Longevity Briefs: Reprogramming Cells To Reverse Ageing

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

What makes heart cells, brain cells and other cell types different despite containing the same genetic code? Epigenetic modifications – changes that alter how the genetic code is read – determine cellular identity. As we age, undesirable epigenetic alterations can occur that cause cellular identity to drift. Exposing these cells to a group of proteins called Yamanaka factors results in epigenetic reprogramming, in which cellular identity is erased and the cells in question become stem cells. Scientists have discovered that by tightly controlling exposure to Yamanaka factors, it is possible to erase only the age-related epigenetic alterations without affecting cellular identity, a technique known as partial reprogramming.

In this study, researchers investigate whether Yamanaka factors can be used to reverse a phenomenon they term ‘mesenchymal drift’. This refers to their observation that in human tissue biopsies, cells tended to drift from their original cellular identity in older age, boosting the activity of genes characteristic of mesenchymal cells. Mesenchymal cells can develop into a variety of other cell types and are involved in wound healing.

The discovery:

The researchers’ first observation from tissue biopsies was that genes associated with mesenchymal drift showed increased expression in samples from patients with chronic diseases like Alzheimer’s disease, atherosclerosis and osteoarthritis among others. They also found that lower mesenchymal drift could be used to predict longer survival in patients with idiopathic pulmonary fibrosis (formation of scar tissue in the lungs). This suggested that mesenchymal drift could be a contributor to chronic disease.

Researchers then investigated whether it would be possible to reverse mesenchymal drift with Yamanaka factors. As a first investigation, they exposed cells from an elderly human donor to Yamanaka factors and observed how gene expression changed during reprogramming. They found that mesenchymal genes were reprogrammed earlier on during the process, suggesting that there was a time window for reversing mesenchymal drift with partial reprogramming.

Finally, the researchers put this idea to the test in live mice. They found that controlled exposure to Yamanaka factors for varying periods of time was associated with significantly reduced mesenchymal drift gene expression in the liver, kidneys and spleen, as well as non-significant trends in other organs. However, not all cell types were affected in the same way. In the pancreas, most cell types actually showed an increase in mesenchymal drift-associated gene expression.

The implications:

This research suggests that partial reprogramming could reverse mesenchymal drift, a phenomenon that is associated with various chronic age-related diseases. Previous studies have suggested that partial reprogramming can delay some aspects of ageing and extend lifespan in mice, and reversing mesenchymal drift may be just one of many benefits to partial reprogramming. The effects of partial reprogramming in humans are still unknown and come with significant risks (such as reprogramming progressing too far), so we shouldn’t expect to reap the benefits any time soon. Further optimisation and study will also be required to understand why some cell types were affected differently to others.