Gut Microbiota Shape Inflamm-aging Cytokines and Account for Age-dependent Decline in DNA Damage Repair

Failing to properly repair damaged DNA drives the aging process. Here we show that with age there is a decline in the resolution of foci containing γH2AX and pKAP-1 in DEN-treated mouse livers that was already evident at a remarkably early age of 6-month. Moreover, at this age we also observed an increase in ‘inflamm-aging’ cytokines, specifically TNFα and IL-1β that extended to 12-months of age. Hence, we postulated that age-related decline in DNA damage repair may stem from age-related inflammation. In agreement with the notion that gut microbiota provide tonic stimulatory signals that are important for priming elevated levels of inflammatory cytokines, the decline in the repair of DSBs was reversed via antibiotic treatment or MyD88 ablation in 6-month old mice and accompanied with reduced cytokine expression. On the other hand, feeding young mice with high-fat diet (HFD) enhances inflammation and facilitates the decline in DDR, and this latter effect could be reversed by antibiotic treatment. In the liver, Kupffer cells are the major source of ‘inflamm-aging’ cytokines. Accordingly, Kupffer cell replenishment or their inactivation by gadolinium chloride reduced cytokine expression and reversed the decline in DSBs repair. We have previously demonstrated how macrophage facilitates DNA damage repair in neighboring cells via the release of HB-EGF and here we show in vitro how presence of ‘inflamm-aging’ cytokines in-and-of themselves, are sufficient for ablating HB-EGF-assisted DSBs rejoining. Our results reveal a previously unrecognized interplay between commensal-dependent inflammatory response and age-dependent decline in DNA damage repair.