The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging

The risk of chronic diseases caused by aging is reduced by caloric restriction (CR)-induced immunometabolic adaptation. Here, we found that the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), was inhibited by 2 years of 14% sustained CR in humans and elevated by obesity. SPARC converted anti-inflammatory macrophages into a pro-inflammatory phenotype with induction of interferon-stimulated gene (ISG) expression via the transcription factors IRF3/7. Mechanistically, SPARC-induced ISGs were dependent on toll-like receptor-4 (TLR4)-mediated TBK1, IRF3, IFN-β, and STAT1 signaling without engaging the Myd88 pathway. Metabolically, SPARC dampened mitochondrial respiration, and inhibition of glycolysis abrogated ISG induction by SPARC in macrophages. Furthermore, the N-terminal acidic domain of SPARC was required for ISG induction, while adipocyte-specific deletion of SPARC reduced inflammation and extended health span during aging. Collectively, SPARC, a CR-mimetic adipokine, is an immunometabolic checkpoint of inflammation and interferon response that may be targeted to delay age-related metabolic and functional decline. [Display omitted] •Caloric restriction in humans decreases matricellular protein SPARC in adipose•SPARC stimulates interferon response in macrophage via glycolysis and IRF7•SPARC converts M2 macrophages to M1 macrophages by activating TLR4•Depletion of SPARC in adipocyte decreases “inflammaging” and extends health span Caloric restriction (CR) reduces inflammation and enhances longevity, but the identity of CR-mimetics that improve health span is unclear. Ryu et al. reveal that sustained CR in humans reduces adipose SPARC. Elevation of SPARC promotes interferon-response and inflammation, while reduction of SPARC in adipocytes protects against aging-related inflammation and metabolic dysfunction.