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. [ABSTRACT FROM AUTHOR]