RNA Splicing Factor SRSF1 Emerges as a Powerful New Regulator of Aging

Aging leaves a measurable fingerprint on the activity of our genes. As cells grow older, the precise choreography of gene expression that keeps tissues functioning gradually dissolves, giving way to chronic inflammation, protein misfolding, and a slow drift away from each cell’s original identity. For more than a decade, scientists have tried to reverse these molecular signatures by reprogramming cells with the Yamanaka factors, the four transcription factors that can reset adult cells to a stem-like state. While partial reprogramming has shown genuine promise in animal studies, concerns about toxicity, loss of cell identity, and even cancer have kept researchers searching for safer alternatives. Now, a team led by Alexandru M. Plesa and Sascha Jung, working in the laboratory of George Church at Harvard University and with collaborators in Spain and Luxembourg, reports in Nature Aging that a single RNA-processing protein, SRSF1, can make old cells look young again at the level of their transcriptomes, without erasing what those cells are, and that boosting this factor in aging mice slows frailty and extends lifespan.

The study began with a computational foundation. The researchers built an interpretable transcriptomic age predictor specifically calibrated in human fibroblasts, the connective tissue cells that have long served as a workhorse of aging research. Drawing on transcriptomes from 133 donor lines spanning ages 1 to 96 years, the model distilled aging down to 292 genes whose activity tracks the passage of biological time. These genes cluster into recognizable biological processes, including WNT signaling, translation initiation, actin organization, histone methylation, and endoplasmic reticulum stress. Importantly, the model captured distinct kinetic patterns of aging: some processes, such as ER quality control and translation initiation, decline steadily and continuously with age, while others, like histone methylation and actin polymerization, respond late and exponentially, and still others, such as sodium transport, follow a biphasic trajectory. This architecture gave the team a quantitative yardstick for biological age that could be applied to any fibroblast sample.

With the age predictor in hand, the researchers turned to an unbiased search for factors capable of turning back the transcriptomic clock. They assembled a library of 95 plasmids for overexpression screening: 89 candidate genes prioritized through a network-based approach that combined protein-protein interaction data from the STRING database with the strength of age-associated expression changes, plus five known aging modulators including ATG5, CXCR2, HES1, KAT7, and the OSKM reprogramming cocktail, along with a blue fluorescent protein control. Each candidate was introduced into aged fibroblasts, and the resulting transcriptomes were scored by the age predictor. The screen’s standout hit was SRSF1, a well-known splicing factor that binds RNA and controls how messenger RNA transcripts are cut and pasted together before they are translated into protein. When SRSF1 was induced in aged fibroblast lines, the cells’ predicted transcriptomic age dropped by a median of 16.2 years after just three days of expression, a striking and technically reproducible rejuvenation effect.

What makes this result particularly notable is what did not happen. Partial reprogramming with OSKM factors is famously accompanied by dramatic morphological changes: fibroblasts lose their characteristic spindle shape, shrink in size, and drift toward pluripotency programs, raising the specter of uncontrolled cell growth. In the new study, OSKM expression produced exactly these changes by day three of induction, and even short one-to-three-day inductions left lasting positive age shifts of more than 37 to 54 years in some donor lines after the factors were withdrawn. SRSF1-expressing cells, by contrast, retained their spindle-shaped fibroblast morphology and cell body area throughout induction, showed no sustained age shifts after doxycycline withdrawal, and did not activate pluripotency programs. The rejuvenation was also confirmed with an orthogonal measurement: the Skin and Blood DNA methylation clock, an entirely independent biomarker of aging based on chemical tags on the genome rather than gene expression, also registered reduced age in SRSF1-treated cells.

At the functional level, SRSF1 induction produced a multidimensional rejuvenation across molecular hallmarks of aging. In aged fibroblasts, the factor reduced senescence, the state of permanent growth arrest that accumulates in aging tissues and secretes inflammatory signals; it eased proteostatic stress, the burden of misfolded and damaged proteins; and it dampened inflammatory signaling pathways. When delivered as synthetic mRNA rather than DNA, SRSF1 significantly reduced senescence-associated beta-galactosidase activity, a classic marker of cellular aging, in both young and old donor cell cohorts. The factor also improved stress resilience: aged fibroblasts carry roughly 64 percent higher levels of reactive oxygen species after a hydrogen peroxide challenge than young cells, and SRSF1 treatment trended toward reducing this oxidative burden. Collagen synthesis, which declines modestly with age, increased by about 14 percent in aged cells treated with SRSF1, and the treated cells showed a tendency toward faster closure of scratch wounds in vitro, a measure of regenerative capacity.

