Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

TLDR

Chronic inflammation is linked to both normal and pathological ageing. In nfkb1(-/-) fibroblasts, heightened NF‑κB, COX‑2, and ROS signaling amplifies autocrine/paracrine feedback that stabilizes DNA damage, driving accelerated senescence. Knocking out nfkb1 induces chronic low‑grade inflammation that accelerates ageing, reduces liver and gut regeneration, and elevates telomere‑dysfunctional senescent cells, whose frequencies predict lifespan; anti‑inflammatory or antioxidant treatment rescues regeneration and lifespan.

Abstract

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1(-/-) tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor.