Are Yamanaka Factors the Path to Reversing Aging?

By Sohom Haldar

Rejuvenation, the reversal of aging, has often been the focus of many science-fiction shows, such as Doctor Who, and other forms of popular culture. However, for much of the last century, rejuvenation has only seemed to be a myth and not potentially real. However, research of the Yamanaka factors may soon change this for good.

To start with, what is the cause of aging? One of the main reasons for aging is the build-up (or accumulation) of errors within the epigenome. Epigenetics is how the environment and individual behaviour cause changes in the function of DNA and RNA, changes that are reversible and do not change the base sequence of DNA. The epigenome is linked with epigenetics and is a record of the chemical changes to the DNA and histone proteins of an organism over its lifetime. The rate of introduction of these epigenetic errors into DNA increase throughout life, leading to senescence, deregulated homeostasis and more, finally resulting in aging and eventually, death.

The Yamanaka factors were discovered during a study between 2006 and 2012 by Professor Shinya Yamanaka. This led to Yamanaka receiving the Nobel Prize for Physiology or Medicine in 2012 so this discovery is evidently ground-breaking. Professor Yamanaka was the first person to produce induced pluripotent stem cells (iPS cells) from adult human body cells in 2006, using 24 transcription factors. Transcription factors are proteins that determine whether a section of DNA is transcribed into messenger RNA (mRNA). These 24 transcription factors were known to be important for embryonic stem cells in their process of differentiation. Over six years, Professor Yamanaka decreased these transcription factors to four, only the required and most important factors for iPS cell production: Sox2, Oct4, c-Myc, Klf4, together called the Yamanaka factors.

How are the Yamanaka factors (YF) useful for epigenetic rejuvenation? YF can be applied to adult cells to rejuvenate them, reversing errors within the epigenome, that partially would lead to aging. Theoretically, these rejuvenated cells can work as new specialised adult body cells, without the epigenetic errors, meaning that aging slows or reverses partially in the person of interest. This general process is called transient programming among other names.

However, this theory is flawed in one important way. When large doses of YF are applied to adult body cells, these cells become iPS cells, which mean that the identity of these cells has been erased. An example of what this means follows: If a liver tissue cell has a large dose of YF applied to it, this cell becomes an iPS cell. This cell is pluripotent, so it can differentiate into many different types of cells, not just liver tissue cells. The dangerous part of this is shown by the fact that when whole mice had large amounts of YF applied to them, the mice’s cells lost their functions and so, from iPS cells, cancerous cells formed, producing tumours that killed the mice.

Despite this setback, research on YF has been continued by Dr Sebastiano of Stanford University, who found that if a low dosage of YF is applied to cells, crucially during a short period of time, the adult body cells in question did not lose their identity but did still lose their epigenetic errors.

It is expected that as this research continues, aging will be a change that cannot just be masked cosmetically, but reversed, or at the minimum, slowed down. YF will most likely have a crucial part in not just rejuvenation medicine, but all specialities of medicine in the future, and that the discoveries presented here are just the start for YF in medicine.

References:

GEN - Genetic Engineering and Biotechnology News. 2020. iPSC Tech Rejuvenates Aging Muscle Cells to Give Mice Youthful Strength. [online] Available at: <https://www.genengnews.com/news/ipsc-tech-rejuvenates-aging-muscle-cells-to-give-mice-youthful-strength/> [Accessed 5 June 2021].

Kozlov, M., 2020. Genetic Reprogramming Restores Vision in Mice: Study. [online] The Scientist Magazine®. Available at: <https://www.the-scientist.com/news-opinion/genetic-reprogramming-restores-vision-in-mice-study-68232> [Accessed 5 June 2021].

Weintraub, K., 2016. Aging Is Reversible-at Least in Human Cells and Live Mice. [online] Scientific American. Available at: <https://www.scientificamerican.com/article/aging-is-reversible-at-least-in-human-cells-and-live-mice/> [Accessed 5 June 2021].