Epigenetics - can we really turn APOE4 off?

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mike
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Re: Epigenetics - can we really turn APOE4 off?

Postby mike » Fri Aug 30, 2019 11:16 am

Here is a good article that discusses both glucose and ketone metabolism in the brain.
http://www.jneurosci.org/content/38/30/6665

I use evolution of man to try to understand the ApoE gene and its various forms. What was man eating when E4 was the only version? During the period when Man's brain was growing, the digestive track was getting smaller. Both typical when more meat is added to the diet, and less vegetation. At some point man figured out how to remove toxins from African tubors and started eating carbs as a regular part of the diet. Later on with farming and bread, even more carbs. Based on timing, it makes sense that E3 was in response to tubors and E2 to farming/flour. If this is the case, then it is not a matter of E4 providing benefit at some distant past, but rather the fact that E4 is not able to deal with our current diet. We can try to figure out how to turn our E4 to E2, so we can continue to eat MAD, or we can avoid the foods that cause the problems in the first place. Obviously this isn't all figured out, but I'm guessing the problems derive from the glucose peaks in the brain. If so, then the solution is to try to even out your blood sugar levels in the body. Back when Man ate mostly protein and fat, this was easy for the body to do. Less so with the addition of lower glycemic carbs like yams, and much more so with fast acting carbs like flour. If you don't have metabolic syndrome or full blown diabetes, then your body is able to keep glucose levels relatively even, but even so, a nice sugary something will still drive it up fairly high for a period. From what I've read, short term variations in body glucose result in similar changes in the brain. Keeping to low carb diet will minimize those peaks. Being in ketosis also provides a secondary energy source for the brain that E4s are better able to take advantage of. This along with exercise to protect the BBB is my basic strategy for keeping my neurons from being deprived of fuel and dying. I'm 4/4 and diabetic, so have to be especially careful what I eat, and so I try to avoid almost all carbs.
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Re: Epigenetics - can we really turn APOE4 off?

Postby Julie G » Fri Aug 30, 2019 12:10 pm

This feels timely. New research suggests that the drivers of AD might be ALL epigenetic as opposed to heritable. Read more here. I read full-text and need a translator. :?
The researchers report that testing the modifications they found and comparing them with data from a large clinical trial revealed 27 regions of the genome where epigenetic changes occurred. They further report that the signatures were AD-specific and were not correlated with age. They also found what they describe as "hints" that the signatures they found could lead to a way to identify the disease in patients at a much younger age, allowing for treatment to delay onset. They conclude by noting that they found evidence suggesting that regulation, establishment and maintenance of the epigenetic signatures likely play a role in the progression of AD—they do acknowledge, however, that more work is required to confirm their suspicions

This could be crazy good for us... if we're willing to do the work.

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Re: Epigenetics - can we really turn APOE4 off?

Postby Fiver » Fri Aug 30, 2019 1:11 pm

Hi Julie, I was trying to get through this one yesterday and got side-tracked. I'd believe epi-genetics is a part of it. Though the work on the genes themselves - apoe4 and others - is also pretty convincing.

There are three basic epi-genetic systems, which place or remove "epigenetic" marks on DNA or histones (which are like cord-keepers for DNA that is not currently being used): methylation of DNA, modification of histones, and small non-coding RNA.

I been working on one of these, with sulforaphane recently. It is a natural inhibitor of the enzymes which remove acetyl groups from histones or open or close certain groups of genes, opening or closing genetic programs. It's one of the mustard compounds of broccoli, etc. It survives the gut, is well-absorbed, and passes the BBB. There are all sorts of medical uses for SFN and similar compounds (called HDACis) - in cancer, neurological disorders, migraines, etc. I'm not making any claims or suggestions. Not a real doctor. Besides, people eat broccoli and Brussels sprouts -sources of SFN - all the time. (I'm happy to share info about which plants have higher levels, and food preparation strategies, if anyone is interested). But for those curious any quick google search will turn up dozens of research articles.

Regardless of what it may or may not mean with people's health it is clear that SFN is one way in which epigenetic markers can be altered, at least for some period of time. Other HDACis one could search for would be: trichlorstatin (TSA; not a "statin"), SAHA, sodium butyrate (yes, relatives of ketones), among others. Of course, there are likely side-effects of really trying to alter epi-genetic marks. But I think this is an interesting direction for the research to go.

Hope all is well.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.

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Re: Epigenetics - can we really turn APOE4 off?

Postby floramaria » Fri Aug 30, 2019 1:12 pm

Julie G wrote:This could be crazy good for us... if we're willing to do the work.

