Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates

IF 37 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2026-03-11 DOI:10.1016/j.cmet.2026.02.010

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, Guang-Hui Liu

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引用次数: 0

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.

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维生素C抑制ACSL4减轻灵长类动物铁老化

衰老与氧化应激有关，但具体的药物途径仍然难以捉摸。在这里，我们定义了一个保守的铁脂轴驱动灵长类动物衰老，称为“铁老化”。人类和非人类灵长类动物的多组织分析显示，随着年龄的增长，铁积累加剧了酰基辅酶A （CoA）合成酶长链家族成员4 （ACSL4）的慢性脂质过氧化。与急性铁下垂不同，acsl4介导的这一过程促进细胞衰老和全身功能下降。通过基因编辑对肝脏ACSL4的治疗性抑制可缓解小鼠的衰老表型。通过功能筛选和靶标参与研究，我们确定维生素C （VC）是ACSL4的直接抑制剂。老年猴子长期服用VC超过40个月，可有效减少各组织的铁老化特征，减轻多器官病理，改善神经和代谢功能。多组学衰老时钟表明vc介导的生物年龄逆转。我们的工作确定了铁老化是灵长类动物衰老的核心，可靶向机制，并将VC作为一种可翻译的通过ACSL4抑制的衰老保护策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.