Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK‐ULK1‐Mediated Mitochondrial Quality Control

TL;DR

Reducing dietary protein helps protect the aging heart from obesity-related inflammation by improving mitochondrial health through AMPK-ULK1 signaling.

Contribution

This study reveals a novel mechanism by which dietary protein restriction supports mitochondrial quality control and reduces cardiac inflammation.

Findings

DPR reduced cardiac hypertrophy and heart failure markers in obese middle-aged mice.

DPR suppressed cGAS–STING pathway activation and mitochondrial DNA release into the cytosol.

AMPK–ULK1 signaling was identified as a key driver of mitophagy and mitochondrial homeostasis in cardiomyocytes.

Abstract

Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age‐related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity‐induced cardiac remodeling and inflammaging by activating the AMPK–ULK1 signaling axis and enhancing mitochondrial quality control. In middle‐aged male mice with high‐fat diet‐induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS–STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro‐inflammatory mediators, including IRF3 and IFN‐γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK‐dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity‐mediated inflammaging.

Dietary protein restriction protects the aging heart in the context of obesity by limiting mitochondrial DNA leakage and suppressing cGAS–STING‐driven inflammation. Through AMPK–ULK1‐dependent mitophagy, protein restriction restores mitochondrial quality control, reduces cardiac remodeling, and preserves metabolic homeostasis during obesity‐associated aging.

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