Malic enzyme 1 reverses cardiomyocyte senescence in a nitric oxide-dependent manner

Progressive cardiac aging represents a major risk factor for heart diseases in the elderly population. Malic enzyme 1 (ME1) is an important regulator of redox homeostasis in multiple organs. However, the relationship and underlying mechanism between ME1 and cardiomyocyte senescence in aged heart have not yet been described. Here, we reveal that murine hearts and cardiomyocytes demonstrate age-dependent up-regulation of Me1 gene and protein. Mice with cardiomyocyte-specific Me1 ablation exhibit increased oxidative stress and aggravated heart aging under D-galactose (D-gal) treatment. Moreover, loss of cardiac Me1 also damages heart structure and function during natural aging processes. Supplementation with L-malate (LM), the substrate of ME1, significantly prevents cardiomyocyte senescence both in vitro and in vivo. Mechanistically, the anti-aging effect of cardiac ME1 is dependent on its product nicotinamide adenine dinucleotide phosphate (NADPH), which promotes the enzymatic formation of nitric oxide (NO). Sufficient NO is essential for longevity, and the inhibition of NO synthase (NOS) abrogates LM-provided cardioprotection. These findings collectively demonstrate that targeting ME1 may offer new preventive or therapeutic insights into the treatment of age-associated cardiovascular diseases.