The DOI matches its Crossref record; 127 of the 127 references it cites were found in a registry or an index; none of the 64 sources its claims cite is checked for support yet.
The central role of DNA damage in the ageing process
Open accessAbstract
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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“Even a single DSB suffices to cause full-blown cell cycle blockade13.”
§ The central role of DNA damage in the ageing process > Genome instability at dysfunctional telomeres
What the sources say
- Not checked yetcites [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
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“Some of the physiological alterations in turn boost genome instability thus amplifying the deterioration of homeostasis during ageing.”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
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“Genetic defects in telomere maintenance cause human telomeropathies, including dyskeratosis congenita, aplastic anemia, and pulmonary and liver disease exhibiting multiple progeroid features15.”
§ The central role of DNA damage in the ageing process > Genome instability at dysfunctional telomeres
What the sources say
- Not checked yetcites [15] Martínez, P. & Blasco, M. A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol. 216, 875–887 (2017). source
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In the paper
“During normal ageing, DNA damage occurs continuously on a massive scale, due to numerous exogenous and endogenous genotoxins.”
§ The central role of DNA damage in the ageing process > Effects of DNA damage at the molecular level > The inherently instable genome
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“Increasing evidence suggests that DNA damage is a major driver of age-associated epigenetic changes.”
§ The central role of DNA damage in the ageing process > DNA damage-induced epigenetic alterations
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“In conclusion, accumulating DNA damage is increasingly recognized to drive stem cell exhaustion during ageing through a combination of apoptotis, premature differentiation, cytostatic DNA damage checkpoint signaling, accumulation of mutations, and DNA damage-driven alterations in intercellular communication affecting stem cell niches.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Stem cell exhaustion
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“Recently, attention has focused on the effect of senescence in vivo where purging p16-positive senescent cells in transgenic mice increased mean lifespan as well as aspects of healthspan65.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Cellular senescence
What the sources say
- Not checked yetcites [65] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). D. J. Baker and colleagues revealed that the elimination of senescent cells could delay ageing and provided the conceptual framework for eliminating senescence cells for therapeutic interventions aimed at extending healthspan. source
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In the paper
“The pro-ageing effects of genotoxins are visible during photoaging of the skin but also DNA-damaging chemotherapy accelerates ageing features7.”
§ The central role of DNA damage in the ageing process > Effects of DNA damage at the molecular level > The inherently instable genome
What the sources say
- Not checked yetcites [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
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In the paper
“Cellular senescence permanently arrests cell proliferation in response to various stresses, most of which DNA-damage-related.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Cellular senescence
What the sources say
- Not checked yetcites [61] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961). source
- Not checked yetcites [62] Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). source
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In the paper
“In mice, segmental premature ageing only manifest in telomerase mutants after several generations, likely because their particularly long telomeric repeats take several generations to become critically shortened and thus dysfunctional16.”
§ The central role of DNA damage in the ageing process > Genome instability at dysfunctional telomeres
What the sources say
- Not checked yetcites [16] Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011). source
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- Probably not a substantial claim. 4
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The central role of DNA damage in the ageing process > Abstract
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In the paper
“Application of ‘senolytic’ agents that selectively eliminate senescent cells confirm that they contribute to ageing e.g. in atherosclerotic plaques66 and osteoarthritic lesions67.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Cellular senescence
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > The ultimate cause of ageing
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In the paper
“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”
§ The central role of DNA damage in the ageing process > DNA damage-induced epigenetic alterations
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- 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.
In the paper
“An unprotected telomere resembles a persistent DNA double strand break (DSB) triggering chronic DDR activation resulting in replicative senescence12.”
§ The central role of DNA damage in the ageing process > Genome instability at dysfunctional telomeres
What the sources say
- Not checked yetcites [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
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In the paper
“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).”
§ The central role of DNA damage in the ageing process > Effects of DNA damage at the molecular level > The inherently instable genome
What the sources say
- Not checked yetcites [6] Niedernhofer, L. J. et al. Nuclear genomic instability and aging. Annu. Rev. Biochem. 87, 295–322 (2018). source
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In the paper
“Hence, cellular senescence appears a bona fide part of the DDR or, as in MiDAS, can be attributed indirectly to DNA damage.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Cellular senescence
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Cellular senescence
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > DNA damage-induced epigenetic alterations
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Stem cell exhaustion
What the sources say
- Not checked yetcites [80] Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018). source
- Not checked yetcites [81] Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017). source
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > DNA damage-induced proteostatic stress
What the sources say
- Not checked yetcites [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 yetcites [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
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In the paper
“In time, DNA injuries inevitably accumulate9 making genome instability a true hallmark of ageing (Figure 2).”
