title: Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states.
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.
authors.affiliation: Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.|Department of Systems Biology, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: David
authors.initials: D
authors.lastname: Furman
authors.affiliation: Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Junlei
authors.initials: J
authors.lastname: Chang
authors.affiliation: INSERM U916 VINCO, Institut Bergonié, Bordeaux Cedex, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Lartigue
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bolen
authors.affiliation: Institute of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: François
authors.initials: F
authors.lastname: Haddad
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Brice
authors.initials: B
authors.lastname: Gaudilliere
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ganio
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Gabriela K
authors.initials: GK
authors.lastname: Fragiadakis
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Spitzer
authors.affiliation: CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Douchet
authors.affiliation: CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Daburon
authors.affiliation: CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Moreau
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.affiliation: CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanco
authors.affiliation: CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Déchanet-Merville
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Stanford University, Stanford, California, USA.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Dekker
authors.affiliation: Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jojic
authors.affiliation: Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Kuo
authors.affiliation: Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: CIRID, UMR CNRS 5164, Université Bordeaux 2, Bordeaux Cedex, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Faustin
mesh_terms: D000225:Adenine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology; D002110:Caffeine / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000276:immunology; D059168:Carotid Intima-Media Thickness; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000276:immunology; D015151:Immunoblotting; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D055432:Metabolomics; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects; D009026:Mortality; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D009711:Nucleotides / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D015539:Platelet Activation / Q000187:drug effects; D063177:Pulse Wave Analysis; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D012044:Regression Analysis; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000235:genetics / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology; D059467:Transcriptome; D059289:Vascular Stiffness / Q000235:genetics* / Q000276:immunology; D055815:Young Adult
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D016207:Cytokines; C508585:IL1B protein, human; C587672:IL1B protein, mouse; C507763:IL1RN protein, human; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C435692:NLRC4 protein, human; C548042:NLRC5 protein, human; D009711:Nucleotides; D058915:Purinergic P1 Receptor Antagonists; C495346:TLR5 protein, human; C495368:TLR6 protein, human; C495349:TLR8 protein, human; D051198:Toll-Like Receptor 5; D051216:Toll-Like Receptor 6; D051200:Toll-Like Receptor 8; C017816:N-acetylcytidine; D002110:Caffeine; D003562:Cytidine; D000225:Adenine