Rewinding the clock on ageing: Scientists rejuvenate tissues in middle-aged mice

Cellular rejuvenation therapy has safely reversed signs of aging in mice in a new scientific experiment.

"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 Juan Carlos Izpisua Belmonte, co-corresponding author and a professor in Salk's Gene Expression Laboratory.

"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."

Repeating the trick in humans is far from straightforward, but the findings will fuel interest in radical new therapies that aim to slow or reverse the ageing process as a means of tackling age-related diseases such as cancer, brittle bones, and Alzheimer’s.

“A host of age-related diseases might benefit from this approach,” said Heinrich Jasper, a principal fellow, and director at the US biotech firm Genentech.

As organisms age, it is not just their outward appearances and health that change; every cell in their bodies carries a molecular clock that records the passage of time. Cells isolated from older people or animals have different patterns of chemicals along their DNA, called epigenetic markers, compared to younger people or animals.

Scientists say that adding a mixture of four reprogramming molecules, including Oct4, Sox2, Klf4, and cMyc, also known as "Yamanaka factors," to cells can reset these epigenetic marks to their original patterns. This approach is how researchers can dial back adult cells, developmentally speaking, into stem cells.

The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence, and stress response pathways.

Researchers believe that the observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes.

"What we really wanted to establish was that using this approach for a longer time span is safe," says Pradeep Reddy, a Salk staff scientist and co-first author of the new paper.

"Indeed, we did not see any negative effects on the health, behavior or bodyweight of these animals."

"At the end of the day, we want to bring resilience and function back to older cells so that they are more resistant to stress, injury, and disease," says Reddy.

"This study shows that, at least in mice, there's a path forward to achieving that."

In 2016, Izpisua Belmonte's lab reported for the first time that they could use the Yamanaka factors to counter the signs of aging and increase life span in mice with a premature aging disease.

Researchers are cautious about using Yamanaka factors in humans because previous work has shown that fully reprogrammed cells can turn into clumps of cancerous tissue called teratomas.