§ The central role of DNA damage in the ageing process > Effects of DNA damage at the molecular level > The inherently instable genome
What the sources say
- Not checked yetcites [9] Vijg, J. Aging of the Genome (Oxford Univ. Press, 2007). source
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- Rests on an assumption: Most DNA lesions are efficiently removed, but some escape detection, are irreparable, are repaired too late, or are repaired erroneously.
In the paper
“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.”
§ The central role of DNA damage in the ageing process > Effects of DNA damage at the molecular level > The inherently instable genome
What the sources say
- Not checked yetcites [5] Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993). source
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In the paper
“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).”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Effects of DNA damage at the molecular level > The inherently instable genome
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Mitochondrial dysfunction
What the sources say
- Not checked yetcites [60] Hoch, N. C. et al. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541, 87–91 (2017). source
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Systemic effects of DNA damage > Anti-ageing responses to nutritional interventions are impacting genome stability
What the sources say
- Not checked yetcites [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
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: Reliable quantification of spontaneous DNA damage in animal or human tissues is technically extremely difficult.
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In the paper
“Master regulators of DNA repair affecting multiple DNA repair systems have thus far remained elusive but might await discovery.”
§ The central role of DNA damage in the ageing process > Future prospects
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- 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.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The central role of DNA damage in the ageing process > Systemic effects of DNA damage > Anti-ageing responses to nutritional interventions are impacting genome stability
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
What the sources say
- Not checked yetcites [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
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In the paper
“Also the non-cell-autonomous DDR can compromise the stem cell niche and promote stem cell exhaustion.”
§ The central role of DNA damage in the ageing process > DNA damage-driven Cell Fate Decisions > Stem cell exhaustion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Systemic effects of DNA damage > Anti-ageing responses to nutritional interventions are impacting genome stability
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [101] Wu, C. L. et al. Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene 32, 2682–2689 (2013). source
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In the paper
“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.”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ The central role of DNA damage in the ageing process > Future prospects
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“the first proposals that DNA damage was the main driver of ageing stem from the 1960s115”
§ The central role of DNA damage in the ageing process > Is DNA damage the primary cause of ageing?
What the sources say
- Not checked yetcites [115] Alexander, P. The role of DNA lesions in the processes leading to aging in mice. Symp. Soc. Exp. Biol. 21, 29–50 (1967).
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Since the initial proposals that DNA damage was the main cause and DNA repair the main determinant of ageing117,118”
§ The central role of DNA damage in the ageing process > Future prospects
What the sources say
- Not checked yetcites [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 yetcites [118] Gensler, H. L. & Bernstein, H. DNA damage as the primary cause of aging. Q. Rev. Biol. 56, 279–303 (1981). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Notably, 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]
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“Because of the mechanistic role of DNA damage in affecting most aging hallmarks 33 , including the onset of cellular senescence 34 , we next explored whether SARS-CoV-2 infection would lead to DNA double-strand break accumulation.”
DNA Damage-Induced Inflammatory Microenvironment and Adult Stem Cell Response
Cinat, D., Coppes, R. P., & Barazzuol, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.729136 · Cited by 79
R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage
Chatzidoukaki, O., Stratigi, K., Goulielmaki, E., Niotis, G., Akalestou-Clocher, A., Gkirtzimanaki, K., Zafeiropoulos, A., Altmüller, J., Topalis, P., & Garinis, G. A. (2021) · Science Advances · doi:10.1126/sciadv.abj5769 · Cited by 79
Distinguishing between driver and passenger mechanisms of aging
de Magalhães, J. P. (2024) · Nature Genetics · doi:10.1038/s41588-023-01627-0 · Cited by 79
“As reviewed by many 32,33 , some forms of DNA damage, including somatic mutations 34 , have been found to increase with age, although accurately profiling all types of DNA damage in tissues remains a challenge 35”
SIRT7: the seventh key to unlocking the mystery of aging
Raza, U., Tang, X., Liu, Z., & Liu, B. (2023) · Physiological Reviews · doi:10.1152/physrev.00044.2022 · Cited by 82
Quantifying the stochastic component of epigenetic aging
Tong, H., Dwaraka, V. B., Chen, Q., Luo, Q., Lasky-Su, J. A., Smith, R., & Teschendorff, A. E. (2024) · Nature Aging · doi:10.1038/s43587-024-00600-8 · Cited by 83
Ergothioneine and its congeners: anti-ageing mechanisms and pharmacophore biosynthesis
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“DNA damage, largely in consequence of oxidative stress, plays a critical role in the ageing process and influences several key aspects of the ageing phenotype (Hasty et al., 2003; Kujoth et al., 2005; Schumacher et al., 2021).”
