Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging.

Aging is characterized by progressive functional decline accompanied by distinct transcriptomic and epigenetic alterations. Although partial reprogramming via Yamanaka factors can reverse these signatures and improve cell function, toxicity and efficacy concerns limit their in vivo application, necessitating alternative geroprotective interventions. Here we develop an interpretable transcriptomic age predictor in human fibroblasts and perform a cDNA overexpression screen to identify factors that reprogram aged transcriptomes toward youthful states. This screen identifies the RNA-processing and splicing factor SRSF1 as a regulator of cellular aging that produces robust youthful transcriptional signatures without loss of cellular identity. In vitro, SRSF1 induction restores youthful phenotypes by reducing senescence, proteostatic stress and inflammatory signaling. In aged mice, inducible SRSF1 expression reduces frailty progression by 44% and is associated with a 14% extension of median lifespan (n = 9-10 per group). Our findings establish SRSF1 as a conserved regulator of aging and a promising geroprotective target.