Dietary protein restriction ameliorates cardiac inflammaging via AMPK-ULK1-mediated mitochondrial quality control

Authors: DANTAS, WAGNER - Pennington Biomedical Research Center; ZUNICA, ELIZABETH - Pennington Biomedical Research Center; HEINTZ, ELIZABETH - Pennington Biomedical Research Center; HOPPEL, CHARLES - Pennington Biomedical Research Center; HILL, CHRISTAL - Pennington Biomedical Research Center; MORRISON, CHRISTOPHER - Pennington Biomedical Research Center; AXELROD, CHRISTOPHER - Pennington Biomedical Research Center; Davuluri, Gangarao; KIRWAN, JOHN - Pennington Biomedical Research Center

Submitted to: Aging Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2026
Publication Date: 1/18/2026
Citation: Dantas, W., Zunica, E., Heintz, E., Hoppel, C., Hill, C., Morrison, C., Axelrod, C., Davuluri, G., Kirwan, J. 2026. Dietary protein restriction ameliorates cardiac inflammaging via AMPK-ULK1-mediated mitochondrial quality control. Aging Cell. 25(2). Article e70386. https://doi.org/10.1111/acel.70386.
DOI: https://doi.org/10.1111/acel.70386

Interpretive Summary: Cardiovascular disease (CVD) is the leading cause of death, accounting 17.3 million globally. It is well established that excessive dietary fat intake has been linked to increased risk of obesity, coronary heart disease and stroke. A variety of diet approaches have been proposed for the prevention and treatment of obesity. Recent studies have shown that low protein diet promotes healthy aging in people with obesity. However, the beneficial effects of protein restriction in obese and aging people are unknown. The current study identifies that low protein diet in obese mice leads to reduced inflammation which improves heart function. Considering the epidemiological data on CVD prevalence, dietary interventions play a crucial role in healthy aging. The current study identifies protein restriction in obese aging mice significantly improves heart health and the mice lived longer, thus low protein diet is expected to play a positive role in managing obesity.

Technical 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 restric¬tion (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-'. 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 inflamma¬tion and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.