BackgroundThe DREAM complex functions as conserved master regulator of somatic DNA-repair capacities
Bujarrabal-Dueso, A., Sendtner, G., Meyer, D. H., Chatzinikolaou, G., Stratigi, K., Garinis, G. A., & Schumacher, B. (2023) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-00942-8 · Cited by 79
Self-citationAging of the eye: Lessons from cataracts and age-related macular degeneration
Cvekl, A., & Vijg, J. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102407 · Cited by 77
“DNA damage is one of the primary causes of aging (Schumacher et al., 2021).”
BackgroundSelf-citationMerging the exposome into an integrated framework for “omics” sciences
Price, E. J., Vitale, C. M., Miller, G. W., David, A., Barouki, R., Audouze, K., Walker, D. I., Antignac, J., Coumoul, X., Bessonneau, V., et al. (2022) · iScience · doi:10.1016/j.isci.2022.103976 · Cited by 73
“For example, decades after qualitative whole genome sequencing became viable, the assessment of the accumulation of DNA mutations during aging is a burgeoning field (Schumacher et al., 2021; Vijg and Montagna, 2017).”
BackgroundInheritance of paternal DNA damage by histone-mediated repair restriction
Wang, S., Meyer, D. H., & Schumacher, B. (2023) · Nature · doi:10.1038/s41586-022-05544-w · Cited by 68
Self-citationPregnancy, preeclampsia and maternal aging: From epidemiology to functional genomics
Miller, E. C., Wilczek, A., Bello, N. A., Tom, S. E., Wapner, R. J., & Suh, Y. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101535 · Cited by 78
Obesity accelerates cardiovascular ageing
Ruperez, C., Madeo, F., de Cabo, R., Kroemer, G., & Abdellatif, M. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf216 · Cited by 73
PRC2-AgeIndex as a universal biomarker of aging and rejuvenation
Moqri, M., Cipriano, A., Simpson, D. J., Rasouli, S., Murty, T., de Jong, T. A., Nachun, D. C., Brandine, G. D. S., Ying, K., Tarkhov, A. E., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50098-2 · Cited by 70
Pathological and Inflammatory Consequences of Aging
García‐Domínguez, M. (2025) · Biomolecules · doi:10.3390/biom15030404 · Cited by 78
“At the molecular level, aging is linked to genomic instability [7], resulting in the accumulation of DNA damage [8].”
Zhang, Y., Zou, M., Wu, H., Zhu, J., & Jin, T. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106710 · Cited by 75
“Additionally, cellular senescence commonly involves the DNA damage response (DDR), which has the potential to crosstalk with cGAS (Schumacher et al., 2021; Ahmad et al., 2024; Kornepati et al., 2023).”
BackgroundAccelerated Vascular Aging in Chronic Kidney Disease: The Potential for Novel Therapies
Hobson, S., Arefin, S., Witasp, A., Hernandez, L. N., Kublickiene, K. R., Shiels, P. G., & Stenvinkel, P. (2023) · Circulation Research · doi:10.1161/circresaha.122.321751 · Cited by 64
DNA repair as a shared hallmark in cancer and ageing
Clarke, T. L., & Mostoslavsky, R. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13285 · Cited by 74
Association of Oxidative Stress–Induced Nucleic Acid Damage With Psychiatric Disorders in Adults
Jørgensen, A., Baago, I. B., Rygner, Z., Jørgensen, M. B., Andersen, P. K., Kessing, L. V., & Poulsen, H. E. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.2066 · Cited by 63
Cellular senescence in Alzheimer’s disease: from physiology to pathology
Zhu, J., Wu, C., & Yang, L. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00447-4 · Cited by 74
Skin health and biological aging
Furman, D., Auwerx, J. H., Bulteau, A., Church, G. M., Couturaud, V., Crabbé, L., Davies, K. J. A., Decottignies, A., Gladyshev, V. N., Kennedy, B. K., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00901-6 · Cited by 73
“Damaged DNA affects gene expression, perturbs the fidelity of DNA replication and generates more mutations and chromosomal aberrations 13 .”
