Low-grade, chronic inflammation has been associated with many diseases of aging, but the mechanisms responsible for producing this inflammation remain unclear. Inflammasomes can drive chronic inflammation in the context of an infectious disease or cellular stress, and they trigger the maturation of interleukin-1β (IL-1β). Here we find that the expression of specific inflammasome gene modules stratifies older individuals into two extremes: those with constitutive expression of IL-1β, nucleotide metabolism dysfunction, elevated oxidative stress, high rates of hypertension and arterial stiffness; and those without constitutive expression of IL-1β, who lack these characteristics. Adenine and N4-acetylcytidine, nucleotide-derived metabolites that are detectable in the blood of the former group, prime and activate the NLRC4 inflammasome, induce the production of IL-1β, activate platelets and neutrophils and elevate blood pressure in mice. In individuals over 85 years of age, the elevated expression of inflammasome gene modules was associated with all-cause mortality. Thus, targeting inflammasome components may ameliorate chronic inflammation and various other age-associated conditions.
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We thank the Stanford–Ellison longitudinal cohort volunteers for their participation; Project/Regulatory/Data Manager S. Mackey; Research Nurses S. Swope, C. Walsh, S. French, B. Sullivan, S. Cathey, T. Trela and N. Mastman; Clinical Research Associates A. Goel, T. Quan, K. Span, R. Fleischmann, B. Tse, I. Chang and S. Batra. We also are grateful to The Ellison Medical Foundation for initial support and to the NIH (U19 AI090019) and the Howard Hughes Medical Institute for the remainder (M.M.D.). We also thank H. Maecker and Y. Rosenberg-Hasson (Human Immune Monitoring Core) at Stanford, and R.E. Vance and I. Rauch at the University of California, Berkeley, for kindly providing us with material from NLRC4 and caspase-1 knockout mice. B.F., J.D-M. and J.F.M. were funded by Fondation pour la Recherche Médicale (DEQ20110421287), INCa-Cancéropôle GSO, Ligue contre le Cancer de la Dordogne, and the Conseil Régional d'Aquitaine. We thank the Metabolon Inc. for the metabolite analysis.
The authors declare no competing financial interests.
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Furman, D., Chang, J., Lartigue, L. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 23, 174–184 (2017). https://doi.org/10.1038/nm.4267
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