The research team carried out a transcriptomic reprogramming screen that identified splicing factor SRSF1 as a regulator of aging. SRSF1 extended healthspan and lifespan when delivered to aged mice. This illustration conceptualizes this reprogramming as a transition from an aged, muted cell to a rejuvenated blue cell, with transcript strands emerging in newly spliced configurations and circuit-like patterns symbolizing the functional rewiring of the transcriptome by a single RNA processing factor. Credit: Helen Wang/Wyss Institute at Harvard University
Boosting a single gene, SRSF1, reversed several hallmarks of aging in human skin cells, according to a new study. Delivered to aged mice, it extended median lifespan by 14%.
The study, published in Nature Aging, examined whether a gene could rejuvenate aging cells without erasing their identity. That tradeoff has complicated the use of the Yamanaka factors—four genes that can reprogram mature cells to a pluripotent state, but also raise the risk of cancer.
To find safer alternatives, researchers at the Wyss Institute trained a machine learning model on gene expression profiles from 464 skin fibroblast samples from donors across a wide age range. The model tracks the activity of genes involved in different aging processes, much like separate odometers for different parts of a car, and combines them into a “transcriptomic age.” It accurately detected shifts in cell lines from donors aged 55, 65 and 79 after treatment with lifespan-changing interventions, including the Yamanaka factors.
That predictor then served as the readout in a screen of genes predicted to affect aging, each over-expressed in old fibroblasts. SRSF1, which encodes an RNA processing factor, scored highest. It reduced cellular senescence, inflammatory signaling and proteostatic stress, restored DNA repair programs and registered as more youthful on the epigenetic aging clock. The treated cells also kept their spindle-shaped morphology and fibroblast functions and did not switch on the pluripotency programs triggered by Yamanaka factors.
When the researchers packaged the SRSF1 gene in a liver-tropic adeno-associated virus (AAV) and used it to treat mice, they observed liver rejuvenation and systemic benefits. SRSF1-treated animals grew frail more slowly and lived longer, with median lifespan extended by 14% compared with controls.
SRSF1 helps include alternative exons in messenger RNAs, and the treated tissues showed a strong trend of alternative splicing, though how those changes produce such broad rejuvenation is still being worked out. The researchers suspect that targeting the liver may reverse aging processes in other organs too, with rejuvenation signals amplified across the body.
“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 Alex Plesa, scientist at the Wyss Institute for Biologically Inspired Engineering at Harvard University and first co-author of the study.
Data from Wyss Institute for Biologically Inspired Engineering at Harvard