# Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age‐Associated Metabolic Abnormalities

## TL;DR

This study shows that targeting KDM5A in blood vessel cells can slow aging and improve age-related metabolic issues.

## Contribution

The study identifies the KDM5A/FABP4 axis as a novel therapeutic target for vascular aging and metabolic disorders.

## Key findings

- KDM5A deficiency in endothelial cells worsens aging and metabolic abnormalities in mice.
- Restoring KDM5A levels or inhibiting FABP4 reverses these effects and extends lifespan.
- KDM5A regulates fatty acid metabolism by controlling H3K4me3 enrichment at the FABP4 promoter.

## 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.

This study identifies endothelial KDM5A as a key regulator of aging. KDM5A deficiency accelerates aging by enhancing H3K4me3‐mediated FABP4 expression, disrupting fatty acid metabolism, and promoting multi‐organ senescence. KDM5A restoration or FABP4 inhibition reverses these adverse effects and extends lifespan, positioning the KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and metabolic disorders.