Cellular Rejuvenation Therapy Safely Reverses Mouse Aging

Salk researchers use a Nobel-Prize-winning technology called “cellular reprogramming” to reverse signs of aging in mice safely.

By Yedida Bogachkov, Ph.D.

Key Points:

  • The activation of reprogramming factors – proteins that can turn mature cells back into stem cells – in mice safely rejuvenates skin and kidneys.
  • The rejuvenating effects reduce the activation of genes involved in several age-related pathways, including inflammation, stress, and senescence. 
  • The clocks of aging, as measured by changes to patterns in DNA modifications (epigenetics), were turned back by treatment with reprogramming factors.

While many ancient cultures have dreamt up a version of a river with rejuvenating properties, a so-called “Fountain of Youth,” scientists now have provided a therapy that turns back the clock on our aging bodies.

In a new study published in Nature Aging, researchers from the Salk Institute in San Diego, California, rejuvenated aged mice using a group of proteins known as the “Yamanaka factors.” The scientists created mice that could be manipulated to produce these proteins, made famous for their ability to “reprogram” mature cells to their earliest states as stem cells. When the Yamanaka factors were activated, the researchers safely turned back the biological clocks of aging mice in several tissues, such as the skin and kidneys. This landmark study demonstrates that cell reprogramming is a safe and effective strategy to reduce age-related conditions.

“We are elated that we can use this approach across the life span to slow down aging in normal animals. The technique is both safe and effective in mice,” says senior author Juan Carlos Izpisua Belmonte, professor at the Salk Institute. “In addition to tackling age-related diseases, this approach may provide the biomedical community with a new tool to restore tissue and organismal health by improving cell function and resilience in different disease situations, such as neurodegenerative diseases.”

Full- Versus Partial-reprogramming with Yamanaka Factors

Initially, every embryo (egg cell fertilized by a sperm cell) is pluripotent – able to become any cell type. As humans develop and grow, most of their cells lose this pluripotent ability. The hope is that by restoring pluripotency, researchers can restore youth – wounds will heal faster, metabolisms will speed up, and inflammation will decrease.

Numerous reports indicate that exposing cells to the Yamanaka factors – named for Shinya Yamanaka, who won the 2012 Nobel prize for their discovery – can induce pluripotency within cells. However, complete reprogramming in animals with Yamanaka factors creates an environment rich for tumor development, so scientists have turned to partial-reprogramming, with transient (or inducible) factors, which can potentially rejuvenate cells to a more youthful state.

Long-term Partial Reprogramming Leads to Decreased Age-related Changes with No Obvious Side Effects

The Salk scientists used normally aging mice seven months old (about 38 years old in human years) and ten months old (about 50 years old in human years) and exposed them to the Yamanaka factors for 15 and 12 months, respectively – these were the long-term reprogramming groups. They also had one short-term treatment group exposed to the Yamanaka factors starting at 25 months old (about 75 years old in human years) for one month.

Browder and colleagues found that the mice with long-term reprogramming had rejuvenated skin and kidneys with lowered biological age. These effects included thicker skin, improved wound healing, and reduced age-related metabolic changes. Short-term reprogramming yielded some of these results but was not as robust.

Furthermore, the mice with long-term Yamanaka factor activation did not suffer from physical side effects, including teratoma (tumors formed from reproductive tissues, which may include teeth, hair, and bone) formation, neurological changes, dramatic changes in body weight, or changes in survival rates.

(Markel and Daley (2022) Nature Aging) Effects of Partial Reprogramming with Yamanaka Factors on Rejuvenation Browder et al. used three different mouse cohorts and looked at the impact of Yamanaka factors over both long- and short-term exposures. Long-term treatment led to decreased biological age in the skin and kidney and enriched metabolism genes, along with decreased genes relating to inflammation and senescence. Short-term treatment effects were not as significant.

Long-term Partial Reprogramming Reverses Age-related Genetic Changes

Changes in DNA methylation – modifications to DNA affecting gene activation – are well-known markers associated with aging. The researchers looked at the DNA methylation patterns in various tissues and organs, including the kidney, lung, liver, muscle, skin, and spleen. Significant differences were found only in the skin and kidney with the long-term reprogramming and not the short-term reprogramming, which showed no changes.

However, some enrichment was seen in the genes relating to oxidative stress regulation in the short-term treatment group. In the long-term reprogramming group, the genes associated with cellular metabolism and energy production were upregulated, while genes associated with inflammation and senescence (cells’ age-related inability to grow and divide) were downregulated.

Positive Skin Changes and Metabolic Changes Following Long-term Partial Reprogramming

The researchers found that the genes related to skin cell differentiation were downregulated in the long-term reprogramming group, suggesting that the cells could more easily grow and change into different cell types. Additionally, there was increased proliferation, indicative of increased skin cell turnover, among those mice. The mice also experienced less scarring following wound healing, similar to that in much younger mice.

Furthermore, when the investigators ran lipid (fats and cholesterol) panels on the mice, they found that the age-related elevation of triglycerides (fats) and reduction in phospholipids (like cholesterol) was decreased in the long-term treatment group. The scientists suggest that the lack of changes in the short-term group may be due to age more than the treatment length. The 25-month old mouse cells may just be too set in their way to be rejuvenated, and more research is needed on short-term partial-reprogramming.

The Fountain of Youth in a Petri Dish?

Since their discovery in 2006, the Yamanaka factors have inspired a new way of looking for the fountain of youth. The days of setting sail to reach unexplored lands to find a hidden elixir have passed. Instead, our contemporaries are forging ahead with new ways to utilize the factors to treat various diseases and the typical effects of aging.

Yamanaka factors have been used to reverse age-related DNA modifications within mouse eye cells, along with helping to speed up the healing of eye injuries in older mice. They have also been demonstrated to extend the lifespan of mice plagued by an early aging disease called progeria. However, some scientists are concerned about the Yamanaka factors’ ability to induce tumor formation and the need for manipulation at a genetic level to reap their rejuvenating benefits.

The jury is still out about whether the Yamanaka factors hold the secret to youth and rejuvenation, but they seem to be a step in the right direction. However, there are currently no clinical trials, as scientists still work on tweaking how Yamanaka factors are activated. Still, in the not too distant future, we may be able to join clinical trials offering youth and rejuvenated bodies. Given the choice, would you join for the chance of obtaining youth? 


Browder, K.C., Reddy, P., Yamamoto, M., et al. In vivo partial reprogramming alters age-associated molecular changes during physiological aging. Nat Aging (2022) https://doi.org/10.1038/s43587-022-00183-2

Markel, A. and Daley, G.Q. Dipping a toe in the fountain of youth. Nat Aging (2022) https://doi.org/10.1038/s43587-022-00188-x

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