Novel gene rejuvenation therapy preserves cell identity while reversing age

Every organ and tissue progressively loses function and integrity as it ages. In fact, researchers have identified "hallmarks of aging" that not only present specific processes impacted by age, but are also thought of as levers that, if successfully targeted, could help turn back the aging clock and result in tissue rejuvenation.

Predicting cell age through gene expression

"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.

Envisioning rejuvenating gene therapy

Taking full advantage of their transcriptomic age predictor, the researchers then designed a focused library of genes that were predicted to impact aging and could be over-expressed in aged fibroblast cell lines. "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.

The team scored all library genes using their novel age predictor and analyzed their effects on specific aging features. Coming out on top of this extensive campaign was a gene encoding the RNA processing factor SRSF1, which shifted multiple aging processes toward more youthful states. These rejuvenation effects registered on the epigenetic aging clock and extended to functional hallmarks, reducing cellular senescence, inflammatory signaling, and proteostatic stress, while restoring DNA repair programs. 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.

From rejuventating cells to rejuvenating a whole organism

Finally, the team wanted to see if the observed rejuvenation effects resulting from SRSF1 over-expression also carried over into a much more complex in vivo system. Very intriguingly, when they 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 to controls.

The most prominent role of SRSF1 is that of an "RNA splicing factor" that helps include protein-coding, so-called alternative exon sequences in a subset of mature messenger RNA molecules (mRNAs). These can then be translated by protein-synthesizing ribosomes into proteins, many of which have altered functions. "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. "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."

Other authors on the study are Helen H. Wang, Fawad Omar, Michael Shadpour, David Choy Buentello, Maria C. Perez-Matos, Naftali Horwitz, George Cai, Zhen Kai Ngian, Carol Magalhaes, Amy J. Wagers, and William B. Mair. The study was funded by the Wyss Institute at Harvard University, Aging and Longevity-Related Research Fund, Astera Fund at the Silicon Valley Community Foundation, and Spanish Ministry of Science and Innovation (award # PID2020-118605RB-I00).

Source:

Wyss Institute for Biologically Inspired Engineering at Harvard

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