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

Area of Science:

• Gerontology and metabolic research.
• Pharmacological interventions for aging.

Background:

• Aging is a global health challenge requiring effective interventions.
• Fenofibrate is an approved drug for hyperlipidemia.
• Cellular senescence and metabolic dysfunction are hallmarks of aging.

Purpose of the Study:

• To investigate the anti-aging effects of fenofibrate.
• To elucidate the molecular mechanisms underlying fenofibrate's action.
• To explore fenofibrate's potential as a repurposed anti-aging therapeutic.

Main Methods:

• Fenofibrate treatment in various mouse models of aging (D-galactose induced, aged, SAMP8).
• Lipidomic profiling and histological analysis to assess lipid accumulation.
• Metabolic analyses to evaluate mitochondrial function and CPT1C activity.
• Experiments in Pparα knockout mice to confirm PPARα dependency.

Main Results:

• Fenofibrate treatment delayed systemic aging and reversed cellular senescence in mice.
• Fenofibrate ameliorated age-related lipid accumulation and mitochondrial dysfunction.
• Carnitine palmitoyl transferase 1C (CPT1C) was identified as a key mediator, upregulated by fenofibrate via PPARα activation.
• Anti-aging effects were strictly dependent on PPARα, as fenofibrate had no effect in Pparα knockout mice.

Conclusions:

• Fenofibrate exhibits significant anti-aging properties by activating the PPARα-CPT1C axis.
• This activation improves lipid metabolism and mitochondrial function, counteracting key aging processes.
• Fenofibrate represents a promising, readily available therapeutic for aging, with PPARα as a master regulator and CPT1C as a novel target.