Longevity & AgingSIRT1 Loss Drives Age-Related Heart Failure by Triggering Ferroptosis in Cardiomyocytes
Researchers identified a critical pathway linking aging, metabolic dysfunction, and a form of iron-dependent cell death called ferroptosis in the failing heart. In aged rats and mice, declining SIRT1 expression suppresses the transcription factor GATA4, which in turn reduces levels of the mitochondrial enzyme HADHA. Low HADHA triggers mitochondrial dysfunction, oxidative stress, glutathione depletion, and suppression of GPX4—the master ferroptosis gatekeeper—culminating in cardiomyocyte death and heart failure. Pharmacological SIRT1 activation with resveratrol, or cardiomyocyte-specific SIRT1/GPX4 gene delivery, restored this axis, suppressed ferroptosis, and preserved cardiac function, establishing the SIRT1–GATA4–HADHA pathway as a promising therapeutic target in age-related heart failure.
