A gene involved in RNA processing extended median lifespan by 14 percent and slowed the accumulation of frailty in aged mice, according to a study published in Nature Aging.
The researchers identified the gene, SRSF1, using a screening platform designed to find factors that make old cells behave more like younger cells without causing them to lose their specialized identity. Although the findings suggest a possible route toward therapies targeting age-related decline, the results remain preclinical and were generated in a small cohort of mice.
Partial cellular reprogramming using the Yamanaka factors can reverse some molecular features of aging. However, excessive expression can return mature cells to a pluripotent state and increase the risk of tumor formation. This creates a challenge for researchers seeking the benefits of reprogramming without fundamentally changing cell identity.
“In reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line,” said co-first author Alexandru Plesa in a press release.
The team developed a machine learning model trained using gene-expression data from 464 human fibroblast samples obtained from donors of different ages. Rather than producing a single age estimate from DNA methylation, the model assessed changes in gene-expression programs associated with several cellular processes.
The researchers then used the model to screen genes predicted to influence aging. Overexpression of SRSF1 produced the most consistent reduction in predicted transcriptomic age. In human fibroblasts, it reduced cellular senescence, inflammatory signaling, and proteostatic stress while restoring DNA repair programs. The treated cells retained their morphology and continued expressing genes associated with normal fibroblast functions.
SRSF1 encodes a splicing factor that helps determine which RNA sequences are retained in mature messenger RNA. The researchers are still investigating how the resulting changes in RNA processing produce the observed effects.
To test the candidate in vivo, the team delivered an inducible SRSF1 construct to aged female mice using an adeno-associated viral vector that primarily targeted the liver. Median lifespan increased from 778 to 886 days, while the rate of frailty accumulation fell by approximately 44 percent. The treatment also delayed the onset of sustained frailty by 123 days.
The effects depended on controlling the timing and level of SRSF1 expression. Constitutive overexpression generated higher SRSF1 levels but did not improve skin repair or muscle regeneration, indicating that simply maximizing expression was insufficient.
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