by Patrick Cox
January 10, 2019
Just a few years ago, even talking about age reversal was considered crazy. It was common sense that aging was an inevitable process tied to the physical law of entropy.
Simply put, things tend to fall apart as time goes on, and scientists thought this was how aging functioned as well.
However, things are changing now. The theory of aging has undergone a tumultuous shift. Over the last seven years, success in cellular and animal rejuvenation experiments has started to wear down the consensus.
In respected journals, prominent scientists are now making the case for a mechanistic view of aging—a process that can be changed. For example, the authors of the paper “Rejuvenation by Cell Reprogramming: a New Horizon in Gerontology,” published just last month in Stem Cell Research & Therapy, make exactly this case.
The paper argues in favor of “the epigenetic model of aging,” which we will get to in a bit. It summarizes the findings of many studies showing that the aging process can be reversed not only in cells, but in animal studies.
Since it’s a scientific paper, it reads rather technically. So I enlisted the help of my biologist son, Ian, to try and explain this to you in layman’s terms.
The Cumulative DNA Damage Model of Aging
First off, we should clarify the word epigenetic. The dictionary defines it as “relating to or arising from nongenetic influences on gene expression.”
The old theory—which is now referred to as “the cumulative DNA damage theory of aging”— states that aging is a matter of entropy, the gradual and inevitable decay of our biological systems.
The purported cause, as the paper describes it:
The cumulative DNA damage theory of aging postulates that as an animal ages, toxic reactive oxygen species generated as byproducts of the mitochondria during respiration induce a random and progressive damage in genes thus leading cells to a progressive functional decline.
Reactive oxygen species, or ROS, are chemically unstable forms of oxygen that can easily react with and damage molecules in our cells.
They are a necessary byproduct of breathing and serve as signaling molecules. But they also present a danger: they can damage our DNA and cause mutations, which in some cases could lead to cancer. Over the years, the genetic damage from these reactive oxygen species is accumulating.
So that’s the traditional theory. But some pieces of the story have never quite fit, because there are common biological phenomena that this theory doesn’t explain.
For example, the theory fails to explain one of the most basic functions of life: the fact that we can reproduce.
How can an aged organism with aged cells give rise to a biologically new and undamaged organism?
The Epigenetic Model of Aging
At the point of conception, the zygote cell made from the sperm cell of the father and the egg cell of the mother can produce a perfect, immortal embryonic cell.
The paper makes the case for the epigenetic model of aging not just because of the growing evidence that we can reprogram cells and animals… but also because it would explain these phenomena.
It states that “there are epigenetic marks of aging that increase with age, leading to a progressive derepression of DNA, which in turn causes deregulated expression of genes that disrupt cell function.”
Here, the word epigenetic means different types of marker molecules on our genome that regulate gene expression—specifically, DNA methylation.
DNA methylation means the addition of small single carbon molecules known as methyl groups to our DNA. The presence of a methyl group represses genes by keeping them wound up around the structural proteins called histones. While the genes are wound up around these spool-like histones, they can’t be expressed.
The epigenetic theory states that as we age, we lose these methyl groups. That results in an unraveling of genes and allows for undesirable genes to be expressed.
Here the authors include reference to the work of Stephen Hovarth, who used mathematical algorithms to generate an “epigenetic clock” based on tissue methylation. In humans, this clock predicts biological age with unprecedented accuracy.
The paper states:
According to the epigenetic model, at the time of fertilization, all the epigenetic marks of parental aging are erased from the zygote’s genome, resetting its aging clock back to zero.
This has led to the idea that epigenetics is the driving force in the aging process. And because it is programmable, that means it’s also reversible.
From Cellular to In Vivo Rejuvenation
The story of cellular rejuvenation begins with the first successful cloning of frogs in the 1960s, followed later with the first mammal, Dolly the sheep.
The process of cloning involved taking the nucleus from an adult animal cell, and placing it in a female germ line cell known as an oocyte.
When this happens, the nucleus from the adult frog is rejuvenated to the point of a freshly formed zygote nucleus, from which a whole frog clone will develop.
Back in the 1960s, we didn’t know what it was that reset the biological clock and turned the cell into an embryonic stem cell. We didn’t know why or how the cytoplasm contained in the oocytes acted like an elixir of youth for the cloned cells.
Later—through the works of Shinya Yamanaka in Japan and Michael West in the US—the factors responsible for inducing rejuvenation were isolated. Specifically, Oct3/4, Sox2, Klf4, and c-Myc, which are genes expressed primarily in embryonic stem cells.
West patented these genes that are sometimes referred to as “Yamanaka factors.” In the paper, the authors use the acronym OSKM.
By now, multiple papers have shown that by introducing these factors, we can reprogram an adult cell to its embryonic state.
Just a couple of years ago, we saw the first evidence that this rejuvenation can be carried out in vivo, that means in the body of a test subject.
It was discussed in the 2016 paper, In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming by Ocampo et al. at the Salk Institute.
In this experiment, mice were treated with cyclic expression of the OSKM genes. The mice used were transgenic, meaning they were bred to model advanced-aging diseases such as progeria. These mice age prematurely and become senile at only two months of age.
The study found that after six weeks of partial reprogramming, the treated mice looked younger, and their epigenetic markers matched their appearances.
This shows therapeutic promise. The most important part is that the epigenetic markers of aging disappeared, while the markers of cellular identity were unaffected.
Losing cellular identity would mean loss of function and, worst case, masses of undifferentiated tissue.
This is one of the major concerns about in vivo tissue regeneration, and this study provided proof of concept for this potentially age-reversing biotechnology. This just shows how much biotech progress is accelerating.
Honestly, I find it surprising how fast mainstream science is coming around to the idea that age reversal is not just possible but on its way. Other biotechnologies are progressing at equally astonishing rates.
For example, at the Biotech Showcase this week, I already spoke with scientists who are developing a technology to safely clear out coronary plaque—the number one cause of death in the developed world.
I also spoke with scientists who are looking at the treatment of Alzheimer’s disease from a brand-new perspective, with the potential to completely shift the paradigm of Alzheimer’s therapy.
All of this is happening faster than anyone thinks, and we need to be prepared for it.
— Understanding the Epigenetic Clockwork of Aging originally appeared at Mauldin Economics.