Inhibition of Ferroptosis Delays Aging and Extends Healthspan Across Multiple Species

• DOI: 10.1002/advs.202416559
• Publication Date: 2025-04-01T10:17:37Z
• Authors: Hai‐Jun Fu; Xing‐Yue Zhou; Da‐Lian Qin; Qan Qiao; Qiao‐Zhi Wang; Shi‐Ying Li; Yun‐Fei Zhu; Ya‐Ping Li; Jiang‐Min Zhou; Hui Cai; Fei‐Hong Huang; Lu Yu; Long Wang; An‐Guo Wu; Jian‐Ming Wu; Xiao‐Gang Zhou
• Keywords: Senescence; GPX4; Cognitive Decline

Abstract Ferroptosis, a form of iron‐dependent cell death, plays pivotal role in age‐related diseases; yet, its impact on cellular senescence and healthspan mammals remains largely unexplored. This study identifies ferroptosis as key regulator senescence, showing that inhibition can significantly delay aging extend across multiple species. During is progressively exacerbated, marked by increased lipid peroxidation, oxidative stress, diminished glutathione peroxidase 4 (GPX4) levels. Ferroptosis inducers such Erastin RSL3 accelerate senescence; while, inhibitors liproxstatin‐1 (Lip‐1) ferrostatin‐1 (Fer‐1) effectively mitigate both chemically replicatively induced senescence. In vivo, Fer‐1 extends lifespan Caenorhabditis elegans , enhances motor function, preserves tissue integrity, mitigates cognitive decline prematurely naturally aged mice. These effects are attributed to Fer‐1's upregulation GPX4 ferroptosis. Notably, long‐term treatment (over 6 months) does not adversely affect body weight or induce aging‐related damage but rejuvenates hematological parameters. findings establish critical player dynamics highlight promising strategy lifespan, providing valuable insights for translational approaches combat decline.