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.

热量限制（CR）诱导的免疫代谢适应可以降低因衰老引起的慢性疾病的风险。在这里，我们发现基质细胞蛋白（富含半胱氨酸的酸性分泌蛋白（SPARC））在人类持续 2 年 14% CR 的情况下受到抑制，并因肥胖而升高。SPARC 通过转录因子 IRF3/7 诱导干扰素刺激基因 (ISG) 表达，从而将抗炎巨噬细胞转化为促炎表型。从机制上讲，SPARC 诱导的 ISG 依赖于 Toll 样受体 4 (TLR4) 介导的 TBK1、IRF3、IFN-β 和 STAT1 信号传导，而不参与 Myd88 通路。在代谢方面，SPARC 抑制了线粒体呼吸，而糖酵解的抑制则消除了 SPARC 在巨噬细胞中诱导的 ISG。此外，SPARC 的 N 端酸性结构域是 ISG 诱导所必需的，而脂肪细胞特异性删除 SPARC 可以减少衰老过程中的炎症并延长健康寿命。总的来说，SPARC 是一种 CR 模拟脂肪因子，是炎症和干扰素反应的免疫代谢检查点，可用于延缓与年龄相关的代谢和功能衰退。