Mechanical Fingerprint of Senescence in Endothelial Cells
Chala, N., Moimas, S., Giampietro, C., Zhang, X., Zambelli, T., Exarchos, V., Nazari‐Shafti, T. Z., Dimos Poulikakos, A., & Ferrari, A. (2021) · Nano Letters · doi:10.1021/acs.nanolett.1c00064 · Cited by 64
Best, L., Dost, T., Esser, D., Flor, S., Gamarra, A. M., Haase, M., Kadibalban, A. S., Marinos, G., Walker, A., Zimmermann, J., et al. (2025) · Nature Microbiology · doi:10.1038/s41564-025-01959-z · Cited by 65
“A full cohort assembly was done in metaSPAdes (SPAdes version 3.13.1) in hybrid mode with k -mer sizes of 21, 33, 55 and 77.”
InfluentialWu, L., Sowers, J. R., Zhang, Y., & Ren, J. T. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvac080 · Cited by 65
Salminen, A. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-024-02444-6 · Cited by 61
“The primary cause of aging is still unknown although many investigators have suggested that a loss of DNA integrity, e.g., genome instability, telomere attrition, and dysfunctions in mitochondrial DNA (mtDNA), is a hallmark of the aging process [147].”
BackgroundSomatic mutation rates scale with lifespan across mammals
Cagan, A., Baez-Ortega, A., Brzozowska, N., Abascal, F., Coorens, T. H. H., Sanders, M. A., Lawson, A. R. J., Harvey, L. M. R., Bhosle, S., Jones, D., et al. (2021) · doi:10.1101/2021.08.19.456982 · Cited by 482
The brain–body energy conservation model of aging
Shaulson, E. D., Cohen, A. A., & Picard, M. A. (2024) · Nature Aging · doi:10.1038/s43587-024-00716-x · Cited by 80
“For example, telomere erosion 58 and DNA damage transcriptionally induce and locally recruit the telomere shelterin complex and activate the DNA damage response 36,59 .”
Preis, L., Villringer, K., Brosseron, F., Düzel, E., Jessen, F., Petzold, G. C., Ramírez, A., Spottke, A. E., Fiebach, J. B., & Peters, O. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01529-1 · Cited by 80
“While aging induces a multitude of changes, like DNA damage [43] and mitochondrial dysfunction [44], Cicognola and colleagues hypothesize that changes in BBB function may be associated with age-dependent increases in neuro-inflammation along pericyte degeneration.”
BackgroundTFEB is a central regulator of the aging process and age-related diseases
Abokyi, S., Ghartey‐Kwansah, G., & Tse, D. Y. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101985 · Cited by 61
“Damage accumulated over time in both nuclear DNA and mitochondrial DNA (mtDNA) can trigger cell death and senescence, which in turn may cause inflammation, loss of organ function, and pathological aging (Schumacher et al. 2021).”
BackgroundInfluentialCoffee consumption and cardiometabolic health: a comprehensive review of the evidence
Ungvari, Z. I., & Kunutsor, S. K. (2024) · GeroScience · doi:10.1007/s11357-024-01262-5 · Cited by 69
“Caffeine, in particular, supports the preservation of genomic integrity by enhancing the repair of DNA damage [245], which accumulates with age and contributes significantly to the aging process and the onset of age-related diseases [246].”
BackgroundResearch Progress on the Anti-Aging Potential of the Active Components of Ginseng
Su, J., Su, Q., Hu, S., Ruan, X., & Ouyang, S. (2023) · Nutrients · doi:10.3390/nu15153286 · Cited by 58
“DNA damage is a major driver of aging; it induces permanent cell cycle arrest, and the associated markers accumulate in senescent cells with age [6].”
BackgroundDańczak‐Pazdrowska, A., Gornowicz‐Porowska, J., Polańska, A., Krajka‐Kuźniak, V., Stawny, M., Gostyńska, A., Rubiś, B., Noureddine, S. A., Ashiqueali, S., Schneider, A., et al. (2023) · Aging Cell · doi:10.1111/acel.13845 · Cited by 65
Genome Instability and DNA Repair in Somatic and Reproductive Aging
Panier, S., Wang, S., & Schumacher, B. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-093128 · Cited by 64
Self-citationMicroglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage
Arvanitaki, E. S., Goulielmaki, E., Gkirtzimanaki, K., Niotis, G., Tsakani, E., Nenedaki, E., Rouska, I., Kefalogianni, M., Xydias, D., Kalafatakis, I., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2317402121 · Cited by 50
“Irreparable DNA lesions inadvertently interfere with ongoing transcription in postmitotic neurons or obstruct the process of mRNA synthesis and DNA replication in dividing glial cells leading to cellular malfunction, senescence, or cell death (8), (9).”
