A team led by geneticist George Church at Harvard’s Wyss Institute reports that raising the level of a single protein, called SRSF1, made aged human skin cells look younger in the lab and made old mice less frail1. In the mice, extra SRSF1 cut the build-up of frailty by 44% and was linked to a 14% longer median lifespan2. The study is published in the journal Nature Aging1. The mouse groups were small: 9 to 10 animals each2, all female3.
What happened
SRSF1 is a splicing factor, a protein that edits genetic messages. When a gene is copied into RNA, the working message cells use to make proteins, filler pieces are cut out and the useful pieces can be joined in more than one way3. SRSF1 helps control how those messages are cut and pasted together4. Its levels fall as human skin cells called fibroblasts age3.
The researchers were looking for a way to make old cells act younger without the drawbacks of the best-known method. That method uses the “Yamanaka factors”, four genes that can turn mature cells back into stem cells. Given in short bursts, they can partly turn back signs of aging while cells keep their jobs, but some researchers worry because they also raise the risk of cancer1. They can also make cells lose their identity3.
“In reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line.”
That is how Alex Plesa, the study’s first co-author, put it1.
The evidence so far
A clock built from gene activity
The team first built a computer model that estimates a cell’s age from which genes are switched on, rather than from chemical tags on DNA. It was trained on cells from 133 donors aged 1 to 96, and boiled aging down to 292 genes4. Plesa said the widely used DNA-tag “aging clock” does not scale well to large screens because of high costs and hard-to-interpret changes1.
A screen of candidate genes
The researchers then pushed up the activity of 89 candidate genes, one at a time, in aged skin cells, along with known aging modulators including the Yamanaka factors, and scored the results with their model4. SRSF1 was the strongest hit, with an effect comparable to the Yamanaka factors3. After three days, the cells’ predicted age dropped by a median of 16.2 years4.
Unlike cells given the Yamanaka factors, cells with extra SRSF1 kept their normal spindle shape and did not switch on stem-cell programs4. A separate DNA-tag clock also read them as younger4. In the dish, SRSF1 reduced markers of senescence (worn-out cells that stop dividing but do not die), eased stress from damaged proteins, dampened inflammation signals and switched on DNA repair pathways3.
Old mice
The team then raised SRSF1 in aged mice using a virus that mainly delivers genes to the liver3. A short-term boost reduced frailty by 44%, sped up wound closure, lowered the risk of death and extended median lifespan by 14%3. In the mouse livers, SRSF1 turned down some of the same pathways seen in the human cells: stress responses, inflammation and cell-division programs3.
What it does not show yet
This is a mouse and lab-dish study. Nothing here tests SRSF1 in people. The mouse experiment was small, with 9 to 10 female mice per group3, so no males were tested in that experiment. The journal summary itself is careful: it says extra SRSF1 “is associated with” a 14% longer median lifespan2.
The effect also depended on how SRSF1 was given. When it was switched on constantly at higher levels, there was no toxicity, but it did not improve wound repair or muscle regrowth3. The authors suggest SRSF1 is not a simple “on switch” and that any future treatment would need precise dosing and timing3.
Because the virus mainly reached the liver, it is not clear how much other organs were affected. Plesa said it is “very likely” that targeting the liver can reverse aging in other tissues3, but that is his expectation, not a result the study measured. The authors also note frailty and survival moved together, and suggest slower physical decline is a key reason the mice lived longer3.
Who is behind it
The work was led by Church and run by Wyss Institute scientist Plesa, with the computational biology group of Antonio del Sol at CIC bioGUNE-BRTA in Spain; Sascha Jung is co-first author1. Collaborators in Luxembourg also took part4.
The paper lists financial ties. Several authors, including Plesa and Church, are named as inventors on a patent application covering the use of SRSF1 and other factors in the study2. Plesa and Church are cofounders of, and hold equity in, RegulaBio, an early-stage company developing treatments for age-related diseases2.
Church described the aim of his lab in the institute’s announcement:
“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 healthspan. Our platform and findings on SRSF1 are an important step on that quest.”
That quote comes from the Wyss Institute’s own news release1.
How it fits the field
Since Shinya Yamanaka’s 2006 discovery, researchers have shown that old cells keep some ability to be pushed back toward a younger state1. Much of the field has focused on partial reprogramming with Yamanaka factors, while others look for safer, more controllable options1. This study offers one such candidate and a screening method to find more.
The findings are not new to the field in every respect. An earlier version of the work was posted as a preprint, a paper not yet checked by outside scientists, in November 20235. The newly published version has been through peer review1.
What to watch next
- Whether other labs repeat the mouse results in larger groups that include both sexes.
- Whether ways of raising SRSF1 beyond the liver, or with tighter control of dose and timing, are tested.
- Whether RegulaBio, the company tied to two of the authors2, announces work built on this finding.
