tissues is technically extremely difficult.

    “Second, reliable quantification of spontaneous DNA damage in animal or human tissues appears technically extremely difficult hampering efforts to show an age-related increase to levels that likely impair cellular function and explain age-related pathologies (Text Box 2).”

  • The paper relies on this without support.

    Extreme longevity is rare and individual age-related diseases often involve genes not necessarily related to systemic ageing.

    “Extreme longevity is rare and individual age-related diseases often involve genes not necessarily related to systemic ageing, e.g., lipoprotein genes.”

  • The paper relies on this without support.

    Only DNA repair dysfunction, not defects in proteostasis, antioxidant defense, immune response or any other physiological defense system, is associated with systemic premature ageing.

    “the abundant evidence that only DNA repair dysfunction, not defects in proteostasis, antioxidant defense, immune response or any other physiological defense system, is associated with systemic premature ageing.”

  • The paper relies on this without support.

    When DNA became the genetic material, it was already more stable than RNA, the presumed initial carrier of genetic information.

    “When DNA became the genetic material, it was already far more stable than RNA, the presumed initial carrier of genetic information.”

  • The paper relies on this without support.

    Reducing exogenous DNA damage through UV protection and avoidance of tobacco smoking lowers ageing-associated disease risks.

    “Reducing exogenous DNA damage for example through UV protection and avoidance of tobacco smoking has already proven to lower ageing-associated disease risks.”

  • The paper relies on this without support.

    The majority of spontaneous DNA lesions will inevitably occur.

    “but the majority of spontaneous lesions will inevitably occur.”

  • The paper relies on this without support.

    Photolyase repair enzymes are active in many species but not in placental mammals.

    “An exception are the highly lesion-specific photolyase repair enzymes, active in many species but not placental mammals.”
12 of 12

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PDRN-derived nucleotides prevent activation of cell fate pathways associated with apoptosis or senescence, preserving cellular function and tissue integrity.

    “By facilitating the efficient repair of DNA lesions, PDRN-derived nucleotides prevent activation of cell fate pathways associated with apoptosis or senescence, thereby preserving cellular function and tissue integrity [83,84].”

    From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [83]

    The 'Cellular senescence' and 'Stem cell exhaustion' sections (page not provided) link DNA damage to senescence and, when damage is too extensive, apoptosis. The 'Future prospects' section proposes that reducing DNA damage and augmenting repair could preserve cellular function. The paper does not discuss PDRN-derived nucleotides or show that they facilitate repair and prevent those cell fates. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • This process initiates and maintains cellular senescence, which is a key contributor to organismal ageing and multiple age-related diseases.

    “This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases6,7.”

    From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [7]

  • DNA damage accumulates with age and contributes to age-related phenotypic changes.

    “DNA damage accumulates with age and contributes to age-related phenotypic changes (67).”

    From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [67]

  • Data supporting specific dosages and intensities of progressive resistance training needed to enhance strength, power, muscle mass, bone density, and overall functional capacity is not yet fully defined.

    “data supporting specific dosages and intensities of PRT needed to enhance strength, power, muscle mass, bone density, and overall functional capacity is not yet fully defined [4,5]”

    From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [4]

  • The "aging phenotype" encompasses diverse observable traits, behaviors, and physiological alterations that lead to a gradual decline in organismal functions and an increased susceptibility to age-related diseases.

    “The “aging phenotype” encompasses the diverse array of observable traits, behaviors, and physiological alterations that lead to a gradual decline in organismal functions and an increased susceptibility to age-related diseases [4].”

    From Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR) (2025) · cites this paper as [4]

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Authors
Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. J.
Affiliations
  • University of Cologne (DE)
  • Erasmus MC (NL)
  • Albert Einstein College of Medicine (US)
Corresponding author
Schumacher, Björn
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-04-28
Volume
592
Issue
7856
Pages
695-703
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03307-7
PMC
PMC9844150
OpenAlex
W3158627234
Cited by
907
References
127
Citations by year
2026: 137 · 2025: 208 · 2024: 229 · 2023: 189 · 2022: 112 · 2021: 31 · 2016: 1
FWCI
11.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institute on Aging (P30AG038072, P01AG017242, U19AG056278, P01AG047200)
  • National Heart, Lung, and Blood Institute (U01HL145560)
  • National Institute of Environmental Health Sciences (U01ES029519)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
DNA damage, aging, aging mechanisms, genomic instability, epigenetic modifications, proteostasis, cellular dysfunction, age-related diseases, anti-aging interventions
MeSH terms
Aging, Animals, Cell Differentiation, DNA Damage, DNA Repair, Humans, Cell Lineage

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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