Rejuvenation Factor Extends Lifespan and Healthspan in Mice

A recent study identified SRSF1, an RNA-processing and splicing factor, as a molecule with geroprotective potential. Inducing SRSF1 expression rejuvenated human cells in vitro, extended lifespan, and significantly reduced frailty in mice [1].

Alternative approaches

Differentiated cells have the capacity to rejuvenate if an appropriate molecular environment is provided. The best-known factors that enable cellular rejuvenation are the Yamanaka factors, which can reprogram differentiated cells into induced pluripotent stem (iPS) cells. While cellular reprogramming with Yamanaka factors can reverse aging signatures, it can cause cells to lose their identity. This has prompted researchers to seek alternative approaches, especially since rejuvenation and dedifferentiation processes can be separated [2-4].

“In reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line,” said Alex Plesa, Ph.D., the study’s first co-author.

These researchers searched for an alternative approach to cell rejuvenation by investigating age-associated shifts in gene expression, since the genes that a cell expresses at a given time (the transcriptome) defines the cell’s identity and changes with age.

Building a model

This team started by building a transcriptomic aging model. They trained a machine-learning predictor on gene expression data from primary normal human dermal fibroblasts from people aged 1 to 96 years, teaching it to assess cellular age. They grouped the gene expression data by its associated cellular processes, allowing them to identify modules that best predict chronological age. The model also identified interventions and cellular states that affect cellular age faster than a commonly used DNAm clock, suggesting that gene expression changes are much faster and more sensitive than more stable DNA methylation changes.

“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, but it doesn’t scale well to screening approaches because of high costs and challenges with interpreting its widespread changes,” said Plesa. “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,” said Plesa.

Rejuvenating cells and body

The developed models were used in the screen that identified the age-reversal factor SRSF1, an RNA-processing and splicing factor whose expression declines during fibroblast aging.

The authors built a library of preselected genes previously linked to human-aging-associated networks. They overexpressed those genes in human dermal fibroblasts and used their transcriptomic age predictor to evaluate how each gene affected the cells’ transcriptome. SRSF1 was the most robust hit for transcriptomic rejuvenation (comparable to OSKM). Further cell culture experiments showed that SRSF1 induction reverses multiple hallmarks of aging: it reduced senescence markers and senescence-associated secretory phenotype programs, proteostatic stress, and inflammatory signaling, while inducing DNA repair pathways.

Unlike OSKM-driven rejuvenation, SRSF1-mediated rejuvenation does not cause cells to lose their cellular identity in terms of transcriptional state and morphology, despite reducing transcriptomic and epigenetic age.

At the whole-body level, SRSF1 induction extended healthspan and lifespan in aged mice. Specifically, acute SRSF1 induction reduced frailty by 44%, accelerated wound closure, reduced mortality risk, and extended median lifespan by 14% in aged mice. This was achieved despite using a viral vector with a tropism for the liver, limiting its systemic effects.

“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,” said Plesa.

Based on these results, the authors suggested that delayed physiological deterioration is a key contributor to lifespan extension, since they observed an association between frailty burden and survival. Additionally, comparing gene expression in mouse liver with previously analyzed human fibroblasts pointed to downregulation of similar molecular pathways: age-associated stress responses, inflammatory pathways, and cell-cycle programs following SRSF1 induction. However, these observations came from a small-scale experiment with only 9-10 female mice per group.

Constitutive SRSF1 induction produced higher SRSF1 levels, and while it didn’t cause toxicity, it did not improve wound repair or muscle regeneration. These observations point to the importance of treatment timing and dosing. As the authors suggest, SRSF1 might not be a simple ‘on switch’ for regenerative processes but a precisely regulated molecule. Therefore, designing a future therapy that would use SRSF1 induction would require precise dosing and timing regimens.

Alternatively spliced

The DNA code for a gene is not a direct, straight line of code; it’s made of exons (coding parts) interspaced by introns (non-coding). When the gene is transcribed into RNA (an intermediary between a gene and a protein), some exons can be included, and some can be removed, allowing multiple versions of a given protein and adding another layer of gene expression regulation and protein functions. SRSF1 induction affected these processes and created a “consistent splicing landscape dominated by alternative first exon (~45%) and skipped exon (~25%) events.”

Analyzing this splicing data alongside data on differentially expressed genes pointed to dual regulation of key genes in epigenetic and endoplasmic reticulum pathways, offering insights into SRSF1’s rejuvenation effects; however, future studies are required to understand the mechanistic links between those molecular processes and observed cellular effects, such as tissue rejuvenation.

“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,” said Plesa.

A geroprotective therapeutic target

This study identified SRSF1 as a key player in regulating aging processes and a potential geroprotective target. The authors see it as a potential target for future anti-aging therapies.

“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,” said Plesa.

“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,” said Church, who is a Professor of Genetics at Harvard Medical School. “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.”

Literature

[1] Plesa, A. M., Jung, S., Wang, H. H., Omar, F., Shadpour, M., Choy Buentello, D., Perez-Matos, M. C., Horwitz, N., Cai, G., Ngian, Z. K., Magalhaes, C., Wagers, A. J., Mair, W. B., Del Sol, A., & Church, G. M. (2026). Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging. Nature aging, 6(10), 2057–2073.

[2] Rando, T. A., & Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell, 148(1-2), 46–57.

[3] Olova, N., Simpson, D. J., Marioni, R. E., & Chandra, T. (2019). Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging cell, 18(1), e12877.

[4] Roux, A. E., Zhang, C., Paw, J., Zavala-Solorio, J., Malahias, E., Vijay, T., Kolumam, G., Kenyon, C., & Kimmel, J. C. (2022). Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity. Cell systems, 13(7), 574–587.e11.