The central role of DNA damage in the ageing process

Schumacher, Björn; Pothof, Joris; Vijg, Jan; Hoeijmakers, Jan H.J.

doi:10.1038/s41586-021-03307-7

Cited by 466 publications

(376 citation statements)

References 123 publications

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“…For some the current evidence is quite good, and genomic instability due to defects in DNA repair can lead to segmental progeroid syndromes in mice and men ( Freitas & de Magalhaes 2011 ; Niedernhofer et al . 2018 ; Schumacher et al . 2021 ).…”

Section: Measuring the Hallmarks Of Aging Against The Hallmarks Of Cancermentioning

confidence: 99%

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

Gems

Magalhães

2021

Ageing Research Reviews

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With the goal of representing common denominators of aging in different organisms López-Otín et al. in 2013 described nine hallmarks of aging. Since then, this representation has become a major reference point for the biogerontology field. The template for the hallmarks of aging account originated from landmark papers by Hanahan and Weinberg (2000 , 2011 ) defining first six and later ten hallmarks of cancer. Here we assess the strengths and weaknesses of the hallmarks of aging account. As a checklist of diverse major foci of current aging research, it has provided a useful shared overview for biogerontology during a time of transition in the field. It also seems useful in applied biogerontology, to identify interventions (e.g. drugs) that impact multiple symptomatic features of aging. However, while the hallmarks of cancer provide a paradigmatic account of the causes of cancer with profound explanatory power, the hallmarks of aging do not. A worry is that as a non-paradigm the hallmarks of aging have obscured the urgent need to define a genuine paradigm, one that can provide a useful basis for understanding the mechanistic causes of the diverse aging pathologies. We argue that biogerontology must look and move beyond the hallmarks to understand the process of aging. In its normal state, then, a scientific community is an immensely efficient instrument for solving the problems or puzzles that its paradigms define. ( Kuhn 1962 ) p. 166.

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Section: Measuring the Hallmarks Of Aging Against The Hallmarks Of Cancermentioning

confidence: 99%

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

Gems

Magalhães

2021

Ageing Research Reviews

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“…However, somatic mutations might also be relevant to a late life phenomenon like aging. One theory of aging proposes a causal link between aging and the accumulation of somatic mutations (Zhang and Vijg, 2018;Schumacher et al, 2021;Vijg, 2021). Arguing against this link would be a pattern of aging that is species-specific.…”

Section: Germline Versus Somatic Mutationsmentioning

confidence: 99%

Evolution, Chance, and Aging

Frankel

Rogina

2021

Front. Genet.

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Aging has provided fruitful challenges for evolutionary theory, and evolutionary theory has deepened our understanding of aging. A great deal of genetic and molecular data now exists concerning mortality regulation and there is a growing body of knowledge concerning the life histories of diverse species. Assimilating all relevant data into a framework for the evolution of aging promises to significantly advance the field. We propose extensions of some key concepts to provide greater precision when applying these concepts to age-structured contexts. Secondary or byproduct effects of mutations are proposed as an important factor affecting survival patterns, including effects that may operate in small populations subject to genetic drift, widening the possibilities for mutation accumulation and pleiotropy. Molecular and genetic studies have indicated a diverse array of mechanisms that can modify aging and mortality rates, while transcriptome data indicate a high level of tissue and species specificity for genes affected by aging. The diversity of mechanisms and gene effects that can contribute to the pattern of aging in different organisms may mirror the complex evolutionary processes behind aging.

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“…Persistent DNA damage not only promotes developmental disorders, but also drives a range of age-related chronic conditions like metabolic syndrome, cardiovascular disease, cancer and neurodegeneration 1,2 . Technological advances have strengthened the evidence for accumulation of DNA damaging lesions and DNA mutations with age and disease in several model organisms, as well as humans 1,[3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60

Hamsanathan

Anthonymuthu

et al. 2021

Preprint

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Nuclear DNA damage is intricately linked to cellular metabolism. However, the underlying mechanisms and full range of metabolic alterations that occur in response to persistent DNA damage are not well understood. Here, we use a DNA repair-deficient model of ERCC1-XPF in Caenorhabditis elegans (C. elegans), that accumulates physiologically relevant, endogenous DNA damage, to gain molecular insights on how persistent genotoxic stress drives biological aging. Using an integrated multi-omic approach, we discover that persistent genotoxic stress rewires lipid metabolism. In particular, nuclear DNA damage promotes mitochondrial β-oxidation and leads to a global loss of fat depots. This metabolic shift to β-oxidation generates acetyl-CoA and drives histone hyperacetylation. Concomitantly, we observe an associated change in gene expression of immune-effector and cytochrome (CYP) genes. We identify MYS-1, the ortholog of mammalian histone acetyltransferase TIP60, as a critical regulator of this metabolic-epigenetic axis. Moreover, we show that in response to persistent DNA damage, polyunsaturated fatty acids (PUFAs), especially arachidonic acid (AA) and AA-related lipid mediators are elevated. This elevation of PUFA species requires mys-1/Tip60. Together, these findings reveal that persistent nuclear DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline.

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The central role of DNA damage in the ageing process

Cited by 466 publications

References 123 publications

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

Evolution, Chance, and Aging

Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60

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