Science to Save the World – Cellular Reprogramming

For this episode of Lifespan.io’s general science show, Science to Save the World, we discuss cellular reprogramming, a technique that makes cells biologically young again.

Script

In 2006, a study by Drs. Kazutoshi Takahashi and Shinya Yamanaka showed that it was possible to reprogram cells using just four master genes: Oct4, Sox2, Klf4, and c-Myc, also called OSKM or Yamanaka Factors for short.

A somatic cell is any cell of a living organism other than a reproductive cell. Before the Yamanaka discovery, scientists assumed that egg cells, or oocytes, contained a complex array of factors needed to reprogram a somatic cell into becoming an embryonic cell. After all, they thought, the feat of reprogramming an aged egg cell to make a new animal must be controlled by many factors present in the egg cell.

Takahashi and Yamanaka turned this idea upside down when they showed that just four Yamanaka factors were needed to achieve this transformation. They used these factors to reprogram adult mouse connective tissue cells (fibroblasts) to an embryonic state called pluripotency, a state where the cells behave like an embryonic stem cell, and can become any other cell type in the body. This discovery paved the way for research into how Yamanaka factors might be used for cellular rejuvenation and a potential way to combat age-related diseases.

In 2011, a team of French researchers, including Jean-Marc Lemaitre, first reported cellular rejuvenation using the Yamanaka factors. During their life, cells express different patterns of genes, and those patterns are unique to each phase in a cell’s life, from young to old. This gene expression profile makes it easy to identify an old or young cell. At the time, it was also known that aged cells such as fibroblasts have short telomeres and dysfunctional mitochondria, two of the nine proposed reasons we age.

Jean-Marc Lemaitre and his colleagues tested the effects of Yamanaka factors on aged fibroblasts from normal old people and also from healthy people over 100 years old. They added two additional pluripotency genetic factors to the OSKM mix, namely NANOG and LIN28.

They then examined the effect that this had on the gene expression, telomeres, and mitochondria of these older people. They discovered that together, the six factors were able to reset cells from old donors back into a pluripotent state, meaning that they could become any other cell type in the body. These became known as induced pluripotent stem cells (iPSCs).

The researchers noted that the cells had a higher growth rate than the aged cells from which they had been reprogrammed. They also had longer telomeres as well as mitochondria that behaved in a youthful manner and were no longer dysfunctional. In other words, reprogramming the cells reversed some of the aspects of aging and rolled the cells back to a state similar to that of development.

The final step for the researchers was to guide these iPSCs to become fibroblasts again using other reprogramming factors. The result? The reprogrammed fibroblasts no longer expressed the gene patterns associated with aged cells and had a gene expression profile indistinguishable from those of young fibroblasts. Essentially, they showed that epigenetic alterations (changes to gene expression patterns, a reason we age), were reversed. In addition to this, they also showed that telomere length, mitochondrial function, and oxidative stress levels had all reset to those typically observed in young fibroblasts.

Telomere attrition and mitochondrial dysfunction are two more reasons that we are thought to age. This was the first evidence that aged cells, even from very old individuals, could be rejuvenated. This was followed by a flood of independent studies confirming these findings in fibroblasts and other types of cells. Could Yamanaka factors be used in living animals? Stay tuned for our next episode to find out.