SRSF1 Rejuvenates Aged Cells and Extends Mouse Lifespan Without Erasing Cell Identity

Cellular reprogramming with Yamanaka factors (OSKM) can reverse aging signatures, but it can also strip cells of their identity, which makes it risky as a therapy. Researchers have therefore been looking for ways to rejuvenate cells without dedifferentiating them. A new study suggests that SRSF1, an RNA-processing and splicing factor, may do exactly that.

The team began by building a transcriptomic aging model. They trained a machine-learning predictor on gene expression data from human dermal fibroblasts donated by people aged 1 to 96, and grouped genes into functional modules that best predict chronological age. The model responded to interventions faster than a commonly used DNA methylation clock. It is also cheaper and easier to scale for screening, which the authors see as an advantage.

Using this predictor, the researchers overexpressed a library of genes tied to human aging networks in fibroblasts. SRSF1, whose expression declines as fibroblasts age, was the most robust hit, comparable to OSKM. Inducing it reduced senescence markers, senescence-associated secretory phenotype programs, proteostatic stress and inflammatory signaling, and it activated DNA repair pathways. Cells kept their transcriptional state and morphology even as their transcriptomic and epigenetic ages dropped.

In aged mice, acute SRSF1 induction reduced frailty by 44%, accelerated wound closure, lowered mortality risk and extended median lifespan by 14%. This happened even though the viral vector mainly targeted the liver, which limited systemic exposure. That suggests liver-focused effects may drive much of the benefit, though this remains to be confirmed.

There is nothing here for people to apply today. SRSF1 is a research target, not a supplement or treatment. It does show that rejuvenation and loss of cell identity can be separated, and that gene expression based aging clocks can speed up the search for new geroprotective candidates.

Caveats are significant. The work is preclinical, the lifespan figure is for median rather than maximum lifespan, and long-term safety is unknown. Splicing factors can be oncogenic when overexpressed, so cancer risk needs careful testing. Whether the results carry over to humans is untested.