Scientists at Harvard University and the Wyss Institute in the United States have identified the SRSF1 gene, which activates multiple rejuvenation processes and extends the lifespan of mice by 14%. The findings were published in the scientific journal Nature Aging.
The study, led by George Church and Alex Plesa, focused on identifying factors that could reverse signs of aging without the cancer risk associated with Yamanaka factors — four genes capable of reprogramming mature cells into stem cells. “There is a fundamental trade-off in reprogramming between rejuvenation and cellular identity; achieving one without losing the other requires walking a fine line,” Plesa said.
The team developed a machine-learning algorithm that predicts the “transcriptomic age” of cells based on their gene expression profiles. The researchers used this predictor to screen a library of genes that, when overexpressed, could shift the age-related profiles of old human skin fibroblasts toward a younger state.
The leading candidate was SRSF1, a gene encoding an RNA-processing factor. Its overexpression reduced several hallmarks of aging, including cellular senescence, chronic low-grade inflammation known as “inflammaging,” and proteostatic stress. It also restored DNA repair programs. Importantly, the rejuvenated fibroblasts retained their cellular identity and did not activate the pluripotency programs associated with Yamanaka factors.
The researchers then packaged SRSF1 into an adeno-associated virus (AAV) designed to target the liver and administered it to old mice. The animals experienced slower physical decline and lived longer: median lifespan increased by 14% compared with the control group.
“We are seeing a strong trend toward alternative mRNA splicing, but we are only beginning to understand how these changes activate a multifaceted rejuvenation program in tissues. It is also highly likely that targeting primarily the liver can reverse aging in other organs, as rejuvenation programs may spread and amplify throughout the body,” Plesa said.
According to the authors, SRSF1 is a promising target for anti-aging therapies because it works through mechanisms already used by all cells rather than changing their identity. Resolving challenges related to delivery and dosage could eventually turn this “geroprotective” gene into a rejuvenation therapy.
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