Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

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.

Shortened telomere length in bipolar disorder: a comparison of the early and late stages of disease

“…32 Chronic systemic inflammation has also been shown to accelerate aging via reactive oxygen species-mediated exacerbation of telomere dysfunction. 33 Of note, exacerbated oxidative stress might be a consequence of chronic activation of the autonomic and neuroendocrine stress responses, 13 which is thought to occur in BD. 9 Telomere shortening has also been associated with reduced activity and levels of telomerase, which is the enzyme responsible for catalyzing addition of the necessary telomeric DNA repeats onto the 3 0 ends of the telomere after each cell division.…”

CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

“…Even if they retain long telomeres, CD8+CD27‐ T cells show activated DNA damage responses, specifically persistent DNA damage response associated with dysfunctional telomeres, and mitochondrial dysfunction (Fig. S1), two major characteristics of the senescent phenotype (Passos et al ., 2010; Jurk et al ., 2014). Accordingly, a low ratio of near‐senescent (CD27 − ) to nonsenescent (CD27 + ) CD8T cells also predicted decreased cardiovascular mortality (HR 0.60 [0.41–0.88], P  = 0.01, adjusted for gender, Table S5) although these associations did not remain significant in separate log‐rank analyses for men and women (Fig.…”

“…Our data specify the alterations caused by CMV infection in the lymphocyte compartment that are driving adverse events as those related to cell senescence in the CD4 and CD8 T‐cell compartments. Cell senescence, including immune cell senescence, is associated with telomere dysfunction, MAP kinase activation and mitochondrial dysfunction (Henson et al ., 2009; van de Berg et al ., 2010; Passos et al ., 2010; Lanna et al ., 2013; Jurk et al ., 2014), which in turn cause hyperactivation of NF‐κB‐ and C/EBPβ‐driven secretion of pro‐inflammatory peptides (the so‐called senescence‐associated secretory phenotype or SASP (Coppe et al ., 2008)). Conversely, chronic activation of inflammatory signaling can aggravate the senescent phenotype (Jurk et al ., 2014) and thus contribute to vascular dysfunction and CVD (Wang & Bennett, 2012).…”

Delay discounting, genetic sensitivity, and leukocyte telomere length

“…We first genotype GST pi 1 (GSTP1) single-nucleotide polymorphism (SNP) rs1695, which is extensively linked to inflammatory response (34) and DNA damage (35). As earlier research suggests, inflammatory and oxidative agents play a critical part in telomere shortening, suggesting that such factors may mediate many of the adverse stressors that impinge LTL (36,37). Additionally, we examine two wellstudied estrogen receptor gene SNPs, ESR1 rs3798577 and ESR2 rs2978381, which are associated with endocrine abnormalities and cancer (38)(39)(40)(41)(42).…”