biostudies-literatureYu LNIDDK NIH HHSNIDDK793-807.e5https://www.ebi.ac.uk/biostudies/studies/S-EPMC11070064biostudies-literatureUnknown36(4)Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-β/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespaCell metabolismIgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.PMC11070064R01 DK112943P30 DK063608R01 DK134471Yu LWan QZha SSkowronski AAFan YZhou QQue JLiu QKennedy BKDing LWang LSun LLeDuc CAShao ZWang SLiao CYQiang LfalseIgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-β/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespa2024-01-01T00:00:00Z2024 Apr2026-07-15T11:10:25.997Z2025-07-14T03:02:23.398ZS-EPMC110700643837800110.1016/j.cmet.2024.01.015