BackgroundSelf-citationCopper chaperone antioxidant 1: multiple roles and a potential therapeutic target
Yang, D., Xiao, P., Qiu, B., Yu, H., & Teng, C. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02311-w · Cited by 56
Molecular pathology of rare progeroid diseases
Rieckher, M., Garinis, G. A., & Schumacher, B. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.06.011 · Cited by 50
Self-citationTelomere function and regulation from mouse models to human ageing and disease
Jones-Weinert, C. W., Mainz, L., & Karlseder, J. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00800-5 · Cited by 63
“Interestingly, TIFs also appear to drive ageing in non-proliferative tissues, where rep-lication-associated shortening cannot occur (reviewed elsewhere 238 ).”
Mechanisms Underlying Brain Aging Under Normal and Pathological Conditions
Jin, M., & Cai, S. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00969-9 · Cited by 61
Oxysterols are potential physiological regulators of ageing
de Médina, P., Silvente‐Poirot, S., & Poirot, M. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101615 · Cited by 55
Kong, L., Ye, C., Wang, Y., Zheng, J., Wang, S., Lin, H., Zhao, Z., Li, M., Lu, J., Lu, J., et al. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad078 · Cited by 50
Role of primary aging hallmarks in Alzheimer´s disease
Zhao, J., & Huai, J. (2022) · Theranostics · doi:10.7150/thno.79535 · Cited by 55
“aging-related hallmarks provides a rationale for developing interventions to combat age-related diseases, including AD [25].”
BackgroundDietary Polyphenols as Anti-Aging Agents: Targeting the Hallmarks of Aging
Liu, Y., Fang, M., Tu, X., Mo, X., Zhang, L., Yang, B., Wang, F., Kim, Y., Huang, C., Chen, L., et al. (2024) · Nutrients · doi:10.3390/nu16193305 · Cited by 62
Mechanisms of muscle cells alterations and regeneration decline during aging
Chinvattanachot, G., Rivas, D., & Duque, G. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102589 · Cited by 61
“In general, DNA damage induces epigenetic alterations, mitochondrial dysfunction, and proteostatic stress in various cell types, which ultimately compromise cellular function and influence cell fate decisions (Schumacher et al., 2021).”
Genes and Longevity of Lifespan
Bin-Jumah, M. N., Nadeem, M. S., Gilani, S. J., Al-Abbasi, F. A., Ullah, I., Alzarea, S. I., Ghoneim, M. M., Alshehri, S., Ud-Din, A., Murtaza, B. N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031499 · Cited by 52
“Studies on bats have shown that DNA methylation is negatively linked with longevity of lifespan, and that DNA damage is positively linked with it [19,20].”
BackgroundHematopoietic Stem Cells and the Immune System in Development and Aging
Shevyrev, D., Tereshchenko, V., Berezina, T. N., & Александрович, Р. С. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065862 · Cited by 58
Copp, M. E., Chubinskaya, S., Bracey, D. N., Shine, J., Sessions, G. A., Loeser, R. F., & Diekman, B. O. (2022) · Aging Cell · doi:10.1111/acel.13698 · Cited by 50
“This is consistent with evidence in other tissue systems that supports DNA damage as a key driver of the cellular dysfunction that emerges during aging (Schumacher et al., 2021; Yousefzadeh et al., 2021).”
BackgroundResultInvolvement of p38 MAPK in Leydig cell aging and age-related decline in testosterone
Luo, D., Qi, X., Xu, X., Yang, L., Yu, C., & Guan, Q. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1088249 · Cited by 48
Yin, Q., Tang, T.-T., Lu, X., Ni, W.-J., Yin, D., Zhang, Y., Wen, Y., Jiang, W., Zhang, Y., Li, Z.-L., et al. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-024-01708-5 · Cited by 55
Metadata
- 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
- Venue
- Nature
- Published
- 2021-04-28
- Volume
- 592
- Issue
- 7856
- Pages
- 695-703
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9844150
- OpenAlex
- W3158627234
- Cited by
- 907
- References
- 127
- Citations by year
- 2026: 137 · 2025: 208 · 2024: 229 · 2023: 189 · 2022: 112 · 2021: 31
- FWCI
- 11.49
- Type
- journal article
- Language
- en
- Open access
- green
- pure.eur.nl
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
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