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DNA damage and repair in age-related inflammation

Abstract

Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS–STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation.

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Fig. 1: DNA damage as an inducer of inflammation.
Fig. 2: Retroelement mobilization triggers inflammation via cytoplasmic DNA.
Fig. 3: Mechanisms of senescence-induced inflammation.
Fig. 4: R-loops accumulate with age and drive inflammation.
Fig. 5: Epigenetic changes triggered by lifelong DNA damage lead to induction of RTEs and inflammageing.

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The authors contributed equally to all aspects of the article.

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Correspondence to Andrei Seluanov or Vera Gorbunova.

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V.G. is a consultant for Elysium, Centaura, Genflow Bio and Do Not Age. The other authors declare no competing interests.

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Glossary

Nucleotide excision repair

(NER). A DNA repair pathway that recognizes and removes bulky DNA lesions such as those formed by UV light. NER involves damage recognition, nicks flanking the lesion and removal of the damaged DNA strand, filling in the gap by DNA polymerase and ligation of the nicks to restore the intact DNA molecule. Deficiency in NER is associated with cancer predisposition and premature ageing syndromes.

Senescence-associated secretory phenotype

(SASP). A phenotype associated with cellular senescence, which expresses and secretes a wide variety of inflammatory factors including cytokines, chemokines and growth factors.

DNA double-strand break (DSB) repair

A DNA repair pathway that repairs lesions where both DNA strands are broken. There are two major pathways of DSB repair; homologous recombination uses sister chromatid as a template for repair and non-homologous DNA end joining ligates the broken ends without regard for homology. Defects in DNA repair are associated with several premature ageing and cancer predisposition syndromes.

Inflammageing

Chronic, low-grade sterile inflammation frequently observed during ageing.

Retrotransposons

(RTEs). Genetic elements abundant in mammalian genomes that move throughout the genome by a copy–paste mechanism involving reverse transcription and may accumulate in the cytoplasm, triggering inflammation.

Sterile inflammation

Inflammation arising in the absence of a pathogen or external inflammatory stimuli.

Blind mole rat

A subterranean rodent of the Muroidea superfamily, characterized by long maximum lifespan (>21 years) and resistance to cancer.

HRASV12

An oncoprotein of small GTPase HRAS carrying a constitutively activated mutation on codon Val-12.

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Zhao, Y., Simon, M., Seluanov, A. et al. DNA damage and repair in age-related inflammation. Nat Rev Immunol (2022). https://doi.org/10.1038/s41577-022-00751-y

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