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SRSF1 Gene Delivery Extends Lifespan in Aged Mice
An RNA sequencing and machine learning screening platform identified an RNA-processing factor that reduced markers of cellular aging without erasing cell identity
Identify a gene that can make aged cells show younger molecular features while preserving their specialized identity, and test its effects in aged mice.
Approach:
Gene screening: Researchers trained a machine-learning model on gene-expression data from 464 human fibroblast samples and used it to screen candidate genes.
Cell studies: They assessed SRSF1 overexpression in human fibroblasts for changes in predicted transcriptomic age and cellular features.
Mouse study: An inducible SRSF1 construct was delivered by adeno-associated viral vector, primarily targeting the liver, in aged female mice.
Key Findings:
SRSF1 overexpression produced the most consistent reduction in predicted transcriptomic age among screened genes.
In human fibroblasts, SRSF1 reduced senescence, inflammatory signaling, and proteostatic stress, and restored DNA repair programs; treated cells retained fibroblast morphology and function-associated gene expression.
In aged mice, median lifespan was 886 days with SRSF1 treatment versus 778 days in controls; frailty accumulation was approximately 44% slower, and sustained frailty onset was delayed by 123 days.
Constitutive overexpression did not improve skin repair or muscle regeneration, despite producing higher SRSF1 levels.
Interpretation:
The study reports preclinical evidence that controlled SRSF1 expression can affect cellular aging measures and lifespan in mice. The mechanisms linking altered RNA processing to these effects remain under investigation.
Limitations:
The mouse findings came from a small cohort and involved aged female mice.
The results are preclinical and do not establish effects in humans.
The mechanism by which SRSF1-related RNA-processing changes produce the observed effects is not yet understood.
