Abstract
Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1-/- mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.
Highlights
Modest aerobic exercise suppresses cellular senescence and tumor development We have previously described how the inflammaging phenotype of nfkb12/2 mice leads to development of chronic liver disease and premature aging, resulting in early mortality at around 20 mo [10, 14]
Histological examination of the livers of nfkb12/2 mice at an earlier age of 16 mo revealed the presence of inflammation and steatosis, which became progressively more severe by 19 mo (Fig. 1A)
We detected fewer numbers of hepatocytes carrying damaged telomeres (Fig. 1D); this was assessed by fluorescence in situ hybridization for telomere-associated DNA damage foci (TAF), which is an established quantifiable marker for stable telomere DNA damage and senescence [3, 10]
Summary
Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. We report that modest exercise rebalances preestablished inflammatory and metabolic disturbances in aged nfkb12/2 mice, reverses hepato-steatosis, suppresses cellular senescence, and prevents liver tumorigenesis.
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