Scientists Reverse Aging in Cells and Mice With a Single Gene

Aging has long been treated as an inevitable, one-way decline, a slow accumulation of damage that no intervention could meaningfully undo. That assumption is now being challenged in a striking way. Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University, working with computational biologists at CIC bioGUNE in Spain, have identified a single gene whose over-expression can measurably rejuvenate aged human cells in the laboratory and, when delivered to living animals, slow aging and extend lifespan in mice by 14 percent. The study, published in Nature Aging, describes not a dramatic cellular reset but a carefully calibrated nudge, one that coaxes old tissue back toward youth without erasing the specialized identity that makes each cell useful in the first place.

The scientific foundation for this work was laid two decades ago. In 2006, Shinya Yamanaka demonstrated that over-expressing just four transcription factors, now universally known as the Yamanaka factors, could reprogram mature cells all the way back to a pluripotent, embryonic-like ground state. The discovery earned a Nobel Prize and reshaped developmental biology. What followed was an even more tantalizing observation for aging researchers: when the Yamanaka factors are expressed only in short, carefully timed bursts, they can partially reprogram old cells into a more youthful condition, reversing multiple hallmarks of aging while the cells retain their specialized functions. The implication was profound. Aging, it seemed, does not have to be a one-way street, and even old cells retain a latent capacity for rejuvenation that modern biology might learn to unlock.

Yet the therapeutic promise of the Yamanaka factors has always been shadowed by a serious risk. Because these factors can drive cells all the way back to a pluripotent state, their over-expression raises the danger of cancer formation, and controlling exactly how far the reprogramming proceeds remains a formidable technical challenge. Alex Plesa, a scientist at the Wyss Institute and first co-author of the new study, framed the dilemma succinctly: in reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity, and achieving one without losing the other requires walking a fine line. That tradeoff has motivated a worldwide search for alternative factors that might rejuvenate aging tissues in safer and more controllable ways, and it is precisely this search that the Harvard-led team set out to systematize.

Their first challenge was measurement. How do you score rejuvenation reliably enough to screen hundreds of candidate genes? The most widely used tool, the epigenetic aging clock, reads chemical modifications to the genome that accumulate with age. But as Plesa explained, that approach does not scale well to screening because of high costs and the difficulty of interpreting its widespread changes. Instead, the team reasoned that any genuine rejuvenation process must ultimately manifest itself in altered gene expression programs that restore more youthful cellular functions. Gene expression, they concluded, was the right readout. Working with Antonio del Sol, an Ikerbasque Research Professor at CIC bioGUNE-BRTA in Spain, and postdoctoral fellow Sascha Jung, the study’s co-first author, they built a machine learning algorithm trained on transcriptomic profiles spanning multiple aging processes in human skin fibroblast cells from donors across a wide age range.

The resulting tool, which the team calls a transcriptomic aging model, functions something like a set of odometers for different parts of a car. It tracks changes in the expression of genes involved in distinct biological processes and integrates them into a single accurate overview of a cell’s age and health. Trained on gene expression data from 464 fibroblast samples, the model could pinpoint the transcriptomic age of skin cells from individual donors. Crucially, it also proved sensitive to real biological change: when the researchers treated fibroblast cell lines derived from donors aged 55, 65, and 79 with experimental lifespan-altering interventions, including the Yamanaka factors, the predictor accurately registered the resulting shifts in transcriptomic age. The team now had a scorable, quantitative yardstick for rejuvenation.

With that yardstick in hand, the researchers assembled a focused library of genes predicted to influence aging processes and over-expressed each one in aged fibroblast cell lines, hunting for candidates that could shift the cells’ aging score toward a more youthful value. One gene rose decisively to the top: SRSF1, which encodes an RNA processing factor. Over-expression of SRSF1 reduced features corresponding to several recognized hallmarks of aging, including cellular senescence, the state in which damaged cells stop dividing but refuse to die; proteostatic stress, a disruption of the normal balance and turnover of proteins; and inflammaging, the chronic low-grade inflammation that accompanies aging. The rejuvenation effects also registered on the conventional epigenetic aging clock and extended to the restoration of DNA repair programs, suggesting a broad and genuine reversal of age-associated molecular damage.

Just as important as what changed was what did not. The rejuvenated fibroblasts maintained their identity throughout the intervention. They kept their characteristic spindle-shaped morphology, continued expressing the genes that encode typical fibroblast functions, and did not activate the pluripotency programs that Yamanaka factors switch on. In other words, SRSF1 appears to rejuvenate cells by working through machinery that all cells already use, rather than overriding their identity, which is exactly the property that makes it a safer candidate for therapy than the pluripotency factors. As Plesa put it, the team worked 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.

The decisive test came in living animals. The researchers packaged the SRSF1 gene into a liver-tropic adeno-associated virus, or AAV, a widely used gene delivery vehicle, and treated aged mice. The gene primarily accumulated in the animals’ livers, and the results were remarkable on two fronts. First, the livers themselves showed signs of rejuvenation. Second, and more strikingly, the benefits were systemic: SRSF1-treated animals grew frail more slowly than controls and lived longer, with median lifespan extended by 14 percent. That a single RNA processing factor, delivered mainly to one organ, could slow the aging of the whole organism positions SRSF1 as what the researchers call a geroprotective target, and it hints that rejuvenation programs initiated in one tissue may be communicated and amplified throughout the body.

Exactly how SRSF1 accomplishes its multifaceted effects remains an open and actively pursued question. The protein’s best-known role is that of an RNA splicing factor, one that helps include alternative exon sequences in a subset of mature messenger RNA molecules. These alternatively spliced mRNAs are then translated by ribosomes into proteins with altered functions, effectively allowing one gene to produce a repertoire of protein variants. The team observed a strong trend of alternatively spliced mRNAs following SRSF1 over-expression, but as Plesa acknowledged, they are only just beginning to understand how these splicing changes bring about the multi-faceted rejuvenation program in tissues. Unraveling that mechanism could reveal additional targets and open entirely new avenues for intervention.

For George Church, the Wyss Institute core faculty member and Professor of Genetics at Harvard Medical School who led the study, the work represents a step toward a long-standing ambition: devising clinically useful de-aging strategies by identifying genes that, when engineered for under- or over-expression in aging target tissues, extend human health-span. In his view, aging research is transiting an inflection point where exponential progress in biotechnology is beginning to impact the core aging processes that would otherwise kill 90 percent of us. Significant hurdles remain before SRSF1 could reach the clinic, particularly around delivery and dosing, and further research into its systemic effects is clearly needed. But the study demonstrates something once thought impossible: that a precisely targeted gene, measured against a rigorous transcriptomic yardstick, can turn back key aspects of the aging clock in cells and in a living mammal, without sacrificing what those cells are meant to be.

Subject of Research: Gene expression reprogramming to reverse cellular and organismal aging using the RNA splicing factor SRSF1

Article Title: Reversing age by reprogramming gene expression networks

Article References: Reversing age by reprogramming gene expression networks. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: aging, rejuvenation, SRSF1, gene expression, transcriptomic aging clock, Yamanaka factors, cellular senescence, RNA splicing, gene therapy, lifespan extension, machine learning, geroprotection