Loss of Epigenetic Information as a Cause of Mammalian Aging
The paper “Loss of epigenetic information as a cause of mammalian aging“, that was published in the apex journal Cell on 12.January 2023, is very compelling and deserves more attention. It was published by a team lead out of Harvard and focused on identifying what may be the the core driver of aging and a demonstration of an ability to reverse certain aspects of aging.
In the human body we have roughly 200 different types of cells, such as eye cells, skin cells, brain cells, heart cells, etc. However, they all have the same DNA. The same genetic code/genome at the nucleus of the cell. What makes those cells different and the reason they act and behave differently, is that they have different gene expressions. This means different genes in the cell that are “turned on” and “off”. When a gene is turned on, the protein that that gene codes for, is expressed and made in the cell. While for the genes that are turned off, the proteins are simply not made.
Proteins are the biochemical machines in biology. Thus, when certain proteins are produced, they do stuff and other proteins do not do stuff and the cell acts and behaves very differently. For some cells when you turn genes on and off, you get a neuron. For other cells when you turn them on and off, you get a muscle cell in your bicep. For other cells, you get a heart cell, etc. All of these cells are differentiated by the genes that are expressed. The general term for the expression of genes is the epigenome.
Epigenome
An epigenome basically refers to these systems whereby certain parts of the DNA, certain segments of genes, are uncoiled a little bit. If you zoom in on the DNA, there are 23 chromosomes and they are tightly wrapped in coils. When you zoom in even closer, you see that there are segments called nucleosomes. A nucleosome is like a bead and a bunch of DNA is wrapped around the bead. How closely those beads are together, and how much of the DNA is wrapped, allows a segment of the DNA to be opened up and then expressed. In other words, copies of the DNA are turned into RNA, which floats into what is called the ribosome.
Ribosome
The ribosome is the “protein printer“. The more these little segments of genome are exposed, the more they are expressed and there are certain chemicals, methyls and acetyls, that sort of attach to the genome and certain elements that allow parts of the chromosome to wrap up and get really tightly bound, or to unwrap and to express the gene. You can think of the epigenome like the software, and the genome/DNA is the hardware. Thus, the hardware basically defines what you can make, while the epigenome defines what is being made (what is turned on and what stuff is turned off).
The current main school of thought has been that aging meant that over time the DNA in our cells was mutating and errors were accumulating in the DNA and as a result of those errors, the cells start to dysfunction. What this paper and this work proves is that it may not be mutations in the DNA that is causing aging, but actually changes in the epigenome and that the DNA remains fairly stable and consistent over time.
Information Theory of Aging
Every second of your life about a million breaks in DNA in cells throughout your body are happening. Your DNA is being broken up and then there is a lot of mechanisms in your cell that fixes the DNA when it breaks. It turns out that our body’s mechanism for this is actually really good at fixing the DNA, so the DNA does not change as part of this. What seems to be happening is as your DNA gets fixed, the epigenome (the acetyl and methyl groups on the gene, on the chromosome) do not get put in the right place. Over time the epigenome degrades and this is considered the Information Theory of Aging.
Imagine making a lot of copies of a photo, using a photo printer, over time. Every time you make a copy, there is a little error, and those errors accumulate. The errors that accumulate cause the epigenome to change and as a result certain genes are turned on that are supposed to be off, and vice versa. Those cells start to get dysfunctional because the wrong proteins are being made and the cell can no longer do what it is supposed to do.
The ribosome (the photo printer in this analogy) is a static protein. It just does its function, and since there are hundreds of ribosomes in a cell, if one of them is dysfunctional its function ceases and then the other ribosomes step in and do the work instead. Thus, the ribosomes are constantly running.
The Epigenome Itself is the Core Driver of Aging
In this study they basically took two mice populations and facilitated so that one population caused its DNA to break at three times the rate of the other population. As the DNA broke, they could see that this mouse population got older faster (based on various age specific measures). Then they sequenced the DNA of the two populations of mice and showed that the older mice were genetically identical to the other mice that that stayed young. This tells us that it is the epigenome, and not the DNA itself that is changing.
Then they applied Yamanaka factors (four protein molecules) to the DNA of cells which cause all of the gene expression to reset back to looking like a stem cell (as all of the differentiated cells come from a stem cell). When doing this, the older population of mice suddenly started to act younger and all of the measures of age reversed. They did this across different tissue types, and measured this in a lot of different ways such as cognitive function, heart cellular, etc. When they applied those Yamanaka factors to the mice, they lived 107% longer than they were supposed to, but more importantly the health span improved making them healthier in terms of improvement of a vast amount of measures of healthiness in the body.
As a result, this is not just a fantastic new proof point of how Yamanaka factors can actually reverse age, but it demonstrates that the epigenome itself is the core driver of aging. Consequently, this paper might be one of the seminal papers that really propels the further work in figuring out how Yamanaka factors and other similar transcription factors can be applied in specific ways to actually reverse aging and cause the cells to start functioning correctly again.
There is a lot of work that remain, but now we have a much stronger proof point that the Information Theory of Aging may be the right way of looking at aging, that it is tied to the epigenome and that there are solutions that can work in reversing aging. This validates a lot of the work and the money that is going into this space both in the public and the private sector. At this stage, a lot of new startups are pursuing the opportunity to figure out how we can use these transcription factors to reverse aging, which may lead us to much healthier lives.
If you have long-term heart disease the cells can get healthier, but be aware that epigenetic reprogramming can not eliminate e.g. the calcium plaque in your arteries, which is a totally different health problem. There is also a plaque element with Alzheimer’s, but the cause of that and the cellular dysfunction may be reversible. Also, as people get older, protein intake and processing is reduced, contributing to loss of muscle mass. Thus, considering the musculoskeletal system, which has four primary soft tissues: skeletal muscles, tendons, ligaments and articular cartilages, it could definitely lead to a reduction of injury rates for elderly people.
There may be clinical trials coming to market really fast, particularly with ex-vivo therapeutics (where you take cells out of your body, apply the Yamanaka factors, and then put them back in your body) for certain tissue types such as eye cells, or T cells in your blood. There is a lot of ways that this may come to market faster and it is not just about reversing your age overall, but reversing the age of certain cell types in your body that can then have profound health impacts in the near term. Maybe some number of years down the road, we figure out a way to reverse the age of all the cells in our body and the whole body becomes more youthful. However, for now it is going to be targeted cells in a very specific way to reverse aging and improve health.
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