Tissue Repair Slows in Old Age but These Proteins Can Speed It Back Up
As people grow older, their bodies lose the ability to heal quickly and efficiently. Wounds take longer to close, organs recover more slowly after illness, and tissues accumulate damage that is never fully repaired. Scientists have long known this happens, but understanding why it happens at the cellular level—and how to reverse it—has been a major challenge. New research from the University of California, San Francisco (UCSF) now sheds light on this problem and offers a promising path forward.
The study identifies a group of gene-regulating proteins, known as transcription factors, that can restore youthful behavior to aging cells and improve tissue health in older animals. The findings were published in Proceedings of the National Academy of Sciences (PNAS) in January 2026 and represent a major step toward understanding how aging affects tissue repair.
Why tissue repair slows as we age
One of the key reasons tissue repair declines with age lies in the behavior of fibroblasts. These cells are essential for maintaining the extracellular matrix, the structural scaffold that holds tissues and organs together. Fibroblasts produce collagen and other structural proteins, respond to injury, and coordinate the repair process.
In young bodies, fibroblasts are active, responsive, and efficient. They quickly turn on the genes needed for healing and tissue renewal. Over time, however, fibroblasts begin to slow down. Their gene activity changes, their metabolism becomes less efficient, and their ability to multiply and repair damage declines. This gradual slowdown contributes to problems like fibrosis, poor wound healing, and organ dysfunction.
The UCSF researchers focused on understanding what changes inside fibroblasts as they age, and more importantly, whether those changes can be reversed.
Comparing young and old cells at the genetic level
To answer these questions, the research team compared young fibroblasts and old fibroblasts grown in laboratory conditions. By analyzing gene expression patterns, they identified clear differences in how the two cell populations behaved. Older fibroblasts showed widespread changes in which genes were turned on or off, reflecting a loss of cellular youth.
Rather than targeting individual genes, the scientists took a broader approach. They looked for transcription factors, proteins that control the activity of many genes at once. Because transcription factors act like master switches, adjusting them has the potential to reset entire genetic programs associated with aging.
Using advanced computational modeling, the team pinpointed transcription factors that appeared to drive age-related changes in fibroblasts. This analysis led to a list of around 30 transcription factors with the potential to reverse aging at the cellular level.
Reprogramming old fibroblasts to act young again
The researchers then tested their predictions experimentally. Using CRISPR-based gene regulation tools, they altered the activity of these transcription factors in old fibroblasts. Importantly, this did not involve permanently changing the DNA sequence. Instead, it involved adjusting gene expression, nudging the cells toward a younger state.
The results were striking. Changing the level of any one of these roughly 30 transcription factors was enough to trigger a youthful gene expression pattern in old fibroblasts. Even more impressive, modifying the levels of four specific transcription factors improved key functional traits, including cellular metabolism and the ability of fibroblasts to divide and proliferate.
In other words, the cells were not just looking young at the genetic level—they were behaving young.
Testing rejuvenation in aging mice
Cell culture experiments are important, but the real test is whether these changes can improve tissue health in living organisms. To explore this, the UCSF team collaborated with other researchers to examine the effects of transcription factor manipulation in older mice.
One transcription factor in particular stood out: EZH2. When levels of EZH2 were increased in mice that were 20 months old—roughly equivalent to a 65-year-old human—the effects on liver health were significant.
The treated mice showed a reversal of liver fibrosis, meaning excess connective tissue buildup was reduced. Fat accumulation in the liver was cut by about 50%, and the animals displayed improved glucose tolerance, a key indicator of metabolic health. Together, these results suggest that adjusting transcription factor activity can rejuvenate aging tissues, not just isolated cells.
What makes this approach different from other anti-aging research
Much of aging research has focused on damage control: repairing DNA mutations, clearing out damaged proteins, or reducing inflammation. This study takes a different approach by targeting gene regulation itself.
Instead of fixing individual problems one by one, transcription factors allow scientists to reset entire genetic programs associated with aging. This strategy is powerful because aging affects many systems at once, and addressing it likely requires broad, coordinated changes rather than isolated fixes.
The researchers used a system called the Transcriptional Rejuvenation Discovery Platform (TRDP), which allowed them to systematically test how individual transcription factors influence aging-related gene expression. This platform could be used in the future to explore rejuvenation strategies in other cell types and tissues.
Why fibroblasts matter beyond wound healing
Fibroblasts do more than patch up injuries. They influence organ structure, immune responses, and even cancer progression. In aging tissues, dysfunctional fibroblasts can promote chronic inflammation and fibrosis, contributing to diseases of the heart, lungs, liver, and skin.
By restoring youthful function to fibroblasts, it may be possible to improve tissue health across multiple organ systems. This makes fibroblasts an especially attractive target for therapies aimed at healthy aging rather than just disease treatment.
What this means for the future of aging research
While this research does not suggest that humans will soon receive transcription factor treatments to reverse aging, it provides a clear roadmap for future studies. It demonstrates that age-related decline is not necessarily permanent and that cells retain the capacity to respond to rejuvenating signals even late in life.
The findings also raise important questions about safety, precision, and long-term effects. Transcription factors control many genes, and altering them must be done carefully to avoid unintended consequences. Future research will need to explore dosage, tissue specificity, and potential side effects before any clinical applications can be considered.
Still, the study represents a major conceptual shift. It shows that aging can be addressed at the level of gene regulation, opening new possibilities for treating age-related diseases and improving quality of life in older adults.
The people behind the study
The research was led by Janine Sengstack, who conducted the work as a graduate student in the laboratory of Hao Li, professor of Biochemistry and Biophysics at UCSF. The study involved a multidisciplinary team of scientists with expertise in computational biology, genetics, and aging research, highlighting the collaborative nature of modern biomedical science.
Research paper reference
Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation
Proceedings of the National Academy of Sciences (2026)
https://doi.org/10.1073/pnas.2515183123
