Splicing Factor SRSF1 Overexpression Produces a More Youthful Transcriptome and Slows Aging in Mice
Researchers are engaged in finding alternative ways to induce the desirable epigenetic rejuvenation produced by exposing cells to the Yamanaka factors, without the risk of losing cell state to dedifferentiation and the creation of induced pluripotent stem cells that could give rise to tumors. Yamanaka factors are a challenging basis for many forms of therapy because it would be somewhere between difficult and impossible to reconcile the different requirements for dose and timing for different cell populations in a tissue. Here, screening leads researchers to a splicing factor that is capable of producing some degree of epigenetic rejuvenation in cells and extended healthy life in mice. Splicing factors are of interest because each influences the expression of many different genes, potentially thousands of genes, and thus represent centralized points of control over cell state and behavior. This result will likely encourage a range of existing programs aimed at better understanding what can be achieved by manipulation of splicing factor activity.
The therapeutic use of Yamanaka factors is causing concern for some researchers because their overexpression also raises the risk of cancer formation. Researchers have therefore been hunting other factors for rejuvenating aging tissues in safer and more controllable ways. However, "in reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line."
In this study, researchers designed a machine learning algorithm trained on gene expression (transcriptomic) profiles across multiple aging processes in human skin fibroblast cells spanning a wide age range. This predictor accurately pinpointed the "transcriptomic age" of skin cells obtained from several donors. Leveraging this age predictor as a scorable readout then enabled the team to screen a focused collection of genes that were predicted to affect aging processes in one way or another. The goal was to identify candidates that, when over-expressed, could shift the originally assigned aging score of old fibroblast cell lines to a more youthful score.
The top-scoring gene, encoding an RNA processing factor known as SRSF1, was indeed able to reduce features that corresponded to several hallmarks of aging, such as a biological process where damaged cells stop dividing but do not die (cellular senescence), disruptions in the normal balance and turnover of proteins (proteostatic stress), and chronic low-grade inflammation (also dubbed "inflammaging"). Importantly, the rejuvenated fibroblasts maintained their identity: they kept their specific spindle-shaped morphology, continued the expression of genes that encode typical fibroblast functions and didn't induce the pluripotency programs that Yamanaka factors turn on. Importantly, when delivered to aged mice, where it primarily accumulated in the liver, SRSF1 reduced the animals' rate of aging and extended their lifespan by 14%, highlighting SRSF1 as a "geroprotective" target.
Link: https://wyss.harvard.edu/news/reversing-age-by-reprogramming-gene-expression-networks/