Option Bot Review



Epigenetic modification is DNA methylation

Over the past century, in a concentrated effort targeting diet, medicine, and sanitation, we have seen the world's average life expectancy more than double (Roser 2019). This trend isn't just limited to developed western countries either. It's true for most underdeveloped countries as well; Mali, South Sudan, Central African Republic and Chad being the most so (United Nations 2019). Since 1950, their projected life expectancies have increased 125, 116, 68 and 53 percent respectively.
It's hard to have any qualms with these results. General health is improving, childhood mortality is decreasing, and it's projected that by 2030 around 70% of 8-year-olds will have a living great-grandparent (Xu 2015), but one thing that hasn’t changed regarding aging is the dramatic, often times devastating, phenotypic transformation that is associated with it. And as more and more people fall victim to the seemingly unavoidable maladies that are coupled with a long lifespan, the more urgent it will be to figure out how to restore a youthful phenotype to those who have lost stability in their genome and epigenome.
Something as complex as aging most likely cannot be ameliorated by isolating and "fixing" a single genetic mechanism, but some sort of anti-aging concoction might be the way to go. Two main concerns that this concoction would need to address are genomic instability and the accumulation of epigenetic alterations.
As we've learned throughout the class, one type of epigenetic modification is DNA methylation. These modifications tend to repress active transcription of genes by inducing a heterochromatic state, which is a much more compact state than its active euchromatin counterpart. One theory of aging is that these accumulated DNA methylations play a role in the senescence of cells, and in general the propagation of age-related illnesses. On top epigenetic modifications that do not directly affect the DNA itself, genomic instability inevitably arises as a consequence of growing older. This means that the DNA, down to its base pairs, has a higher tendency to undergo alterations/mutations, and consequently increases the number of senescent cells and the possibility of activating of oncogenes. Whether or not this genomic instability is a result of aging or if causes it is not quite known, but it is an issue that researchers are attempting to tackle.
While still in the works, one lab out of Stanford has posted their initial results in using induced pluripotent stem cells (which is essentially the genetics equivalent of hitting the reset button) as a way to impede age-related phenotypic transformations. These transformations may be brought on by epigenetic changes which, as described by the team, may "eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis." (Sarkar 2019). Or in other words, the hallmarks of aging.
In order to induce pluripotent stem cells from normal cells, the integrity of the genome must be upheld while overexpressing a few transcription factors that help revert the cell into an embryonic cell type state. In the process, the epigenome is wiped entirely clean, which, as implied earlier, may be beneficial in slowing down the process of aging.
Although not a 2019 study, a group of researchers implemented this strategy in prematurely aging mice through the use of partially reprogrammed pluripotent cells (Ocampo 2016). The results of this cellular reprogramming experiment showed improvements in cell metabolism and a reduction of reactive oxygen species, which play a vital role in oxidative damage of the genome, and as a result drives aging of the cell. One very important conclusion drawn from this experiment suggests that "epigenetic remodeling during cellular reprogramming acts as a driver of the improvement of age-associated phenotypes." And this is what the researchers at Stanford hoped to show in human cells.
The development of the epigenetic clock, which looks at DNA methylation levels to determine the age of a cell, has allowed for the Stanford researchers to pinpoint how successful their cellular reprogramming was. Looking at three distinct groups of human cells, clear improvements in their health can be observed post-transient reprogramming. In human fibroblasts and endothelial cells, rapid reversal of cellular aging and the aforementioned epigenetic clock were observed. Chondrocytes saw reduced inflammation. And aged muscle stem cells had heightened response times like that of a younger muscle cell. In all three experiments, cellular identity was preserved. This implies that the applied transient reprogramming can induce a more youthful version of the original cell, and that the induced stem cell will not stochastically become a different type of cell.
With more research on the technique, I believe that this Epigenetic Reprogramming of Aging (ERA) has huge therapeutic implications in combatting age-related pathology and in turn increasing worldwide life expectancies.
With every new therapeutic technique comes its own set of ethical, legal, and social issues. I view the ERA as being less problematic than most stem cell therapies, at least ethically, because induced stem cells are used. This means that aged somatic stem cells revert to an embryonic-like state, but embryonic stem cells are not used. Socially, it is difficult to gauge the possible financial constraints that would be present, but I’m assuming in its infancy the therapy would likely be relatively expensive, and probably only available for the rich until it becomes more commonplace. Since it has been proven that "induced pluripotent stem cells don't increase genetic mutations," the path to introducing this therapy to in vivo and ex vivo human trials would likely have less hurdles to face (Mjoseth 2017).
In my opinion, the possible implications of this therapy are profound. This therapy could theoretically turn back the clock for people experiencing the ill-effects of aging, while possibly increasing the time that we spend in our "peak" physical and mental phenotypic state. And if we are able to eventually implement this on a world-wide scale, we should expect to see further increases in life expectancies, which I think is a great thing – although some ordinary social constructs may have to evolve to better suit our ever-aging population.
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