Abstract
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.
MeSH terms
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Adenine / pharmacology
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Adult
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Aged
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Aged, 80 and over
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Aging / genetics*
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Aging / immunology
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Animals
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Blood Platelets / drug effects
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Blood Pressure / drug effects
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / immunology
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Caffeine / pharmacology
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / immunology
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Carotid Intima-Media Thickness
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Cell Line
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Cytidine / analogs & derivatives
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Cytidine / pharmacology
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Cytokines / immunology
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Cytokines / metabolism
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Female
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Humans
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Hypertension / genetics*
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Hypertension / immunology
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Immunoblotting
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Inflammasomes / genetics*
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Inflammasomes / immunology
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Inflammation / genetics*
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Inflammation / immunology
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin 1 Receptor Antagonist Protein / immunology
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Macrophages / immunology
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Male
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Metabolomics
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Mice
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Middle Aged
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Monocytes / drug effects
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Mortality
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Neutrophil Activation / drug effects
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Neutrophils / drug effects
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Nucleotides / metabolism
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Oxidative Stress / genetics
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Oxidative Stress / immunology
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Phenotype
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Platelet Activation / drug effects
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Pulse Wave Analysis
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Purinergic P1 Receptor Antagonists / pharmacology
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Regression Analysis
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Toll-Like Receptor 5 / genetics
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Toll-Like Receptor 5 / immunology
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Toll-Like Receptor 6 / genetics
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Toll-Like Receptor 6 / immunology
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Toll-Like Receptor 8 / genetics
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Toll-Like Receptor 8 / immunology
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Transcriptome
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Vascular Stiffness / genetics*
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Vascular Stiffness / immunology
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Young Adult
Substances
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins
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Cytokines
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IL1B protein, human
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IL1B protein, mouse
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IL1RN protein, human
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Inflammasomes
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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NLRC4 protein, human
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NLRC5 protein, human
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Nucleotides
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Purinergic P1 Receptor Antagonists
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TLR5 protein, human
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TLR6 protein, human
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TLR8 protein, human
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Toll-Like Receptor 5
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Toll-Like Receptor 6
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Toll-Like Receptor 8
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N-acetylcytidine
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Caffeine
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Cytidine
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Adenine