Mitochondrial metabolism and epigenetic crosstalk drive the SASP (RNA-Seq_2)

Senescent cells drive age-related tissue dysfunction largely through the persistent activation of the senescence-associated secretory phenotype (SASP). Here, we identify key mitochondrial metabolic pathways, including the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY), as critical regulators of the SASP. These pathways fuel histone acetylation at SASP gene loci, promoting their expression. Targeted inhibition of SLC25A1 or ACLY suppresses SASP expression without affecting cell cycle arrest, underscoring their potential as selective therapeutic targets for mitigating age-related inflammation. Furthermore, pharmacological inhibition of SLC25A1 reduces systemic inflammation and extends healthspan in aged mice. Our findings suggest that disrupting metabolic reprogramming in senescent cells offers a promising strategy to ameliorate aging-associated pathologies.