Church’s lab identifies SRSF1: it shifts gene activity in old human skin cells toward a youthful state, and old mice given the gene have a 14% higher median lifespan than controls

Church’s lab identifies SRSF1: it shifts gene activity in old human skin cells toward a youthful state, and old mice given the gene have a 14% higher median lifespan than controls

On October 14, Nature Aging published a paper by Harvard’s Alex Plesa, George Church and colleagues. The Yamanaka factors, four genes that turn an adult cell into a stem cell, rejuvenate old cells but can erase their specialized identity and increase cancer risk. Church’s lab sought a single gene that could rejuvenate a cell while preserving its specialized identity.

Epigenetic clocks estimate age from chemical marks on DNA, but they are poorly suited to screening genes, Plesa explains in a press release from Harvard University’s Wyss Institute: they are expensive, and changes in those marks are difficult to interpret. Any rejuvenation, he says, inevitably changes gene activity, which can therefore serve as a readout of age.

Plesa and Church proposed a method for estimating cellular age from gene activity in a 2023 paper and trained their age prediction model on fibroblasts, the connective tissue cells of the skin. They selected 89 candidate genes based on their connections in a protein network and the magnitude of age-related changes in their activity. Each gene was introduced into old cells from men aged 55, 65 and 79 and switched on for three days. SRSF1 ranked in the bottom ten of the 89 candidates during selection but performed best in the experiment: it reduced the predicted age of cells from the 79-year-old donor by 16,2 years.

The SRSF1 protein regulates splicing, helping determine which segments of a gene’s RNA copy are retained in the final RNA. Cells with SRSF1 retained the spindle shape of fibroblasts, while cells with the Yamanaka factors activated stem cell genes and began to shrink on the third day. SRSF1 reduced signs of cellular senescence and inflammation. Epigenetic clocks provided a second, independent measure: two days after the gene had been switched on for five days, they showed an age reduction of 8 years in two of the three donors and an increase of 3 years in the third.

Previous work had linked SRSF1 to the splicing of targets of mTOR, a regulator of cell growth. The researchers therefore suppressed the SRSF1 counterpart in nematodes. This left the lifespan of ordinary worms unchanged but shortened the lifespan of long-lived mutants with reduced mTOR activity.

In mice, the gene was delivered using the AAV8 virus, which primarily targets the liver, and switched on with the antibiotic doxycycline. Control mice received the same virus carrying the gene for the fluorescent protein GFP. Old female mice were randomly assigned to groups of 9 and 10 and given doxycycline from about 20 months of age. According to the mouse lifespan table, median lifespan was 778 days in controls and 886 in mice given SRSF1. Seven of the ten SRSF1 mice outlived the longest-lived control mouse, which lived for 865 days. Their frailty index, a composite measure of about thirty health indicators, rose 44% more slowly.

“We see a pronounced pattern among alternatively spliced mRNAs, but we are only beginning to understand how these changes produce a multifaceted program of tissue rejuvenation.”

This is how Plesa describes the current understanding of the mechanism.

SRSF1 has been described as a proto-oncogene: in 2007, a small excess was enough to transform indefinitely dividing rodent fibroblasts into cells that produced sarcomas in mice. In the 2023 preprint, an early version of the paper, the authors reported no observed harmful effects in mice and attributed this to SRSF1 self-regulation. In their response to reviewers, they report that high expression of the introduced gene activates feedback that returns SRSF1 to normal levels.

Plesa and Church founded RegulaBio, a company developing therapies for age-related diseases. They are listed as inventors on a patent application covering the use of SRSF1.