Urolithin A Provides Cardioprotection and Mitochondrial Quality Enhancement Preclinically and Improves Cardiovascular Health Biomarkers in Humans [mouse_cardiac_aging]

Cardiovascular diseases (CVDs) remain the primary cause of global mortality. Nutritional interventions hold promise to reduce CVD risks in an increasingly aging population. However, few nutritional interventions are proven to support heart health and act mostly on blood lipid homeostasis rather than at cardiac cell level. Here, we show that mitochondrial quality and dysfunction are a common hallmark in human cardiomyocytes upon heart aging and in chronic conditions. Preclinically, the post-biotic and mitophagy activator, Urolithin A (UA), reduced both systolic and diastolic cardiac dysfunction in models of natural aging and heart failure. At a cellular level, this was associated with a recovery of mitochondrial ultrastructural defects and mitophagy. In humans, UA supplementation for 4 months in healthy older adults significantly reduced plasma ceramides clinically validated to predict CVD risks. These findings extend and translate UA's benefits to heart health, making UA a promising nutritional intervention to support cardiovascular function as we age. Overall design: .Twenty-four male C57BL/6Rj mice aged 21 months old and eighteen male C57BL/6Rj mice aged 8 weeks old were purchased from Janvier Labs (France). Mice were collectively housed in cages in controlled room at 22°C and 12 h light/ dark cycle at Biomeostasis' facilities. All animals were allowed ad libitium access to an irradiated normal chow diet (NC, irradiated pellet A04; SAFE, Villemoisson-sur-Orge, France) and to ultrapure and laboratory-grade acidified water (Aquavive®, INNOVIVE, France). For 8 weeks, 21-months-old and 8-week-old mice were treated by oral gavage, either with a vehicle solution (0.5% carboxymethylcellulose) (21 months vehicle, n=12 or 8 weeks vehicle n=9) or with UA at 50mg/ml (21 months UA, n=12 or 8 weeks UA, n=9). One day after the last dosing, overnight-fasted mice were anaesthetized by Isoflurane. The hearts were collected, weighed and the LV and RV were separated. LV was embedded in OCT. Excess OCT was trimmed away from the frozen tissues block with a sterile scalpel blade.