Wyss Institute researchers built a gene-expression aging clock, screened genes for rejuvenating effects and found that SRSF1 reversed aging signs in human cells and extended median lifespan in mice by 14 percent.
In 2006, the Japanese scientist Shinya Yamanaka showed that just four genes could turn adult cells back into stem cells, erasing their identity and much of their age. The discovery, which earned him a Nobel Prize, opened a new field of research into rejuvenating cells. But it came with a catch: wiping cells back to a stem-like state can cause them to lose their function and, in some cases, form tumors.
Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and their collaborators have now searched for a safer route. In a study published in Nature Aging, they report that boosting a single gene, called SRSF1, made aged human cells look younger without changing their identity, and extended lifespan in aged mice.
“It has been a long-standing goal of my lab to devise clinically useful de-aging strategies by identifying genes that, when engineered in the genome for under or over-expression in aging target tissues, extend human health-span,” said George Church, a core faculty member at the Wyss Institute and professor of genetics at Harvard Medical School, who led the study. “Our platform and findings on SRSF1 are an important step on that quest.”
Walking a fine line
The central challenge in rejuvenation research is balance. Alex Plesa, a scientist at the Wyss Institute and the study’s co-first author, said that “in reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line.”
To find genes that could strike that balance, the team needed a way to measure age in cells quickly and at scale. The most widely used tools, epigenetic clocks, read chemical marks on DNA that accumulate with age.
“The most prominently used ‘aging clock,’ the epigenetic aging clock, assesses chemical modifications to the genome that occur with age as one of the hallmarks of aging,” Plesa said. “But it doesn’t scale well to screening approaches because of high costs and challenges with interpreting its widespread changes.”
A clock based on gene activity
Instead, the researchers built a machine learning model that estimates a cell’s age from its gene expression, the pattern of which genes are switched on and off. They trained this transcriptomic age predictor on gene expression data from 464 samples of human skin fibroblasts, the cells that produce connective tissue, collected from donors across a wide range of ages.
“The idea of predicting the age of cells based on their gene expression made a lot of sense since every rejuvenation process inevitably has to manifest itself in altered gene expression programs that lead to the recovery of more youthful cell functionalities,” Plesa said.
The team tested the clock on fibroblasts from donors aged 55, 65 and 79, treating them with interventions known to affect lifespan, including the Yamanaka factors. The clock tracked shifts in the cells’ transcriptomic age.
A screen finds SRSF1
The researchers then over-expressed genes from a focused library in aged cells and used the clock to see which made the cells look younger. The top performer was SRSF1, a protein involved in RNA splicing, the process by which cells edit the messages copied from genes before using them to make proteins.
SRSF1 had wide-ranging effects. It reduced cellular senescence, a state in which damaged cells stop dividing and release inflammatory signals. It also lowered inflammatory signaling and stress on the cell’s protein-folding machinery, restored DNA repair programs and lowered the readout of an epigenetic clock.
Crucially, the rejuvenated cells remained fibroblasts. They kept their characteristic spindle shape and fibroblast gene expression, and did not switch on the programs that turn cells into stem cells.
Longer lives in mice
To test the gene in living animals, the team delivered SRSF1 to aged mice using an adeno-associated virus, or AAV, a harmless virus widely used in gene therapy. The version they used targets the liver, where the gene mainly accumulated. Treated mice became frail more slowly and lived longer, with median lifespan extended by 14 percent compared with controls.
“We were working on the premise that over-expressing a single gene with validated rejuvenation outcomes could eventually be advanced into an organ or tissue-specific gene therapy if combined with the right delivery system,” Plesa said.
The researchers suspect the liver’s influence extends beyond itself. “It is also very likely that primarily targeting the liver can reverse aging processes in other organs and tissues and that rejuvenation programs can be communicated and thus amplified within the body,” Plesa said.
Much still unknown
How SRSF1 works remains unclear. “We observed a strong trend of alternatively spliced mRNAs, but we are only just starting to understand how these changes bring about the multi-faceted rejuvenation program in tissues,” Plesa said.
There are other reasons for caution. Results in mice often do not translate to humans, and a 14 percent extension in median lifespan, while substantial, comes from a single study. SRSF1 also has a complicated reputation: in some contexts, excess SRSF1 has been linked to cancer, so any therapy would need to be carefully controlled and tested for safety.
The work involved collaborators at CIC bioGUNE in Spain, including Antonio del Sol and co-first author Sascha Jung. It 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.
Church sees the field at a turning point. “Aging research is transiting an inflection point where the exponential progress of biotech is impacting the core aging processes which would otherwise kill 90% of us,” he said.
Notes
- Plesa, A., Jung, S., et al. “Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging.” Nature Aging, 14 October 2026.
- Wyss Institute for Biologically Inspired Engineering at Harvard University. “Reversing age by reprogramming gene expression networks.” EurekAlert!, 14 October 2026. https://www.eurekalert.org/news-releases/1147754.