Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates

Lixiao Liu; Zikai Zheng; Wanbang You; Peng Yang; Yifan Wen; Yicheng Qiao; Shuai Ma; Hui Zhang; Shuo Zhang; Gang Xu; Chencan Ma; Ao Tian; Mengmeng Jiang; Tongtong Zhang; Lingling Geng; Jingyi Li; Xiaoyan Sun; Feibo Wang; Muzhao Xiong; Yuanhan Yang; Xiaoyong Lu; Xiaoyu Jiang; Xueda Dong; Zhiyi Zhang; Ying Huang; Baohu Zhang; Qin Qiao; Shuhui Sun; Yanling Fan; Yusheng Cai; Kaowen Yan; Yiyuan Zhang; Ying Jing; Yaobin Jing; Qiaoran Wang; Jinghui Lei; Ansheng Tan; Zichu Han; Pradeep 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

doi:10.1016/j.cmet.2026.02.010

Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates

Cell Metab. 2026 Apr 7;38(4):673-693.e17. doi: 10.1016/j.cmet.2026.02.010. Epub 2026 Mar 11.

Authors

Lixiao Liu¹, Zikai Zheng¹, Wanbang You², Peng Yang¹, Yifan Wen², Yicheng Qiao³, Shuai Ma⁴, Hui Zhang⁵, Shuo Zhang¹, Gang Xu⁶, Chencan Ma³, Ao Tian², Mengmeng Jiang⁷, Tongtong Zhang⁸, Lingling Geng⁹, Jingyi Li⁴, Xiaoyan Sun¹, Feibo Wang¹⁰, Muzhao Xiong¹¹, Yuanhan Yang², Xiaoyong Lu¹, Xiaoyu Jiang², Xueda Dong¹², Zhiyi Zhang¹³, Ying Huang¹⁴, Baohu Zhang², Qin Qiao¹¹, Shuhui Sun⁵, Yanling Fan¹¹, Yusheng Cai⁷, Kaowen Yan⁷, Yiyuan Zhang¹⁵, Ying Jing⁹, Yaobin Jing¹⁶, Qiaoran Wang¹¹, Jinghui Lei⁹, Ansheng Tan¹⁷, Zichu Han¹, Pradeep Reddy¹⁸, Amin Haghani¹⁹, Concepcion Rodriguez Esteban¹⁸, Feng Zhang²⁰, Zhili Liu²¹, Ning Liu³, Si Wang²², Steve Horvath¹⁹, Jiayin Yang⁶, Juan Carlos Izpisua Belmonte¹⁸, Weiqi Zhang²³, Jing Qu²⁴, Guang-Hui Liu²⁵

Affiliations

¹ China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁴ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
⁵ Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
⁶ Liver Transplant Center, Organ Transplant Center, Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610041, China; Laboratory of Liver Transplantation, Institute of Organ Transplantation, Key Laboratory of Transplant Engineering and Immunology, National Humanities Center, West China Hospital of Sichuan University, Chengdu 610041, China.
⁷ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
⁸ Department of Breast Plastic Surgery, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100000, China.
⁹ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
¹⁰ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
¹¹ China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
¹² State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
¹³ State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
¹⁴ Department of Neurology, Renji Hospital, Chongqing University, Chongqing 400061, China.
¹⁵ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
¹⁶ Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education, International Center for Aging and Cancer, Hainan Medical University, Haikou 571199, China.
¹⁷ Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
¹⁸ Altos Labs San Diego Institute of Science, San Diego, CA 92121, USA; Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
¹⁹ Altos Labs San Diego Institute of Science, San Diego, CA 92121, USA.
²⁰ Division of Orthopaedics, Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou 324000, China.
²¹ Department of Orthopedic Surgery, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
²² Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
²³ China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: zhangwq@big.ac.cn.
²⁴ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China; Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
²⁵ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Human Organ Physiopathology Emulation System, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 41819088
DOI: 10.1016/j.cmet.2026.02.010

Abstract

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.

Keywords: ACSL4; NRF2; aging; ferro-aging; iron; primate; senescence; vitamin C.

MeSH terms

Aging* / drug effects
Aging* / metabolism
Animals
Ascorbic Acid* / pharmacology
Cellular Senescence / drug effects
Coenzyme A Ligases* / antagonists & inhibitors
Coenzyme A Ligases* / genetics
Coenzyme A Ligases* / metabolism
Female
Ferroptosis / drug effects
Humans
Iron / metabolism
Lipid Peroxidation / drug effects
Liver / drug effects
Liver / metabolism
Long-Chain-Fatty-Acid-CoA Ligase
Male
Mice
Primates

Substances

Coenzyme A Ligases
Ascorbic Acid
Iron
Long-Chain-Fatty-Acid-CoA Ligase