[ExI] Epigenetic Age Reversal by Drugs

[avant at sollegro.com]

Here is something I wanted to put forward to discuss. In the last two 
decades since I was in graduate school, a lot of progress has been made 
in understanding the mechanism of aging. Back then, the prevailing 
theory of aging was what could be called the "cumulative error model" of 
aging where aging was caused by an accumulation of damage to DNA, 
mitochondria, and other essential cellular components through reactive 
oxygen species, UV, ionizing radiation, etc until the cell and organism 
succumbed to a general state of dilapidation. Nowadays, there is a model 
called the Information Theory of Aging where aging is caused by genetic 
information that keeps young organisms young is lost as the organism 
ages, sometimes through damage and mutation, but most often through 
epigenetic modifications to those genes.

Briefly, epigenetics has been found to be the mechanism by which cells 
differentiate or specialize from pluripotent stem cells to functional 
somatic cells with specific jobs, like the beta cells of the pancreas 
which secrete insulin.  Epigenetics works by the chemical modification 
of the DNA and histones that compose the chromatin in the cell, such 
that the chromatin is either open with the genes within that region of a 
chromosome available for transcription and expression, or the chromatin 
is tightly wound up and closed with the genes unavailable for 
transcription and expression. This method makes sense, since genes like 
oncogenes are necessary for an embryo to grow and develop from a single 
cell to an adult with trillions of cells. But once the adult form is 
reached, those oncogenes need to be shut down and effectively put into a 
vault to prevent them from being expressed, because if they are 
expressed in  adults, they cause cancer.

In 2006, Takahashi and Yamanaka found four transcription factors, OCT4, 
SOX2, KLF4, and c-MYC, responsible for unlocking the chromatin in 
regions containing the genes associated with cellular differentiation or 
identity. For example, they could take skin cells from an old person, 
and using those transcription factor, turn them back into stem cells, or 
even reprogram them entirely into youthful neurons.

So with that introduction out of the way, here is the big news. Yang et 
al discovered a fast efficient way to screen large numbers of drugs to 
see which ones had an effect on causing aged senescent cells to develop 
youthful phenotypes as if they had overexpressed the transcription 
factors discovered by Takahashi and Yamanaka. They used their high 
throughput screening method to identify six different drug cocktails 
some which seem to reverse aging in mouse cells and others which worked 
on human cells. Keep in mind that these drugs were only tested in cell 
culture in a petri dish (in vitro) and not on living organisms (in 
vivo), nonetheless, this sets the stage for a lot of future research.

Stuart LaForge
--------------------------------------------------------
Links
https://www.aging-us.com/article/204896/text
https://scitechdaily.com/age-reversal-breakthrough-harvard-mit-discovery-could-enable-whole-body-rejuvenation/

Abstract
A hallmark of eukaryotic aging is a loss of epigenetic information, a 
process that can be reversed. We have previously shown that the ectopic 
induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals 
can restore youthful DNA methylation patterns, transcript profiles, and 
tissue function, without erasing cellular identity, a process that 
requires active DNA demethylation. To screen for molecules that reverse 
cellular aging and rejuvenate human cells without altering the genome, 
we developed high-throughput cell-based assays that distinguish young 
from old and senescent cells, including transcription-based aging clocks 
and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We 
identify six chemical cocktails, which, in less than a week and without 
compromising cellular identity, restore a youthful genome-wide 
transcript profile and reverse transcriptomic age. Thus, rejuvenation by 
age reversal can be achieved, not only by genetic, but also chemical 
means.