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 lifespan. Further, targeting FcRn by antisense oligonucleotide restores WAT integrity and metabolic health in aged mice. These findings pinpoint IgG as a hidden culprit in aging and enlighten a novel strategy to rejuvenate metabolic health.

新陈代谢明显下降是衰老的基础；然而，驱动因素仍然不明。在这里，我们报告说，IgG 在衰老过程中积累，特别是在白色脂肪组织 (WAT) 中，从而损害脂肪组织功能和代谢健康。热量限制 (CR) 会减少 WAT 中 IgG 的积累，而补充 IgG 则会抵消 CR 的代谢益处。 IgG 通过 Ras 信号传导激活巨噬细胞，从而通过 TGF-β/SMAD 途径诱导 WAT 纤维化。一致的是，B 细胞缺失小鼠可以免受与衰老相关的 WAT 纤维化、炎症和胰岛素抵抗的影响，除非暴露于 IgG。有条件地消除巨噬细胞中的 IgG 回收受体、新生儿 Fc 受体 (FcRn) 可防止 IgG 在衰老过程中积累，从而延长健康寿命和寿命。此外，通过反义寡核苷酸靶向 FcRn 可恢复老年小鼠 WAT 的完整性和代谢健康。这些发现明确指出 IgG 是衰老的隐藏罪魁祸首，并启发了一种恢复代谢健康的新策略。