[AWC 1st Place] Epigenetic Reprogramming — The Elixir of Life?

Look at this graph of life expectancy against time from 1770 up to 2021; notice how there’s a spike in life expectancy from 30 years in 1870 to 72 years in 2021. Within less than 2 centuries, the life expectancy of a human has more than doubled.

Figure 1: Graph showing human life expectancy from 1770 to 2021. Image taken from

Our World in Data.

This is all thanks to rapid advancements in medical research, with the discovery of antibiotics being arguably the largest breakthrough in longevity to date, extending human life expectancy by 23 years on average (Hutchings, Truman and Wilkinson, 2019). That being said, the increase in life expectancy has gradually slowed down, causing many to think that we may be approaching our biological limit. Regardless, researchers in the field of longevity have not given up and continue to churn out research suggesting we may be able to live longer than we thought.

Enter epigenetic reprogramming, a growing field that aims to “reverse” aging by ameliorating epigenetic changes in our cells.

What is aging?

Aging is a multifaceted biological process that manifests as a gradual decline in physiological function and homeostatic mechanisms with time. The process of aging holds significance as it is generally associated with risks of many diseases including cancer (White et al., 2014), metabolic disorders (Xia et al., 2021), cardiovascular diseases (North and Sinclair, 2012), and neurodegenerative diseases (Hou et al., 2019).

What is epigenetics?

Ever wondered why there are different cells in our body, although every cell in the body has the same set of genomes? Well, it’s because of epigenetics.

Our genome consists of tens of thousands of genes stored in the form of double-stranded deoxyribonucleic acid (DNA) in the nucleus of each cell. In order for a gene to be expressed, the DNA has to be transcribed into ribonucleic acid (RNA) and translated into proteins. DNA is usually coiled around a protein called histones, like a thread wound around a spool, to form chromatin (Quina, Buschbeck and Di Croce, 2006). The chromatin can exist as loose euchromatin, which can be accessed and facilitates gene expression, or dense heterochromatin, which is inaccessible and blocks gene expression (Li, Carey and Workman, 2007). Chemical alterations to histone proteins as well as DNA molecules can induce the formation of either euchromatin or heterochromatin. Chemical alterations to histone proteins include acetylation, methylation, phosphorylation, and ubiquitylation. Acetylation of histones is generally associated with the expression of genes (Bannister and Kouzarides, 2011), while methylation, phosphorylation, and ubiquitylation are less straightforward in their effects and could cause both repression and expression of genes (Al, Simpson and Ishwarlal Jialal, 2019). Chemical alterations of DNA molecules usually involve methylation of a cytosine nucleotide in a cytosine-guanine sequence. Methylated cytosines recruit gene suppressor proteins and reduce interaction between DNA and transcription factors (Moore, Le and Fan, 2012).

The difference in which genes are expressed or not determines the fate of a cell, whether it becomes a neuron, a muscle cell, or other lineages of cell types. The regulation of chemical alterations by various factors such as molecular signaling, lifestyle, environment, and disease states is known as epigenetics (Al, Simpson and Ishwarlal Jialal, 2019). Simply, epigenetics refers to the reversible process of altering which specific genes are expressed without any

underlying changes to the genome.

Figure 2: Graphical representation of the formation of chromatin from histones and DNA.

Image taken from the National Human Genome Research Institute.

Epigenetics and Aging

Although the exact causes of aging have not been pinpointed, continuous research has characterized the cellular and molecular hallmarks of aging. One of those hallmarks is epigenetic alterations. In young individuals, cells within each cell type have the same gene expression, due to having similar epigenetic information. However, as an individual ages, epigenetic changes occur spontaneously due to environmental and internal factors. This results in the formation of abnormal chromatin, characterized by different histone variants being incorporated, altered DNA methylation patterns, and altered histone modification patterns. Altered epigenetic information leads to different transcriptional patterns, and can also lead to genetic mutations (Pal and Tyler, 2016). As a result of the different transcriptional patterns and mutations, genes are expressed incorrectly. Cellular dysfunction may ensue due to the expression of certain genes, or the production of misfolded proteins (Douglas and Dillin, 2010).

Figure 3: Overview of epigenetic changes during aging. Image taken from Science

Advances.

Rewinding the clock of life

Despite the apparently unidirectional process of aging, the ability of the aging clock to be put on hold and reversed is fundamental to the nature of life. With every fertilization event, a zygote is formed, in the case of humans from the fusion between a sperm cell and an egg cell, both of which have chronological age measuring into the decades. Yet, the product of this noble merging is a cell that somehow erases any trace of aging. This reprogramming process is even more accentuated in experiments using somatic cell nucleus transfer, in which the nucleus of a somatic cell is transferred to an enucleated oocyte, such as the pioneering work of Dr. John Gurdon that showed for the first time that differentiated nuclei from tadpole intestinal or muscle cells could be transferred into enucleated Xenopus eggs and give rise to mature and fertile male and female frogs (Gurdon, 1962).

Figure 4: Prof. John B. Gurdon SCNT experiment. Image taken from Gurdon, 2013,

Nobel Lecture.

The fact that the nuclei were capable of giving rise to viable embryos that were themselves capable of developing into fertile adults and did not exhibit premature aging is evidence that the chronological age of the donor nuclei had been reset. The fact that somatic cells can be rejuvenated and have their pluripotency (ability to differentiate into any cell lineage) restored has opened the doors to many seeking to induce pluripotent states in cells by synthetic means.

Epigenetic reprogramming

Over the years, numerous research has sought to induce pluripotency, but one has risen as a major player in the field — epigenetic reprogramming. As cells differentiate and age, they accumulate epigenetic alterations that allow them to maintain their identity and remain stable. The theory is that by reversing the epigenetic alterations, we are able to revert cells into their primordial states, forming induced pluripotent stem cells (iPSCs).

Pioneering work was done back in 2006 by Yamanaka and Takahashi whereby they discovered the overexpression of four transcription factors: Oct4, Sox2, Klf4, and c-Myc, now known as “Yamanaka factors” or “OSKM, rearranges the epigenetic landscape, and converts somatic cells to a pluripotent state (Takahashi and Yamanaka, 2006). This research had such a large impact that Shinya Yamanaka received the Nobel Prize in Physiology or Medicine in 2012.