Fenofibrate targets PPARα-CPT1C axis to reverse aging by regulating lipid metabolism and mitochondrial function

Aging poses a growing global health burden, creating an urgent need for effective interventions. This study reveals that fenofibrate, a clinically approved drug for hyperlipidemia, exerts significant anti-aging effects by targeting fundamental aging processes. We demonstrated that fenofibrate treatment delays systemic aging in D galactose-induced aging mice, 18-month-old mice and SAMP8 mice and reverses cellular senescence. Mechanistically, fenofibrate ameliorates age-related lipid accumulation, as evidenced by lipidomic profiling and histological analyses in both cellular and animal models. Notably, we identify carnitine palmitoyl transferase 1 C (CPT1C) as a crucial mediator of fenofibrate's ability to restore mitochondrial function in senescent cells, as validated by comprehensive metabolic analyses. Fenofibrate is a specific peroxisome proliferator activated receptor α (PPARα) agonist. These effects are mediated through PPARα activation, upregulating downstream metabolic regulators CPT1C. Fenofibrate cannot reverse aging in Pparα -/- mice, establishing that its anti-aging effects are strictly PPARα-dependent. Our findings demonstrate that fenofibrate delays aging progression of mice and reverses cellular senescence in the PPARα-dependent way. Fenofibrate attenuates lipid accumulation and mitochondrial dysfunction in senescent cells and aged mice by activating the PPARα-CPT1C axis. This research provided the first evidence that pharmacological PPARα activation can directly modulate natural aging through coordinated improvement of lipid metabolism and mitochondrial function. The clinical relevance is underscored by the safety profile and widespread use of fenofibrate, suggesting its immediate potential as a repurposed anti-aging therapeutic. Furthermore, this work establishes PPARα as a master metabolic regulator of aging processes and reveals CPT1C as a novel therapeutic target for age-related metabolic dysfunction. • Fenofibrate delays systemic natural aging in multiple aging mice models. • PPARα directly reversed natural aging through lipid and mitochondrial metabolism. • The PPARα-CPT1C axis is a novel therapeutic target for age-related dysfunction.