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              Advocacy & Research for Unlimited Lifespans


Methylation showing gradual reduction in genomic function


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#1 johnhemming

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Posted 25 December 2023 - 06:51 PM




The concept of an Epigenetic Clock has been around for some time. The idea is that there are markers on DNA from which it is possible to work out someone's biological age. The idea of "biological age" is that it is in essence a measurement of how healthy someone is. People with the same chronological age, but different biological ages differ in their health status. My own personal view is that in fact the overall health of an individual is a driven by the status of all of the cells. Hence one person can have a particularly unhealthy pancreas whilst another person has a particularly unhealthy kidney. However, the idea of a biological age is useful to the extent that it is an easy concept to understand even if realistically it is an oversimplification.

There is then the idea that if you can reduce someone's biological age that means improving their health status. This is a good approach in the sense that we ideally would be trying to ensure people are so healthy that on a day to day basis with ups and downs in health they end up not needing any medical care. The question then is how to measure biological age. There are quite a few formulae that try to assess mortality based upon a combination of biomarkers. The most well known is Morgan Levine's phenoAge test. Some of these can be seen on the biohacking.tools website. It was spotted, however, that the patterns of methylation markers on the DNA correlated with chronological age. The suggestion was then made that these patterns could be used to indicate the biological age.

Various companies have set up to enable people to measure their epigenetic ages. Trudiagnostic.com are one of these. Their approach can be distinguished from others in that they report analyses of the methylation markers using a number of different algorithms. They are also the core providers for the Rejuvenation Olympics. I have used a number of companies for tests, but I have used Trudiagnostic three times this year and my results are in this table.


Algorithm 6th April 5th July 15th November OmicAge 64.098 58.432 58.362 PaceOfAging 0.78 0.82 1.051 Fitness Age x x 46.55 Intrinsic Epigenetic Age (Horvath) 62.94 59.28 53.38 Extrinsic Epigenetic Age (Hannum) 47.25 45.8 36.59


So, picking the most favourable result (36.59) my biological age according to the EEA algorithm is 37. Given that I am 63 that sounds positive. However, I still look like someone a lot older. However, some of my biomarkers such as Cystatin-C (0.76 mg/l) and C Reactive Protein (<0.15 mg/l) are indicative of a better health status than the average 63 year old.

In the end, my objective in biohacking is to improve my health. Because a lot of my protocol is novel it is good to have confirmation that what I am doing is having a positive effect on the methylation of DNA.

I have for some time wondered about what DNA methylation is all about. In one way you can think of a cell as a form of analogue computer that decides what proteins to produce with some really complex logic systems around various biochemical systems. One of the control systems is the availability of Acetyl-CoA in the cytosol. When there is a lot of Acetyl-CoA around it means that the cell has quite a bit of spare energy and hence it can produce both a wider range of proteins and more proteins in a given period of time. This happens via the need to open up the Histone (which holds the DNA) so that RNA Polymerase II can transcribe it into Messenger RNA. Acetyl-CoA is needed to open up the Histone in a process called acetylation.

What, however, happens with Methylation?
It is generally accepted that Methylation acts to repress the transcription of a gene. There is, however, an interesting question as to what the interplay is between demethylation (the removal of the methyl group) and transcription of a gene. There is a paper Unraveling the functional role of DNA demethylation at specific promoters by targeted steric blockage of DNA methyltransferase with CRISPR/dCas9 which looks at the extent to which transcription causes demethylation rather than demethylation directly causing transcription. Looking at my own data, however, the changes in methylation levels which are consistent are as a result of an intervention which operates to increase the probability and quantity of gene expression particularly through additional transcription (but also through translation). It, therefore, appears from my data that gene expression has a direct effect of reducing methylation. I would not necessarily be surprised if premature termination of RNA Polymerase II caused methylation to occur in some way, but in the broader sense DNA gets methylated over time for various reasons. Hence if the genes are not actually being transcribed then they simply get more methylated and more repressed. This is logical from the perspective of not wasting energy. If there is not enough energy to transcribe a particular gene it would be helpful if that gene got methylated so the energy used to part transcribe it was not wasted on not doing very much. Alternatively the transcription process may be slowed down by methylation. That would have a similar effect as it would reduce the usage of acetyl-CoA and ATP. Having a system where the main energy constraint (acetyl-CoA availability) is the only constraint on transcribing genes would be quite energy demanding anyway. However, if that then leads to methylation blocking even the start of the transcription process then that would avoid wasting either acetyl-CoA or ATP.

Sticky gene expression
The effect of the above would be to give a certain amount of stickyness to gene expression. Once a gene gets quite methylated a certain amount of effort is needed to get it readily transcribing. In a sense we see this at the macro level in that the cellular response to changes is gradual and has a tendency to stick where it is.

Active DNA Demethylation
Active DNA demethylation—The epigenetic gatekeeper of development, immunity, and cancer is a paper which looks at active demethylation (which I assume is the process behind transcription causing demethylation.

RNA Pol II stalling
The interplay between methylation of DNA and acetylation of the histone is interesting. I wonder if a methylated DNA causes RNA Pol II to stall. Then there is the question as to what happens if the histone that RNA Pol II is stuck at is then deacetylated which would cause some form of aberrant termination. This will be hard to monitor in real time, but can be looked at in a macro sense as to what the effects of inhibiting the HDAC/KDAC are. Perhaps it is possible to look at the sites at RNA Pol II is stalled at and whether the DNA is methylated at or around that point.

Increased Methylation rates reduce lifespan
DNA methylation rates scale with maximum lifespan across mammals is a paper that looks at methylation rates and concludes that the faster the DNA gets methylated the shorter the lifespan of the animal. This, of course, is logical. If cells function by expressing genes and gene expression is reduced by methylation (and lack of acetyl-CoA) then there would come a point at which cells are functioning at such a low level that the animal dies.

Edited by johnhemming, 25 December 2023 - 06:52 PM.

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