Key Points
Moderate exercise reduces inflammaging, liver tumors, and chronic liver disease.
Key molecular changes include lipid metabolism, oxidative damage, and senescence.
Increased NAD+, sirtuin activity, and inflammatory and metabolic reprogramming occur.
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.
Footnotes
↵1 D.A.M. and C.L.W. are joint last authors.
This work was supported by Cancer Research U.K. Programme Grant C18342/A23390 and Medical Research Council (MRC) Programme Grants MR/K0019494/1 and MR/R023026/1 (to D.A.M.). A.B. was funded by the MRC and U.K. Research and Innovation Centre for Ageing and Vitality at Newcastle University Award MR/L016354. J.F.P. and D.J. were funded by National Institute for Health Research Grant P01AG62413.
The online version of this article contains supplemental material.
- Received September 4, 2020.
- Accepted December 3, 2020.
- Copyright © 2021 The Authors
This article is distributed under the terms of the CC BY 4.0 Unported license.