Researchers at Harvard University identified the RNA-processing factor SRSF1 as a regulator of aging capable of shifting aged human skin cells toward younger profiles without erasing their specialized identity. Regulated expression of the factor increased median lifespan in aged female mice by approximately 14 percent, rising from 778 to 886 days in a study of 19 aged female mice.
SRSF1 Identified Via Screen
Laboratory efforts to reverse biological aging have relied on the Yamanaka factors for more than a decade. These four transcription factors reset mature cells back to a stem-like state. Shinya Yamanaka and colleagues first demonstrated this method in 2006. Partial reprogramming shows promise in animal models. Yet it carries inherent risks including toxicity, loss of cellular identity, and potential oncogenesis.
Alexandru M. Plesa and Sascha Jung led a research team in the laboratory of George Church at Harvard University, alongside collaborators in Spain and Luxembourg. They turned to computational screening to find a safer alternative.
The investigators constructed an interpretable transcriptomic age predictor calibrated on human fibroblasts. These are connective tissue cells widely used in aging research. This model distilled biological aging down. The team then assembled a library of 95 plasmids for overexpression screening, prioritizing 89 candidate genes through network analysis combining protein-protein interaction data from the STRING database with age-associated expression changes. Testing these candidates across aged donor lines revealed that SRSF1 emerged as a candidate across multiple molecular measurements.
Cellular Rejuvenation Without Identity Loss
Sweeping cellular reprogramming methods can destabilize cell identity. Introduction of SRSF1 into aged human fibroblasts achieved molecular rejuvenation while preserving specialized cellular characteristics instead. Treated cells maintained their characteristic spindle-shaped morphology and cell body area during induction. They showed no sustained age shifts following doxycycline withdrawal, and avoided the coordinated activation of pluripotency programs. Old skin cells can acquire more youthful molecular features without surrendering their specialized identity.
An independent biomarker confirmed these gene expression changes. The Skin and Blood DNA methylation clock measures chemical tags on the genome rather than RNA transcripts. It registered reduced biological age in the treated cells. Furthermore, functional assays demonstrated that senescence-associated enzyme activity fell across five donor lines, and inflammatory signaling decreased in subsequent testing.
In reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line.
Alexandru M. Plesa
Lifespan Extension in Aged Mice
The investigators delivered the mouse Srsf1 gene using an adeno-associated viral vector targeting the liver to test whether these cellular effects translate to living mammals. The lifespan experiment involved 19 aged female mice, split between 10 treated animals and nine viral-control subjects. Gene delivery occurred at 561 days of age, with regulated gene induction beginning later at 606 days.
The intervention produced a measurable survival advantage. Median lifespan reached 886 days in the SRSF1 group, compared with 778 days in the control group. That extension of 108 days represents an increase of approximately 14 percent over the control median. Repeated frailty measurements combined with survival data estimated an approximately 44 percent slower accumulation of age-related decline in strength, endurance, and health parameters.
Shared Gene Signatures Suggest Conserved Longevity Pathways
Cross-species comparisons identified shared gene signatures between SRSF1-treated human fibroblasts and mouse liver tissue, pointing to conserved longevity pathways.
SRSF1 is essential for normal cellular function and alternative splicing, but it also acts as a proto-oncogene whose overexpression is linked to cancer biology. The findings remain preclinical, with larger replication studies, long-term safety testing, and careful control of gene expression still needed before these preclinical findings can be evaluated for human applications, building on decades of prior longevity research.