HMGCS2-PPARα signaling activates the prolongevity gene CISD2 to delay liver aging

Here, we identify an HMGCS2-PPARα signaling pathway that regulates the prolongevity gene CISD2 and liver aging. Using naturally aged mice, we show that late-life administration of the citrus flavonoid hesperetin restores hepatic CISD2 expression, improves liver pathology, and partially reverses aging-associated transcriptomic alterations.

Mechanistically, we identify HMGCS2 as a molecular target of hesperetin and demonstrate that HMGCS2 interacts with PPARα to activate CISD2 transcription through a PPAR response element (PPRE) in the CISD2 promoter. Genetic and transcriptomic analyses reveal that the protective effects of hesperetin are largely CISD2-dependent, as they are significantly attenuated in hepatocyte-specific Cisd2 knockout mice. Consistent with these findings, PPARα and CISD2 expression decline with age in human liver tissues.