SRSF1 shows promise in reversing cellular aging while preserving cell identity
Aging progressively impairs tissue integrity and cellular function through interconnected biological processes collectively described as the hallmarks of aging. Growing evidence indicates that these processes may be modifiable, raising the possibility that age-related functional decline could be partially reversed rather than remaining an irreversible process.
A major milestone came with the discovery that transient expression of four reprogramming factors, commonly known as the Yamanaka factors, can partially restore youthful characteristics in aged cells. Unlike prolonged expression, which can drive cells toward pluripotency and increase the risk of uncontrolled growth, short-term exposure can reverse several aging-associated changes while preserving cellular specialization. However, the potential for loss of cellular identity and tumor formation has limited direct therapeutic application.
A recent study published in Nature Aging has identified SRSF1, an RNA-processing factor, as a potential alternative approach to cellular rejuvenation. The strategy focused on identifying individual genes capable of reversing molecular features of aging without forcing mature cells into a pluripotent state. To enable large-scale screening, a machine-learning-based transcriptomic aging predictor was developed using gene-expression profiles obtained from human skin fibroblasts representing a broad age range. Instead of relying solely on epigenetic modifications, the approach evaluated changes in gene-expression programs associated with multiple biological processes involved in aging. The resulting model generated a measurable estimate of cellular or transcriptomic age.
The model successfully detected age-related differences across fibroblast cell lines derived from individuals aged 55, 65 and 79 years. The predictor also detected shifts toward younger molecular states following experimental interventions known to influence cellular aging, including transient exposure to reprogramming factors. A focused gene library was subsequently screened to identify genes capable of reducing the predicted age of older fibroblasts. SRSF1 emerged as the leading candidate. Increased SRSF1 expression produced changes across several important aging-associated pathways, including cellular senescence, inflammatory signaling and proteostatic stress. DNA-repair programs also showed restoration toward more youthful activity.
An important feature of the findings was preservation of cellular identity. Following SRSF1 overexpression, fibroblasts retained their characteristic morphology and continued expressing genes associated with fibroblast-specific functions. Unlike Yamanaka-factor-mediated reprogramming, SRSF1 did not activate broad pluripotency programs. The findings therefore suggest a potential route toward rejuvenation that does not require erasing cellular specialization.
SRSF1 primarily functions as an RNA splicing factor, regulating the processing of messenger RNA through alternative exon selection. The resulting changes can modify the proteins produced by cells and potentially influence multiple biological pathways simultaneously. Although substantial changes in alternative RNA splicing were observed following SRSF1 activation, the precise mechanisms linking altered RNA processing with broad rejuvenation remain under investigation.
The potential benefits extended beyond cultured cells. SRSF1 was delivered to aged mice using a liver-targeting adeno-associated viral vector. Treatment produced prominent effects in the liver and was associated with slower development of frailty and a 14% extension in median lifespan compared with untreated controls. The findings also raise the possibility that rejuvenation initiated in a single organ could generate broader systemic effects. Molecular signals originating from rejuvenated tissues may potentially influence aging-associated processes elsewhere in the body, although this possibility requires further investigation.
The development of a transcriptomic aging predictor provides an additional tool for identifying rejuvenation targets and screening interventions. Unlike conventional aging clocks that primarily measure epigenetic alterations, transcriptomic profiling can directly capture functional changes in gene-expression programs associated with cellular state.
SRSF1 represents a promising geroprotective target because it appears to promote youthful cellular functions while preserving cellular identity. Further studies are required to establish the mechanisms responsible for these effects, determine optimal delivery and dosing strategies, evaluate long-term safety, and establish whether similar benefits can be reproduced across different tissues. The findings support continued investigation of RNA-processing pathways as potential therapeutic entry points for tissue rejuvenation and age-related functional decline.
References
- Plesa AM, Jung S, Wang HH, Omar F, Shadpour M, Choy Buentello D, et al. Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging. Nature Aging. 2026;6:2057–2073. doi:10.1038/s43587-026-01234-8.