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

Fenofibrate treatment delays systemic aging in multiple mouse models of aging.

• Three distinct aging models were used: D-galactose-induced aging mice, 18-month-old naturally aged mice, and SAMP8 mice (a senescence-accelerated mouse strain).
• Fenofibrate is a clinically approved drug currently used for hyperlipidemia treatment.
• The study assessed systemic aging outcomes across these models using histological and metabolic analyses.

Fenofibrate reverses cellular senescence in vitro.

• The anti-aging effects were demonstrated in both cellular and animal models.
• Cellular senescence reversal was validated through comprehensive metabolic analyses.
• Lipidomic profiling and histological analyses were used to characterize senescence-related changes.

Fenofibrate ameliorates age-related lipid accumulation in both cellular and animal models.

• Lipid accumulation changes were evidenced by lipidomic profiling.
• Histological analyses confirmed lipid changes in both cellular and animal models.
• Age-related lipid accumulation was identified as a fundamental aging process targeted by fenofibrate.

CPT1C (carnitine palmitoyl transferase 1C) was identified as a crucial mediator of fenofibrate's ability to restore mitochondrial function in senescent cells.

• CPT1C is identified as a novel therapeutic target for age-related metabolic dysfunction.
• The role of CPT1C was validated by comprehensive metabolic analyses.
• CPT1C is a downstream metabolic regulator upregulated by PPARα activation.
• This represents the first identification of CPT1C as a mediator of fenofibrate's anti-aging effects.

The anti-aging effects of fenofibrate are strictly PPARα-dependent, as fenofibrate cannot reverse aging in Pparα-/- mice.

• Pparα knockout (Pparα-/-) mice were used to establish mechanistic dependency.
• Fenofibrate failed to exert anti-aging effects in Pparα-/- mice.
• Fenofibrate is described as a specific PPARα agonist.
• PPARα is established as a master metabolic regulator of aging processes based on these findings.

Fenofibrate attenuates mitochondrial dysfunction in senescent cells and aged mice through the PPARα-CPT1C axis.

• Mitochondrial function restoration was validated by comprehensive metabolic analyses.
• The mechanism involves PPARα activation leading to upregulation of downstream CPT1C.
• Both cellular senescence models and aged mouse models showed mitochondrial dysfunction attenuation.
• This represents coordinated improvement of lipid metabolism and mitochondrial function.

This study provides the first evidence that pharmacological PPARα activation can directly modulate natural aging.

• The modulation occurs through coordinated improvement of lipid metabolism and mitochondrial function.
• The study used naturally aged 18-month-old mice as one model to demonstrate effects on natural aging.
• Prior to this work, direct modulation of natural aging by PPARα activation had not been demonstrated.