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Transcriptomic reprogramming screen identifies SRSF1 as a central regulator of aging and lifespan - EPIC

ABSTRACT: Aging is characterized by progressive functional decline accompanied by distinct transcriptomic and epigenetic alterations. While partial reprogramming via Yamanaka factors can reverse these signatures and improve cell function, safety and efficacy concerns limit their in vivo application, necessitating novel age reversal factors. Here, we develop a functionally interpretable transcriptomic age predictor in human fibroblasts and perform a targeted cDNA overexpression screen to identify interventions that reprogram aged transcriptomes toward youthful states. This screen identifies the RNA-processing and splicing factor SRSF1 as a central regulator of cellular rejuvenation that produces robust youthful transcriptional signatures without loss of cellular identity. In vitro, SRSF1 induction restores youthful phenotypes by reducing senescence, reactive oxygen species, proteostatic stress, and inflammatory signaling. In aged mice, inducible SRSF1 expression reduces frailty progression and increases overall lifespan. Our findings establish SRSF1 as a conserved regulator of organismal aging and a promising therapeutic target for safe in vivo rejuvenation.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE326022 | GEO | 2026/08/15

REPOSITORIES: GEO

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Transcriptomic reprogramming screen identifies SRSF1 as a central regulator of aging and lifespan

Project description:Aging is characterized by progressive functional decline accompanied by distinct transcriptomic and epigenetic alterations. While partial reprogramming via Yamanaka factors can reverse these signatures and improve cell function, safety and efficacy concerns limit their in vivo application, necessitating novel age reversal factors. Here, we develop a functionally interpretable transcriptomic age predictor in human fibroblasts and perform a targeted cDNA overexpression screen to identify interventions that reprogram aged transcriptomes toward youthful states. This screen identifies the RNA-processing and splicing factor SRSF1 as a central regulator of cellular rejuvenation that produces robust youthful transcriptional signatures without loss of cellular identity. In vitro, SRSF1 induction restores youthful phenotypes by reducing senescence, reactive oxygen species, proteostatic stress, and inflammatory signaling. In aged mice, inducible SRSF1 expression reduces frailty progression and increases overall lifespan. Our findings establish SRSF1 as a conserved regulator of organismal aging and a promising therapeutic target for safe in vivo rejuvenation.

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