The critical question was whether these cellular effects would translate into benefits in living animals. To test this, the team used inducible viral delivery, packaging the Srsf1 gene into adeno-associated virus vectors under the control of a doxycycline-activated Tet-On system, allowing them to switch expression on and off in aged mice. The results were remarkable: inducible SRSF1 expression reduced the progression of frailty, a composite measure of age-related decline in strength, endurance, and health, by 44 percent, and was associated with a 14 percent extension of median lifespan, with 9 to 10 mice per group. Sustained frailty onset, defined as a frailty index exceeding 0.18, was delayed by approximately 123 days in the SRSF1-treated animals. In skin wound-healing experiments, wounds in aged mice closed significantly faster with SRSF1 expression, reaching a partial restoration of the regenerative capacity seen in young animals, although the effect depended on the delivery regimen and was not observed with all expression strategies.

Molecular analysis of the treated mice revealed that SRSF1’s benefits extended across tissues. In the liver, SRSF1 expression reduced epigenetic age acceleration as measured by an intervention-optimized DNA methylation clock, shaving off about half a year of apparent age. Gene set enrichment analysis across tissues showed that SRSF1 modulated pathways involved in bioenergetics, immune signaling, and cellular homeostasis, and many of these processes were classified as age-opposing when compared against the Tabula Muris Senis reference atlas of mouse aging. Strikingly, a cross-species comparison revealed shared signatures between SRSF1-treated human fibroblasts and mouse liver tissue, including reduced stress response, reduced inflammation, and altered cell adhesion and cell cycle programs, suggesting that the factor acts through conserved longevity pathways rather than species-specific mechanisms.

The evolutionary conservation of this pathway received direct experimental support from studies in the roundworm Caenorhabditis elegans. The worm homolog of SRSF1 is a gene called rsp-3, and when the researchers knocked it down with RNA interference in long-lived raga-1 mutant worms, a strain in which the nutrient-sensing mTOR pathway is dampened, the worms’ characteristic lifespan extension was suppressed. The result, confirmed in independent repeats with 120 to 159 worms per group, places SRSF1 squarely within one of the most intensively studied longevity networks in biology, the same nutrient-sensing axis targeted by rapamycin and dietary restriction. It also connects the new findings to an older body of evidence showing that splicing factor expression changes with age in both mice and humans, and that variations in splicing factor transcripts correlate with lifespan.

SRSF1 is not an obvious anti-aging target. The factor has a well-documented dual personality: it is essential for normal cell function, governing progenitor-specific alternative splicing in epithelial tissues and acting as a master switch of gene expression in the immune system, but it is also a known proto-oncogene whose overexpression is associated with cancer cell biology. The authors and several coauthors are listed as inventors on a patent application covering the therapeutic use of SRSF1 and related factors, and two of them are cofounders of an early-stage company developing therapeutics for age-related diseases, disclosures that underscore the translational ambition behind the work. The tension between geroprotection and oncogenesis will need careful resolution, and the mouse data, while encouraging, come from relatively small groups and a defined delivery system.

Nevertheless, the study represents a conceptual advance in how rejuvenation targets are found. Rather than starting from the Yamanaka factors and trying to make them safer, the team started from a quantitative definition of the aged state and screened for any gene that could reverse it while preserving cell identity. The answer, an RNA-binding splicing factor rather than a transcription factor, suggests that the aging transcriptome may be held in an aged configuration partly at the level of RNA processing, and that correcting the splicing machinery can ripple outward to restore youthful patterns of gene expression, protein homeostasis, and tissue function. If the findings hold up in larger animal studies and can be delivered safely, SRSF1 and the screening platform that uncovered it could open a new chapter in the search for interventions that extend not just lifespan, but the healthy years of human life.

Subject of Research: Identification of the splicing factor SRSF1 as a conserved regulator of aging through transcriptomic reprogramming screens

Article Title: Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging

Article References: Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging. (n.d.). https://doi.org/10.1038/s43587-026-01234-8

Image Credits: AI Generated

DOI: 10.1038/s43587-026-01234-8

Keywords: SRSF1, aging, transcriptomic clock, partial reprogramming, splicing factor, senescence, geroprotection, lifespan extension, C. elegans, frailty, gene expression, epigenetic clock