Harvard Study: SRSF1 Gene Reverses Aging in Mice

Researchers at Harvard University's Wyss Institute have identified a gene that can reverse multiple hallmarks of aging while leaving cells' identities intact. The gene, SRSF1, extended healthspan and lifespan in aged mice in a study published in the journal Nature Aging, according to the Wyss Institute and reported by News-Medical.

Treated animals lived longer than untreated controls and showed a slower progression of age-related frailty. The team describes the gene as a "geroprotective" target: it works through machinery every cell already uses, rather than overriding cell identity the way earlier reprogramming techniques do.

An aging clock built from gene expression

The study was led by George Church, Core Faculty member at the Wyss Institute and Professor of Genetics at Harvard Medical School, and spearheaded by Wyss Institute Scientist Alex Plesa, in collaboration with the computational biology group of Antonio del Sol at CIC bioGUNE-BRTA in Spain.

Before hunting for a gene, the team needed a way to measure age in a dish. Most labs rely on the epigenetic aging clock, which tracks chemical modifications to the genome, but that approach is expensive and hard to scale for screening many genes, Plesa said. Instead, the team built a machine learning model trained on gene expression data from 464 fibroblast samples taken from donors across a wide age range. The model predicts what the researchers call "transcriptomic age": how old a cell's gene expression program looks, rather than the age of the donor.

The model accurately detected shifts in transcriptomic age in fibroblast lines from donors aged 55, 65 and 79 after treatment with lifespan-changing interventions, including the Yamanaka factors. With the model as a scoring tool, the team overexpressed a focused library of genes in aged fibroblasts and looked for candidates that moved the cells' aging score toward a younger profile. the gene, which encodes an RNA processing factor, came out on top.

the gene's best-known role is as an RNA splicing factor. It helps decide which protein-coding segments, called alternative exons, get included in mature messenger RNA molecules, and those messages are then translated into proteins with altered functions. The researchers observed a strong trend of alternatively spliced mRNAs in the rejuvenated cells, though Plesa said the team is only beginning to understand how those changes drive the broader rejuvenation program.

Rejuvenation without losing cell identity

In cultured cells, boosting the gene pushed several hallmarks of aging toward more youthful states. It reduced cellular senescence, the process in which damaged cells stop dividing but refuse to die; eased proteostatic stress, a disruption of the normal balance and turnover of proteins; and lowered chronic low-grade inflammation, sometimes called "inflammaging." The cells also restored DNA repair programs, and the improvements registered on the epigenetic aging clock.

Crucially, the rejuvenated fibroblasts kept their identity. They retained their spindle-shaped morphology and kept expressing genes tied to typical fibroblast functions, without switching on the pluripotency programs that the Yamanaka factors activate. That distinction matters because the therapeutic use of Yamanaka factors worries some researchers: overexpressing them raises the risk of cancer formation. "In reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line," Plesa said.

The 2006 discovery of the Yamanaka factors by Shinya Yamanaka, which earned a Nobel Prize, showed that aging cells retain a latent capacity for rejuvenation: expressed in short bursts, the four genes can partially reprogram old cells to a more youthful state. the gene appears to tap into that same capacity while leaving the cell's identity intact, a safer and more controllable route that could eventually be advanced into an organ- or tissue-specific gene therapy once the right delivery system is found, Plesa said.

From cells to whole animals

To test whether the effect carried over into a living organism, the team packaged the the gene gene in a liver-tropic adeno-associated virus (AAV) and treated aged mice. The therapy accumulated mainly in the liver, where it produced measurable rejuvenation, and the animals also showed systemic benefits beyond the liver: they grew frail more slowly and lived longer, with median lifespan extended by 14 percent compared with controls.

Plesa said it is likely that targeting the liver can reverse aging processes in other organs as well, adding that rejuvenation programs may be communicated and amplified within the body. Because the gene works through machinery that all cells already use, solving delivery and dosing could turn the gene into a rejuvenation therapy, according to the researchers, with further work aimed at mapping its systemic effects.

Church said the work advances a long-running goal of his lab to find de-aging strategies based on genes that extend healthspan when engineered for under- or over-expression in aging tissues. Donald Ingber, Founding Director of the Wyss Institute, said the study shows how genetic and AI-driven tools can open new avenues for research into healthy aging. The study was funded by the Wyss Institute, the Aging and Longevity-Related Research Fund, the Astera Fund at the Silicon Valley Community Foundation, and the Spanish Ministry of Science and Innovation.

For now, the results apply to mice. Read more in our Science section and coverage of recent Health research. Co-authors including Amy J. Wagers and William B. Mair plan further research into the gene's systemic effects in vivo, which could uncover additional targets and viable rejuvenation strategies. Any therapy for people would still require years of further testing.