Harvard-led team identifies SRSF1 as a candidate 'youthful' gene factor, with lifespan signal in mice

Researchers at Harvard’s Wyss Institute and Harvard Medical School, working with colleagues in Spain and Luxembourg, have reported a way of hunting for factors that nudge aging human skin cells toward a younger gene-expression pattern. Their top hit, a gene-splicing protein called SRSF1, was associated with delayed frailty and a longer median lifespan in small groups of mice. The paper was published in Nature Aging on October 14, 2026.

What the researchers did

Partial reprogramming, which uses the “Yamanaka factors” to push cells toward a younger state, has drawn heavy interest in aging research. The authors note that toxicity and efficacy concerns limit its use in living animals, so they looked for alternatives.

First, they built an “interpretable” transcriptomic age predictor: a model that estimates a cell’s age from the activity of its genes, trained on human skin fibroblasts. Then they ran a screen in which they switched on candidate genes (a cDNA overexpression screen) and measured whether cells’ predicted age moved toward youth. This identified SRSF1, a protein involved in RNA processing and splicing. They then tested SRSF1 in cultured cells, in aged mice using an inducible gene-delivery system, and in the roundworm C. elegans.

What they found

According to the abstract, SRSF1 produced “robust youthful transcriptional signatures without loss of cellular identity”. In cell culture, inducing SRSF1 was associated with lower senescence, less proteostatic (protein-handling) stress and less inflammatory signaling. In aged mice, inducible SRSF1 expression reduced frailty progression by 44% and was associated with a 14% extension of median lifespan, with 9 to 10 animals per group.

Details from the extended-data legends, which we also read, add some texture:

• SRSF1 expression in human fibroblasts fell by about 15% between young and old donors (133 donor lines aged 1 to 96).
• In one donor line (four technical replicates), a three-day SRSF1 induction lowered predicted transcriptomic age by a median of 16.2 years in the authors’ model. That is a change in a gene-activity score, not a measured change in a person’s age.
• Cells expressing the Yamanaka factors changed shape markedly by day three, whereas SRSF1-expressing cells kept a typical fibroblast appearance.
• Mice with SRSF1 delayed the age of sustained frailty onset by about 123 days (P = 0.0487), although only 6 of 10 treated and 4 of 9 control animals reached that point.
• Results were mixed in some other tests. A version driven by a constant (CAG) promoter did not change wound closure, and muscle-fiber size was not rescued in aged mice. On a liver epigenetic clock, SRSF1 reduced age acceleration by 0.5 years (P = 0.021), with no difference on a pan-tissue clock.
• In worms, knocking down the SRSF1-like gene rsp-3 suppressed the longevity of a long-lived strain.

What this means

The study is best read as a proof of concept for a method: use a gene-activity “clock” to screen for factors that move cells toward a younger profile, and look for options that avoid the identity loss seen with full Yamanaka-factor expression. SRSF1 is now a candidate for further work in animals. The authors call it “a promising geroprotective target”, which is a research hypothesis rather than a result in people.

Limits of the evidence

• Animal and cell data only. Nothing here has been tested in humans, and mouse findings frequently do not carry over.
• Small groups. The headline lifespan and frailty results come from 9 to 10 mice per group, and some wound-healing experiments used two to four mice.
• Clock readouts are proxies. A younger-looking gene-expression score is not the same as better health or longer life.
• Gene delivery. The mouse work used a viral vector, which is an experimental delivery tool.
• Conflicts of interest. Several authors, including co-corresponding author George M. Church, are named inventors on a patent application covering SRSF1 and other factors. A. M. Plesa and G. M. Church are cofounders of, and hold equity in, RegulaBio, an early-stage company developing therapeutics for age-related diseases.
• Funding: the Aging and Longevity-Related Research Fund, the Astera Fund, the Wyss Institute and the Spanish Ministry of Science and Innovation, among others.
• What we read: the abstract, figure titles, extended-data legends and declarations on the journal page. The main results text was not available in the version we accessed, so we have not described details beyond those sections.

Sources

• Plesa AM, Jung S, et al. Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging. Nature Aging, October 14, 2026. DOI: 10.1038/s43587-026-01234-8 (journal page, opened for this article)

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