Sex- and Age-Dependent Metabolic and Inflammatory Pathways in Cardiomyopathy: The Role of Sirtuins, Inflammaging and Mitochondrial Homeostasis

Aging and biological sex modulate cardiomyopathy through interconnected metabolic, inflammatory and mitochondrial pathways. Aging impairs Sirt1/Sirt3-AMPK signaling, promotes low-grade inflammation and mitochondrial dysfunction, while sex hormones shape dimorphic resilience and vulnerability across the life course. In dilated cardiomyopathy (DCM) and inflammatory cardiomyopathy (DCMI), age aggravates Sirt1 loss, triggers compensatory AMPK activation and reduces mitochondrial proteins (TOM40/TIM23/SOD2), particularly in older men. In DCMI, Sirt1 levels stay stable but processes differ by sex. Older men show increased mitophagy; women have impaired biogenesis. Inflammaging with elevated NF-κB/IL-12 and macrophage infiltration is stronger in men. E2 suppresses NF-κB/ROS via ERα/β and promotes M2 polarization, whereas testosterone enhances PGC-1α-dependent metabolism but amplifies fibrosis. Collectively, these findings define an age-sex framework of cardiomyopathy vulnerability and support precision strategies targeting sirtuins, inflammasomes and hormone-related pathways to slow or modify disease progression.