RNA Sequencing of Mouse Liver Post Caloric Resrtiction and Anti-Anging Interventions

Caloric restriction (CR) extends lifespan in mammals but the stringent 20% reduction in food intake is challenging to sustain; therefore, validating pharmacological mimics is of high interest. It has been previously reported that a SERPINE1 mutation in an Amish cohort links to a 10-year lifespan increase and improved metabolism. SERPINE1 encodes for Plasminogen Activator Inhibitor-1 (PAI-1) which is a clinical predictor of vascular stiffness, hypertension, and diastolic dysfunction. Moreover, PAI-1 amplifies accumulation of senescent cells as a component of the senescence associated secretory phenotype (SASP). Here, we compared hepatic transcriptomic profiles in mice after 8 weeks of CR, rapamycin, metformin, or the PAI-1 inhibitor TM5614 versus an ad libitum control. CR induced extensive changes (1087 genes downregulated, 1145 upregulated), while TM5614 showed the closest mimicry (211 down, 218 up), sharing ~50% of CR’s differentially expressed genes, including downregulated Il11ra1 and upregulated Per2, tied to longevity and metabolism. Rapamycin and metformin showed minimal overlap with CR. Gene Ontology analysis revealed CR and TM5614 downregulated metabolic pathways, and both countered gene-length-dependent transcription decline, an emerging measure of an aging transcriptomic landscape. TM5614 presents as a CR mimic, offering an alternative to CR to extend healthspan.