Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age‐Associated Metabolic Abnormalities
Year: 2025
Type: article
Abstract: Vascular aging accelerates the gradual deterioration of systemic organ function, yet its key driving factors are still largely unexplored. Here, it is demonstrated that lysine-specific demethylase 5A (KDM5A) decreases and histone H3 lysine 4 (H3K4me3) increases in vascular endothelial cells (VECs) isolated from ageing mice and VEC senescence models. KDM5A deficiency exacerbated endothelial cell aging in vitro. Endothelial-specific KDM5A-deficient mice exhibit shortened lifespan and multiple senescent phenotypes, including fat accumulation, reduced thermogenic capacity, skeletal kyphosis, and age-related liver lesions, while maintaining VECs-specific KDM5A levels attenuates these adverse metabolic abnormalities and prolongs lifespan. Mechanistically, endothelial KDM5A deficiency aggravates aging-associated fatty acid (FA) metabolism disorders by enhancing H3K4me3 enrichment at the promoter region of FA-binding protein 4 (FABP4), which leads to active FABP4 transcription. Together, the study reveals the regulatory mechanisms of KDM5A in age-dependent metabolic disorders and identifies KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and related organ dysfunction.
Source: Advanced Science
Authors: Rifeng Gao, Lifeng Liang, Ling Yang, Chunyu Lyu, Yang Lyu, Weijun Yang, Jiaran Shi, Wei Wei, Jiahui Cheng, Xiaolei Sun, Xian Zhu, Chao Chen, Xiaoting Xu, Jianchuang Qi, Wenli Li, Yizhe Zhang, Xiao Zhang, Yan Zhou, Aiqiang Dong, Juntao Chen, Bo Li, Kun Yang
Institutions: Second Affiliated Hospital of Zhejiang University, Zhejiang University, Capital Medical University, Beijing Friendship Hospital, Shanghai Jiao Tong University, Shanghai Chest Hospital, Zhejiang Chinese Medical University, Shanghai Medical College of Fudan University, Fudan University, Ningbo University, Ningbo Medical Center Lihuili Hospital, Renji Hospital, Zhongshan Hospital
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
Awards: G27705873, G3260616131, G6801920265
OpenAlex ID: W4416208307