As we grow older, the body’s ability to bounce back from injury or illness steadily weakens. Cuts heal more slowly, organs recover less completely, and the cumulative wear of time becomes harder to repair. New research from the University of California, San Francisco, suggests this decline may not be inevitable. Scientists there have identified a group of gene regulators — proteins that control when genes are switched on or off — that appear capable of restoring some of the ageing body’s lost capacity for self-repair.
The researchers focused on fibroblasts, a vital but often overlooked type of cell. Fibroblasts construct and maintain the scaffolding that sits between cells, providing shape, strength, and structural support to tissues and organs throughout the body. This cellular framework is constantly under strain from everyday wear, illness, and injury, and fibroblasts typically work continuously to repair and renew it. With advancing age, however, these cells become less active, and the tissues they support begin to deteriorate.
As fibroblasts slow down, the consequences ripple outward. Structural damage accumulates, healing becomes inefficient, and organs become more vulnerable to disease. When the scientists examined older fibroblasts, they found clear molecular signs of decline, particularly in the way these cells expressed their genes. Patterns that were once tightly regulated had become disordered, reflecting the broader breakdown in cellular function associated with ageing.
Using computational analysis, the team traced these changes back to a specific set of transcription factors — gene regulators that orchestrate large networks of genetic activity. These factors appeared to be key drivers of the ageing process in fibroblasts. By identifying which transcription factors were responsible, the researchers uncovered a potential way to reverse age-related changes at their source, rather than simply treating their downstream effects.
To test this idea, the scientists compared gene expression in young and old fibroblasts grown in laboratory dishes, then used advanced modelling to pinpoint which transcription factors were pushing cells towards an aged state. They subsequently used CRISPR-based techniques to adjust the activity of these factors in older fibroblasts. Remarkably, altering the levels of any one of thirty transcription factors was enough to trigger a youthful pattern of gene expression. In particular, changes to four of these regulators significantly improved cellular metabolism and restored the cells’ ability to multiply — two hallmarks of younger, healthier fibroblasts.
The work extended beyond cell cultures into living organisms. In collaboration with colleagues specialising in anatomy and ageing, the team showed that increasing levels of a transcription factor called EZH2 rejuvenated the livers of elderly mice. These animals, roughly equivalent in age to humans in their mid-sixties, showed dramatic improvements: liver fibrosis was reversed, fat accumulation was reduced by half, and glucose tolerance improved. Together, the findings suggest that carefully reprogramming gene regulation could one day form the basis of therapies aimed at treating, or even reversing, diseases driven by ageing rather than simply managing their symptoms.
More information: Janine Sengstack et al, Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation, Proceedings of the National Academy of Sciences. DOI: 0.1073/pnas.2515183123
Journal information: Proceedings of the National Academy of Sciences Provided by University of California – San Francisco
