You’ve heard the old saying that age is just a number. But what if you could lower that number by about 30 years? Epigenetic researchers from the Babraham Institute in the UK say it’s possible. What’s more, they have proven it experimentally, using a new method based on Shinya Yamanaka’s Nobel Prize-winning technique to create stem cells.
The study, recently published in eLife, demonstrates how older skin cells can be restored and rejuvenated by erasing some of the genetic marks that make them specialized. The process, in effect, partially reprograms cells, allowing them to retain their identity as skin cells, just biologically younger.
As mentioned in previous articles, biological aging (the actual age of our cells, tissues, and organs) is caused by various factors and processes– many of which are due to errors that accumulate in the epigenome. Over time, the body reacts to environmental conditions and life experiences, causing chemical modifications within cells that alter genes expression. Epigenetic mechanisms, like DNA methylation and chromatin remodeling, regulate these processes. Therefore, assessing cellular epigenetic elements can more accurately estimate ‘true’ age.
“Our understanding of aging on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells,” said the lead author of the study, Dr. Diljeet Gillfrom a biologist at the Babraham Institute.
One approach to determining biological age is through the use of an epigenetic clock. This biochemical test measures DNA methylation or the accumulation of methyl marks attached to DNA. Several studies have found numerous regions along the DNA where methylation levels correlate with age. Because this mechanism is reversible, it opens the possibility of developing antiaging interventions.
In the current study, the scientists wanted to keep the characteristics that make the cells unique for skin but substantially reduce their DNA methylation age. So, they devised a new method, called maturation phase transient reprogramming (MPTR), where reprogramming aspects are selectively expressed to the point of rejuvenation and then withdrawn.
The method uses the same four key molecules (or Yamanaka factors) used to make induced pluripotent stem cells (iPS cells) but has an adjusted exposure time. Typically, IPS cells take about 50 days for complete reprogramming. Here, the team limited the cells’ incubation time to just 13 days, allowing age-related modifications to be removed, with only a brief loss in cell identity.
With time to grow under normal conditions, the cells reacquired their original somatic fate as skin cell fibroblasts. The team believes this was most likely due to persistent epigenetic memory and gene expression, which can remain during the intermediate stages of transient reprogramming. In addition, DNA methylation array and RNA sequencing analysis confirmed the cells’ restored identity, as did the observation of collagen production, a major function of dermal fibroblasts.
Remarkably, the cells were much more youthful than their middle-age donors by about 30 years as measured using an epigenetic clock and by analyzing transcriptome changes. They also tested the cells’ tissue repair response and found the treated fibroblasts were faster at healing cuts than older cells. Next, the team plans to conduct more studies to see if MPTR’s rejuvenating effects are constant.
Although the exact mechanisms underlying the success of this new cellular reprogramming method have yet to be determined, the work is significant and holds promise for the eventual development of therapeutics to treat skin damage as well as other age-related diseases conditions.
“Our results represent a big step forward in our understanding of cell reprogramming,” said Diljeet. “We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work.”
Source: D. Gill, et al. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. eLife, April 8, 2022.
Reference: A jump through time – new technique rewinds the age of skin cells by 30 years. Babraham Institute, April 8, 2022.