SCIENCE+CULTURE

Reversing Aging With Epigenetic Reprogramming

The Information Theory of Aging and Age Reversal Using Yamanaka Factors

In-Woo Park
Ellemeno
Published in
8 min readNov 30, 2022

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Photo by CDC on Unsplash

For as long as humans have existed, or since the medieval philosophers and theologians developed the concept of time being finite, we recognize that any living organism will eventually experience death. This understanding of mortality puts value into life, and it drives us to do the things we do every day.

However, with recent breakthroughs in the field of human longevity, we’re able to reject the idea of death being set in stone. We’ve made discoveries that hint at the possibility of extending our health span and curing many of the diseases that threaten humanity. We’ve even reversed this process of aging in mice, and we’re not that far from doing the same to humans.

But before we get into all of that cool stuff, let’s take a step back and reassess what aging actually is.

The Process of Aging

Think of cars. Over time parts wear down, metal rusts, filters get plugged, and so on.

The same happens with our bodies. Oxidative damage, telomere shortening, and exposure to radiation are some of the many processes that contribute to the wear-and-tear theory of aging.

Wear-and-tear theory sees cells as being like socks that only last so long before they become threadbare or get holes. They can patch themselves, like socks, but only so many times before they just don’t work anymore. -Mark Stibich, PhD, FIDSA

But it’s also important to recognize that there’s more than one theory of aging. The wear-and-tear theory is just one of many. There’s immunological theory, endocrine theory, free radicals theory, and the list goes on. But in this article, we will focus on the information theory of aging, which ties it all together.

A Review of Epigenetics

Every cell in your body has access to your full genome. A skin cell holds the same set of DNA instructions as a liver cell. However, the functions of the two cell types are completely different. Now, why’s this?

This is due to changes in the epigenome, which determines how your DNA is being expressed. Now although they don’t change your actual DNA sequence, they hold the power to determine how the sequence is being read.

But how exactly does this work?

There are two primary mechanisms in which gene suppression or activation can be induced, the first being histone modification. In our cells, nuclear DNA is tightly packed in the form of chromatins, which are winded around spool-like proteins called histones.

When histones tightly ‘spool’ or become tightly packed together, proteins that transcribe or ‘read’ the gene have trouble accessing the DNA. This results in that particular gene being inactivated. On the other hand, when histones ‘unspool’ or become loosely packed, the proteins that ‘read’ the gene can easily access the DNA; thus, activating it.

Histone deacetylation and acetylation (Image by Author)

Another way gene expression can be regulated is through a process called DNA methylation.

DNA methylation (Mariuswalter, 2016)

DNA methylation works by adding a methyl group (CH₃) to the cytosine nucleotide of DNA, which will then inhibit transcription for that gene. In other words, these methyl groups highlight certain regions of your DNA and indicate whether they’re activated or not.

These patterns of gene activation/ inactivation form histone marks, which represent the epigenetic information in our cells. What makes this so significant is that it tells the cell what type of cell to be. It’s what allows a skin cell to be a skin cell, and a liver cell to be a liver cell.

But how does this relate to aging?

The Information Theory of Aging

The information theory of aging developed by David Sinclair, A.O., Ph.D., implies that the loss of epigenetic information is what primarily causes aging.

Adapted from The information theory of aging: Hacking immortality? (Vujin, A., Dick, Kevin., 2020)

Every day there are trillions of DNA double-strand breaks in our bodies. These breaks occur due to natural radiation, chemical reactions within the cell, and occasionally during cell division. But since these breaks happen quite frequently, our cells are well prepared for them and do a sufficient job in repair.

However, like many natural processes, sometimes things go wrong. In the effort that our cells go to stick the chromosomes back together and reset the epigenome’s structure, there are times when they fail to do so. Histones aren’t returned to the right places, and DNA methylation occurs in places where it shouldn’t. This disruption in gene expression is also known as epigenetic noise.

Model for Large-Scale Chromatin State Transitions (Zhu et al., 2013)

The accumulation of epigenetic noise causes cells to lose their epigenetic information and forget what type of cell they were supposed to be. In other words, they lose their identity.

When one or two of our cells are affected by this, we’ll hardly notice. But as more and more cells lose their identity, we’ll start noticing a decline in our health. We develop symptoms of aging, and we become more susceptible to diseases such as Alzheimer’s or cancer.

