Before writing this article, I gave a talk at Microsoft explaining Age Reversal. Feel free to check it out!
Increasing human longevity is one of the most important and impactful problems we are currently tackling right now. It has been a mission since the dawn of human civilization to find the proverbial “fountain of youth”.
So far in the longevity field, there have been two strategies: extending lifespan and age reversal. There have been significant developments in extending lifespan with the 3 longevity pathways, shortening telomeres, and senescent cell accumulation. But today I want to deep dive into age reversal.
First, we need a little background on Epigenetics
Each cell in your body has access to your full genome, or 3 billion base pairs. Each unique cell, however, does not need every gene for its function. A liver cell has a different function than a nerve cell.
What controls what genes are used in a cell is called the epigenome. The epigenome has two mechanisms in which it can suppress genes: proteins called histones, and DNA methylation.
Your chromosomes are made up of tightly packed DNA which is called chromatin. The chromatin tightly winds around the histone proteins which makes those genes inaccessible.
Tightly wrapped chromatin is inaccessible to transcribed (transferred into RNA) which makes the gene in that part inactive. On the flip side, chromatin that is not tightly wrapped is able to be transcribed and is active.
The other way to regulate gene expression is through methylation. What are known as methyl groups (CH₃) bond to the cytosine nucleotide (the C in ATCG). You can think of these methyl groups like a highlighter telling whether or not to transcribe it into RNA.
As you age your epigenome changes. The reasons for this are still debated, some liken it to DNA damage, the effect is that gene expression in your cell changes. What is known as “epigenetic noise”, genes that should be off turn on, and vice-versa.
And just as the longevity researcher David Sinclair puts it, your nerve cell is no longer fully a nerve cell, it may be part skin cell. Your body starts to lose its identity. No wonder our bodies start to malfunction when as they get older if they are progressively turning into other cells. When a cell becomes changed it is known as senescent and stops performing cell division and begins to release toxins which can cause inflammatory diseases.
The question becomes, is there any way to delay or even reverse this process? Recent insights have found that it is actually possible to reverse the age of our epigenome. To understand how this experiment was conducted, there are two key technologies to understand.
The Horvath Clock
In 2015, a study conducted by Steve Horvath introduced a novel way to measure biological age. It is based on the levels of methylation in your epigenome. There are 353 cytosine locations or CpG islands that are measured to see if there is a methyl group there. The more methylation you accumulate the older you are. This is known as the Horvath Clock.
Theoretically, you could be chronologically aged 30 years old but biologically aged 50 years old. The rate at which you are aging is accelerating faster than realtime. Using this rate of aging you could extrapolate and determine the chances of developing terminal diseases and even when you could die.
A big benefit of the Horvath clock is that it can take in many different types of tissues and cell types. That means you can compare how old your liver is to your lungs.
The Horvath clock also is a great tool used by researchers developing anti-aging therapies. It allows for quick feedback on how old organisms develop instead of having to wait for their whole lifespan to get that data.
A good analogy for the Horvath Clock and epigenome is a car. When you first get a brand new car it is nice and shiny and all polished up. As time goes on, rust accumulates on the car and it accumulates quicker if you don’t take good care of the car. The Horvath clock is effectively measuring the “rust” in your epigenome, to see how quickly you are aging.
In 2012, Shinya Yamanaka won the Noble Prize for his usage of what is known as the Yamanaka Factors. The Yamanaka Factors are 4 genes that control transcription(transfer of DNA info to mRNA) in your body. What Yamanaka did was insert the four genes, through viral gene therapy (inserting the gene through a virus), into adult cells. Essentially, what the Yamanaka factors then do is wipe off all of the methylation in the cell which turns the adult cell into a stem cell.
Stem cells are cells that can transform into any other cell in the body. They are used to regenerate tissue and are used in a field called regenerative medicine. Adult cells that are transformed into stem cells are known as induced pluripotent stem cells or iPS cells.
Reversal of Aging
The culmination of these two tools led to techniques that could potentially reverse aging. Harvard graduate student, Yuangcheng Lu, who works at Sinclair Lab recently released a paper that could be groundbreaking in this field.
What Lu, and his team at Sinclair Lab, did was use 3 of the Yamanaka factors: Oct4, Sox2, and Klf4 in a viral gene therapy. By not using all four of the factors it would ensure that cells would not turn back to a stem cell-like state. Instead, they retained their cellular identity and their biological age was turned back as shown by the Horvath clock.
This was also shown by an experiment where they crushed the optic nerve in mice. Young nerve cells are able to regenerate but old nerve cells are not. In the old mice that were epigenetically reprogrammed the nerve was able to regenerate.
This is a very profound discovery because it is proof of the concept that cells lifespan can not only be extended but actually reversed. Imagine this same therapy but for humans in degenerative diseases like glaucoma, Parkinson’s, and Alzheimer's.
Since writing this article, I reached out to Yuancheng over Twitter and this is what he had to say about my article!
I have since fixed the typo 😜. Thanks Yuancheng for the support and interest in the article!
In a speculative future, there could be a time where at 25 years old you are injected with a virus that has the 3 Yamanaka factors, and at age 45 you take an antibiotic that could activate the expression of these genes. At 45 years old you could feel like you are 25 years old.
And then this cycle would repeat.
This is such an amazing technology that has incredible potential for age reversal. This raises so many questions in terms of societal changes and new expectations, how work would be changed, and economic and environmental impacts.
But that is the topic for another article.