Nature Aging study identifies splicing factor SRSF1 as regulator of cellular aging and frailty in mice

A transcriptomic screen has identified the RNA splicing factor SRSF1 as a regulator of cellular aging that restores youthful phenotypes in vitro and reduces frailty progression in mice, presenting an alternative pathway to Yamanaka-factor-based cellular rejuvenation.

Researchers developed an interpretable transcriptomic age predictor in human fibroblasts and performed a cDNA overexpression screen to identify factors capable of reprogramming aged transcriptomes.

The screen identified the RNA-processing and splicing factor SRSF1, which, when induced, restored youthful transcriptional signatures without causing a loss of cellular identity.

In vitro experiments showed that SRSF1 expression reduced cellular senescence, proteostatic stress, and inflammatory signaling.

In aged mice, inducible expression of SRSF1 reduced frailty progression by 44% and was associated with a 14% extension in median lifespan (using a sample size of n = 9-10 per group).

Co-authors of the study are listed as inventors on patent application US20250313599A1 and have co-founded RegulaBio, an early-stage company focused on developing therapeutics for age-related diseases.

While partial reprogramming via Yamanaka factors can reverse aging signatures, concerns regarding in vivo toxicity and loss of cellular identity have restricted their clinical translation.

SRSF1 represents a novel, non-Yamanaka target that achieves transcriptomic rejuvenation while maintaining cell identity, potentially offering a safer alternative for in vivo applications.

The research highlights the critical role of maintaining RNA splicing machinery and proteostasis as a systemic mechanism to combat age-related physical decline.

The findings expand the therapeutic landscape of cellular rejuvenation beyond epigenetic reprogramming, elevating alternative splicing as a high-value biological target category.

The intellectual property covering SRSF1 (patent application US20250313599A1) and its translation via the startup RegulaBio indicate immediate commercial interest in targeting RNA-processing pathways for longevity.

This mechanism of action provides an indirect read-through to biotechnology companies targeting alternative splicing and RNA-processing pathways to modulate disease and cellular states.

Translational progress from RegulaBio as it seeks to develop therapeutic candidates targeting SRSF1 or downstream RNA-splicing mechanisms.

Further in vivo validation of SRSF1 delivery methods, such as mRNA or viral vectors, to evaluate tissue-specific safety profiles and long-term efficacy.