A Deeper Look Into DNA Methylation & Epigenetic Clocks

As previously explained, DNA methylation is another way gene expression can be regulated. It’s an epigenetic mechanism that involves transferring a methyl group (CH₃) to a CpG site (sections of the genome where cytosine nucleotides are followed by guanine nucleotides). When the methyl groups bind to the cytosine nucleotide, they form 5-methylcytosine (methylated form of cytosine).

DNA methylation (Labclinics, 2020)

When cytosine nucleotides are methylated, gene transcription is profoundly repressed, preventing DNA from getting transcribed into RNA. Doing so in a controlled manner is what naturally distinguishes certain types of cells and differentiates their unique properties.

However, changes in these methylation patterns are found to be directly associated with the aging process. In general, these changes include local hypermethylation and global hypomethylation, which are both typical epigenetic hallmarks of senescence (the biological term for aging).

Using these patterns of changes in methylation, we are able to develop biological clocks that predict the process of aging. One of which is called the “Horvath Clock.” Named after Steve Horvath, Ph.D., this clock determines the biological age of an organism based on DNA methylation levels.

Comparison of epigenetic age predictors (Stevetihi, 2014)

We can read these biological clocks and tell you how old you actually are. Chronologically, you might be 40. But biologically you may be 50.

In fact, we can use these rates and patterns of methylation, and we can determine the chances of developing terminal diseases, and even predict when you’re going to die.

But the real question is, can we slow this down? Or even better, can we reset the system, the epigenetic structure, so that our cells can function the way they used to?

Epigenetic Reprogramming

There are a number of ways where we can rejuvenate our bodies and extend our health span: caloric restriction, intermittent fasting, NAD supplements, or even taking senolytics to clear senescent cells. These are all ways in which we can slow down the rate of aging.

But how can we reverse aging?

First, we must develop an understanding of the Yamanaka Factors. The Yamanaka factors (also referred to as OSKM genes) are four genes that are highly critical for the production of pluripotent stem cells (cells with the potential to develop into any cell type) from somatic cells. In other words, these factors can turn adult cells into stem cells when they’re over-expressed. And it does this by removing any methylation within the cell.

In 2020, a paper was released from The Sinclair Lab at Harvard Medical School, reporting that the eye of a mouse was epigenetically reprogrammed. But instead of using all four Yamanaka factors, the team only used three: Oct4, Sox2, and Klf4. This allowed the optic nerve cell to restore its youthful DNA methylation patterns while preventing the cell from completely resetting into a stem cell. In other words, the nerve cells had their biological age reversed, but still retained their cellular identity.

Nerve Regeneration (Sinclair Lab, 2020)

With this groundbreaking discovery, the team has not only proved that extending our health span is possible, but they’ve also proved that reversing aging is possible. And how many times can we do this? Maybe it’s twice. Or maybe it’s two-hundred times. Who knows?

Where We’re Headed Next

We often accept aging to be a naturally occurring process and that we can’t do anything about it. But if anything, aging is a disease on its own. As we age, our bodies lose their ability to fight illnesses as a result of epigenetic information being lost. And because of this, we become far more susceptible to other degenerative diseases such as Alzheimer’s, Parkinson’s, osteoporosis, or cancer; to name a few.

In our current world, we spend roughly thirty years experiencing a decline in our health and the last twenty carrying a sickness till it eventually leads to death.

Simulated survivorship curves for various stages of human life histories (Vujin, A., Dick, Kevin., 2020)
Disease or total death rates for the most common diseases of old age (Alzheimer’s Europe, 2009)

But what if this wasn’t the case? What if the symptoms of aging and the diseases that follow it were all things we didn’t have to worry about?

Is it worth the investigation? Is it even considered natural?

As a response to that, nothing humans do nowadays is purely natural. Trying to directly prevent the root cause of aging isn’t any different than transplanting organs or treating cancer using chemotherapy. We’ve evolved over time to learn and control the things that used to control us.

Although we’re very far from resetting every one of our ~37 trillion cells in our bodies, picturing a world where gene therapy can be used to treat age-related diseases is quite conceivable. With incredible breakthroughs such as cellular reprogramming (proven in mice), the field of human longevity continues to work towards a disease-free future.

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In-Woo Park
Ellemeno

17yo | Bio-Researcher | TKS Innovator | Pharmacy Assistant | Human Longevity