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

Abstract

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