Lexiang Yu, Qianfen Wan, Qiongming Liu, Yong Fan, Qiuzhong Zhou, Alicja A Skowronski, Summer Wang, Zhengping Shao, Chen-Yu Liao, Lei Ding, Brian K Kennedy, Shan Zha, Jianwen Que, Charles A LeDuc, Lei Sun, Liheng Wang, Li Qiang
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引用次数: 0
摘要
衰老的基础是明显的新陈代谢衰退;然而,衰老的驱动因素仍然模糊不清。在这里,我们报告了 IgG 在衰老过程中的积累,尤其是在白色脂肪组织(WAT)中的积累,从而损害了脂肪组织的功能和代谢健康。热量限制(CR)会减少 IgG 在白脂肪组织中的积累,而补充 IgG 则会抵消 CR 带来的代谢益处。IgG 通过 Ras 信号激活巨噬细胞,从而通过 TGF-β/SMAD 途径诱导脂肪组织纤维化。一致的是,除非暴露于 IgG,否则 B 细胞无效小鼠不会出现与衰老相关的 WAT 纤维化、炎症和胰岛素抵抗。条件性消减巨噬细胞中的 IgG 循环受体--新生儿 Fc 受体(FcRn)可防止衰老过程中的 IgG 累积,从而延长健康和寿命。此外,通过反义寡核苷酸靶向 FcRn 还能恢复老龄小鼠体内 WAT 的完整性和代谢健康。这些发现将 IgG 定义为衰老的隐性罪魁祸首,并启示了一种恢复代谢健康的新策略。
IgG 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 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.