Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates.

作者：Lixiao Liu, Zikai Zheng, Wanbang You, Peng Yang, Yifan Wen, Yicheng Qiao, Shuai Ma, Hui Zhang, Shuo Zhang, Gang Xu, Chen Ma, Aodi Tian, Mengmeng Jiang, Tongtong Zhang, Lingling Geng, Jingyi Li, Xiaoyan Sun, Feibo Wang, M. Xiong, Yuanhan Yang, Xiaoyong Lu, Xiaoyu Jiang, Xueda Dong, Zhiyi Zhang, Ying Huang, Baohu Zhang, Qin Qiao, Shuhui Sun, Yanling Fan, Yusheng Cai, K. Yan, Yiyuan Zhang, Y. Jing, Yaobin Jing, Qiaoran Wang, Jinghui Lei, Ansheng Tan, Zichu Han, P. Reddy, Amin Haghani, Concepcion Rodriguez Esteban, Feng Zhang, Zhili Liu, Ning Liu, Si Wang, Steve Horvath, Jiayin Yang, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Guang-Hui Liu · 发表于：Cell Metabolism · 年份：2026 · DOI：10.1016/j.cmet.2026.02.010 · 被引用次数：16 · 研究领域：Medicine

Aging is associated with oxidative stress, but specific druggable pathways remain elusive. Here, we define a conserved iron-lipid axis driving primate aging, termed "ferro-aging." Multi-tissue profiling in humans and non-human primates reveals age-progressive iron accumulation, fueling chronic lipid peroxidation orchestrated by acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4). Distinct from acute ferroptosis, this ACSL4-mediated process promotes cellular senescence and systemic functional decline. The therapeutic inhibition of hepatic ACSL4 via gene editing alleviates aging phenotypes in mice. Through functional screening and target engagement studies, we identify vitamin C (VC) as a direct inhibitor of ACSL4. Long-term VC administration in aged monkeys for over 40 months potently reduces ferro-aging signatures across tissues, attenuates multi-organ pathology, and improves neurological and metabolic functions. Multi-omic aging clocks indicate the VC-mediated reversal of biological age. Our work establishes ferro-aging as a core, targetable mechanism of primate aging and positions VC as a translatable geroprotective strategy through ACSL4 inhibition.