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DOI 10.1016/j.cmet.2026.02.010

Медицинская библиотека · Cell metabolism · 2026

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

Liu Lixiao, Zheng Zikai, You Wanbang, Yang Peng, Wen Yifan, Qiao Yicheng, Ma Shuai, Zhang Hui, Zhang Shuo, Xu Gang, Ma Chencan, Tian Ao, Jiang Mengmeng, Zhang Tongtong, Geng Lingling, Li Jingyi, Sun Xiaoyan, Wang Feibo, Xiong Muzhao, Yang Yuanhan, Lu Xiaoyong, Jiang Xiaoyu, Dong Xueda, Zhang Zhiyi, Huang Ying, Zhang Baohu, Qiao Qin, Sun Shuhui, Fan Yanling, Cai Yusheng, Yan Kaowen, Zhang Yiyuan, Jing Ying, Jing Yaobin, Wang Qiaoran, Lei Jinghui, Tan Ansheng, Han Zichu, Reddy Pradeep, Haghani Amin, Rodriguez Esteban Concepcion, Zhang Feng, Liu Zhili, Liu Ning, Wang Si, Horvath Steve, Yang Jiayin, Izpisua Belmonte Juan Carlos, Zhang Weiqi, Qu Jing, Liu Guang-Hui

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Аннотация

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.

Для цитирования: Liu Lixiao, Zheng Zikai, You Wanbang, Yang Peng, Wen Yifan, Qiao Yicheng, Ma Shuai, Zhang Hui, Zhang Shuo, Xu Gang, Ma Chencan, Tian Ao, Jiang Mengmeng, Zhang Tongtong, Geng Lingling, Li Jingyi, Sun Xiaoyan, Wang Feibo, Xiong Muzhao, Yang Yuanhan, Lu Xiaoyong, Jiang Xiaoyu, Dong Xueda, Zhang Zhiyi, Huang Ying, Zhang Baohu, Qiao Qin, Sun Shuhui, Fan Yanling, Cai Yusheng, Yan Kaowen, Zhang Yiyuan, Jing Ying, Jing Yaobin, Wang Qiaoran, Lei Jinghui, Tan Ansheng, Han Zichu, Reddy Pradeep, Haghani Amin, Rodriguez Esteban Concepcion, Zhang Feng, Liu Zhili, Liu Ning, Wang Si, Horvath Steve, Yang Jiayin, Izpisua Belmonte Juan Carlos, Zhang Weiqi, Qu Jing, Liu Guang-Hui. Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates.. Cell metabolism. 2026. DOI: 10.1016/j.cmet.2026.02.010.

Предметные рубрики MeSH

AnimalsCoenzyme A LigasesAgingHumansAscorbic AcidLong-Chain-Fatty-Acid-CoA LigaseMiceIronCellular SenescenceLiverFerroptosisMale
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