And of course we are!
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Re: Epigenetics - can we really turn APOE4 off?

Postby Michae_M » Sun Sep 01, 2019 6:29 pm

One would not want to "turn off" APOE4 or any other APOE type. However, one might be able to correct its function with a small molecule. This is very promising:
Treating apoE4 neurons with a small-molecule structure corrector ameliorated the detrimental effects, providing a proof of concept that correcting the pathogenic conformation of apoE4 is a viable therapeutic approach for apoE4-related AD.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5948154/

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Re: Epigenetics - can we really turn APOE4 off?

Postby Fiver » Mon Sep 02, 2019 10:00 am

Hi Michae_M. I recall being encouraged by the structure corrector studies a few years back but so far it does not seem to have made much progress. It seems the biotech companies of finding more difficult than anticipated in people, compared to cell culture and mice. this approach seems to have the opposite challenges. Structure correctors would be targeted specifically at apoe4 but don't seem to work in humans (yet?). While there are substances well- known to influence the epi-genetic systems of humans, but the results are likely to be rather broad. I hope researchers are hard at work on both approaches!
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Re: Epigenetics - can we really turn APOE4 off?

Postby Julie G » Wed Sep 04, 2019 8:01 am

Hi Julie, I was trying to get through this one yesterday and got side-tracked. I'd believe epi-genetics is a part of it. Though the work on the genes themselves - apoe4 and others - is also pretty convincing.

There are three basic epi-genetic systems, which place or remove "epigenetic" marks on DNA or histones (which are like cord-keepers for DNA that is not currently being used): methylation of DNA, modification of histones, and small non-coding RNA.

I been working on one of these, with sulforaphane recently. It is a natural inhibitor of the enzymes which remove acetyl groups from histones or open or close certain groups of genes, opening or closing genetic programs. It's one of the mustard compounds of broccoli, etc. It survives the gut, is well-absorbed, and passes the BBB. There are all sorts of medical uses for SFN and similar compounds (called HDACis) - in cancer, neurological disorders, migraines, etc. I'm not making any claims or suggestions. Not a real doctor. Besides, people eat broccoli and Brussels sprouts -sources of SFN - all the time. (I'm happy to share info about which plants have higher levels, and food preparation strategies, if anyone is interested). But for those curious any quick google search will turn up dozens of research articles.

Regardless of what it may or may not mean with people's health it is clear that SFN is one way in which epigenetic markers can be altered, at least for some period of time. Other HDACis one could search for would be: trichlorstatin (TSA; not a "statin"), SAHA, sodium butyrate (yes, relatives of ketones), among others. Of course, there are likely side-effects of really trying to alter epi-genetic marks. But I think this is an interesting direction for the research to go.

Thanks for this translation, Fiver. I'm watching my broccoli seeds sprout now! :D

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Re: Epigenetics - can we really turn APOE4 off?

Postby Fiver » Fri Sep 06, 2019 6:27 am

I guess this new news article relates to our discussion of epigenetics....

First hint that body’s ‘biological age’ can be reversed
In a small trial, drugs seemed to rejuvenate the body’s ‘epigenetic clock’, which tracks a person’s biological age.
https://www.nature.com/articles/d41586- ... 18875901=1

A small clinical study in California has suggested for the first time that it might be possible to reverse the body’s epigenetic clock, which measures a person’s biological age.

For one year, nine healthy volunteers took a cocktail of three common drugs — growth hormone and two diabetes medications — and on average shed 2.5 years of their biological ages, measured by analysing marks on a person’s genomes. The participants’ immune systems also showed signs of rejuvenation.

The results were a surprise even to the trial organizers — but researchers caution that the findings are preliminary because the trial was small and did not include a control arm.
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Re: Epigenetics - can we really turn APOE4 off?

Postby Julie G » Fri Sep 06, 2019 2:51 pm

I love this! of course, biological age can be reversed. I fairly regularly check my pulse wave velocity via iHeart. It's a gadget that provides a measurement of arterial stiffness correlated with cardiovascular disease and dementia. It has some silly internal algorithm that correlates results with biological age. Yesterday was a good day :D. I've also had bad days- 60+ when I'm stricken with a virus or didn't get enough sleep. It's fun to be able to actually see the effect that the strategies I'm employing is having upon my vasculature.
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Re: Epigenetics - can we really turn APOE4 off?

Postby SusanJ » Sat Sep 07, 2019 5:02 am

I seem to remember that a component of black nigella seed has HDACi properties. I researched it a ways back as an anti-inflammatory.


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