Cellular rejuvenation therapy: How scientists can reverse ageing

Ageing, a part of life that has so far been inevitable, brings about the onset of several dreaded consequences. The body slows down, organs no longer function like they used to, and the risk for fatal diseases such as Alzheimer’s, cancer, and severe diabetes increases.

This is reflected in our cells, as ageing can lead to long-term epigenetic changes—non-genetic influences that do not change the DNA sequence but affect gene expression. Thus, older organisms' DNA shows chemical patterns different from that of their younger counterparts.

The idea is that if these changes can be prevented, halted, or reversed, then scientists will have achieved the means to prolong life and sustain a healthy ageing process, preventing or even treating its many negative consequences.

This is just what scientists from the Salk Institute in the United States tried to do by experimenting on middle- and old-aged mice with gene therapy, refreshing their old cells.

In a study published in the Nature Aging journal called “In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice,” Salk researchers found that they could partially rejuvenate mice cells to reverse ageing effectively and safely.

Yamanaka factors

In 2016, Juan Carlos Izpisua Belmonte, co-author of the study and professor in Salk’s Gene Expression Laboratory, had found that reprogramming molecules, Oct4, Sox2, Klf4 and cMyc proteins called “Yamanaka factors”, could be used to reset epigenetic changes in cells.

With this, Belmonte’s lab was able to counter the signs of ageing in mice and increase their lifespan.

Later on, his team tested reprogramming Yamanaka factors in younger mice and found that they could speed up muscle regeneration. The findings from Belmonte’s lab led to further experiments, and scientists were able to improve heart and brain tissue functions.

In short, partial reprogramming with Yamanaka factors for a short period could restore the youthfulness of organisms’ cells and extend lifespan. So, in the 2022 study, Salk researchers experimented on the long-term effects of Yamanaka factors.

They used the reprogramming molecules to refresh old cells to younger states in healthy mice in three experimental groups, starting from the mice’s ”middle-age.”

One group consisted of mice that were 15 months old and were treated with Yamanaka factors until they hit 22 months, corresponding to the ages of 50 to 70 in humans. Another group was treated from 12 months until 22 months, or 35 through 70 in humans.

The last group was the control group for the assessment of short-term effects of the same treatment, consisting of 25-month-old mice (80 years old in human years) that were treated for just one month.

After the treatment, the researchers saw that mice that were treated with the Yamanaka factors resembled their younger counterparts more than mice of the same age that were not treated. 

Furthermore, the treatment was more effective in the long term than the short term, and the effects were not as evident after the first half of the long-term treatment as when it was complete. Other than the apparent superiority of long-term treatment, this signals that the reprogramming molecules were reversing ageing, on top of stopping it.

Epigenetic characteristics of the skin and kidneys of long-term treated mice appeared to parallel younger mice. Their skin cells had improved ability to proliferate and exhibited less scarring— the opposite could be expected for older animals—and their blood examination did not show the age-related changes in metabolic molecules one would also expect to see in older animals.

“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,” Salk News quoted Belmonte as saying.

Moreover, the treated mice did not suffer from changes to their blood cells or neurological makeup, and did not show signs of cancer.

“What we really wanted to establish was that using this approach for a longer time span is safe,” Salk News reported 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, behaviour or bodyweight of these animals,” Reddy added.

This is a crucial finding, especially because scientists had previously seen that the use of these reprogramming molecules could lead to cancer in organisms, including human cells.

Consequently, although the treatment is exhilarating because of its potential for extending the human lifespan, it is still too early to figure out whether the above use of Yamanaka factors would have the same effects on human beings.

However, since the treatment was proven to be safe for mice, then there is a chance that one day in the future, a version of the treatment will be available for humans as well— and if not, there is always hope to extend the life-spans of other animals, like pets.

“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. This study shows that, at least in mice, there’s a path forward to achieving that,” says Reddy.