Epigenetics - can we really turn APOE4 off?

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Julie G
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Re: Epigenetics - can we really turn APOE4 off?

Postby Julie G » Sat Sep 07, 2019 10:05 am

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

The human growth hormone (HGH) part of the cocktail feels counterintuitive given it's association with heart disease, some cancers, and diabetes. I understand that metformin and DHEA were used to counteract the latter, but I can't help but wonder if those two might have been more effective with the HGH. Even metformin used for longevity isn't as straightforward as it seems. Here, Peter Attia (who uses it) dives into the possible interaction with exercise.

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Re: Epigenetics - can we really turn APOE4 off?

Postby LG1 » Tue Sep 10, 2019 8:46 pm

I'm about 30 minutes into the podcast where Peter Attia interviews David Sinclair. They speak about this and more at length. I’m already into online rabbit holes researching Horvath's methylation clock and Zymo, the company that uses his research to offer the testing. Totally nerding out on this. This is exciting, incredible stuff. Just WoW!!!
Last edited by LG1 on Tue Sep 10, 2019 10:43 pm, edited 1 time in total.
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Re: Epigenetics - can we really turn APOE4 off?

Postby LG1 » Tue Sep 10, 2019 10:40 pm

Joe Rogan also interviewed David Sinclair today:

https://youtu.be/ZGLL77wYxe8
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Re: Epigenetics - can we really turn APOE4 off?

Postby LanceS » Fri Sep 27, 2019 1:16 am

Emerald wrote:I have a question - I definitely understand the concept of epigenetics and how certain genes can be turned on or off based on emotional, environmental, etc. factors. That said, is APOE4 really one of those genes? Aren't the two copies of APOE we have (whether they're 2, 3, and/or 4) technically always going to be active? I fully understand that we can make choices that influence how APOE works (and significantly decrease the likelihood of Alzheimer's and other issues this way), and APOE interacts with various other genes that can be turned on or off. However, we can't really turn APOE off, can we?

I studied health and diseases, so I apologize if I'm getting too technical. I suspect "turn APOE4 off" is really just a simple way of referring to our ability to make positive choices and lessen its impact (which is totally fine with me!), but wanted to confirm. Thank you!


The research that the Buck Institute researcher published a few years/months ago?

https://www.buckinstitute.org/news/a-su ... lzheimers/

Seems germane here. I would imagine that Sinclair's work will show that the epigenetic conditions that permit / encourage APOE to become so aggressive can be "turned back" ? inside the brain?. But I dunno ... many times human cognitive biases tend to oversimplify the path to success for something that turns out to be much more difficult. The intellectual breadth and span of Sinclair's book makes me wonder if he isn't overreaching, not to mention his aggressive ambitious nature. Haven't read the book yet so unfair to state that from my couch of ignorance. Not familiar enough with the mathematician's work to know if perhaps he has Sinclair covered. Hopefully this APOE4 / Sinclair / mathematician angle will be something that folks will begin to examine if only in the context of renewed interest in epigetic drug development beyond the BBB.

Kind of excited about this space, first time in a while... and I've been doing some HDAC stuff etc with some "feel good" results, but honestly not alot of enthusiasm.

I am not sure how this will all fit for the highly undermethylated amongst us. I feel like I have difficulty with regularly taking my methylation vitamins. Also feel like my fasts end up really changing up my body. To the point where I wonder for undermethylators if the answer isn't some "epigenetic turn back the clock" but a nasty fast that trips up a widespread apoptosis / regrowth cycle. I would guess undermethylated amonst us may have more apoptosis during stress, but I dunno... not sure I buy much of anything I read about undermethylation and its associated implications.

Hope you all are well. Cheers.

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Re: Epigenetics - can we really turn APOE4 off?

Postby cdamaden » Fri Sep 27, 2019 1:10 pm

I'm interested in taking higher dose resveratrol as mentioned in the Attia/Sinclair interview. I looked at my traditional supplement brands of Jarrow and Pure Encapsulations but neither had anything that would give me a manageable number of pills to achieve a dose in the 500-1,000 mg range. There are other brands that do and wanted to know if anyone has recommendations. I noticed Life Extension with 250 mg, Vital Nutrients with 500 mg, NOW with 200 mg, and other brands I don't recognize. Thanks,
Chris

LG1 wrote:I'm about 30 minutes into the podcast where Peter Attia interviews David Sinclair. They speak about this and more at length. I’m already into online rabbit holes researching Horvath's methylation clock and Zymo, the company that uses his research to offer the testing. Totally nerding out on this. This is exciting, incredible stuff. Just WoW!!!
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Re: Epigenetics - can we really turn APOE4 off?

Postby Emerald » Fri Sep 27, 2019 8:09 pm

Sorry, everyone - I think perhaps I wasn't clear. My question was around whether daily lifestyle habits - not surgerical interventions or the quests around undoing aging (which I am far too familiar with) or anything of the sort - could "turn off" the APOE4 gene, similar to how people say certain genes for cancer are only activated when you smoke cigarettes, grew up on a farm with toxic pollutants, etc. It appears that the answer is no, and people saying we can "turn APOE4 off with lifestyle habits" are using that saying more loosely - it's more accurate to say that healthy lifestyle habits can reduce the damage done. So basically, APOE4 is active no matter what, but our behaviors influence how it interacts with our bodies.

That answers my question - thank you! Personally, I'm not as interested in the other possible future interventions right now; I'm familiar with them but know they aren't available to me today or proven. I've read about them, but know they're little further away (such as converting APOE4 into APOE3). And truthfully, I have my own VERY deep reservations with the concept of undoing aging commonly discussed by Sinclair, de Grey, Campisi, Kurzweil's merging with technology, etc., so I don't like to think about it too much. The thought terrifies me for various reasons I won't get into, even if it meant looking and feeling 25 years old for thousands of years until a bus hit me. I do want to die of natural causes one day. I try to stay away from anything related to indefinite lifespans because of these deep resevations, although I understand all the reasons why other people want it. Sorry, I'm not sure if the articles you shared even referenced that specifically, but the idea of reversing aging and living indefinitely is the basis of Sinclair's body of work.

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Re: Epigenetics - can we really turn APOE4 off?

Postby LG1 » Fri Sep 27, 2019 10:59 pm

cdamaden wrote:I'm interested in taking higher dose resveratrol as mentioned in the Attia/Sinclair interview. I looked at my traditional supplement brands of Jarrow and Pure Encapsulations but neither had anything that would give me a manageable number of pills to achieve a dose in the 500-1,000 mg range. There are other brands that do and wanted to know if anyone has recommendations. I noticed Life Extension with 250 mg, Vital Nutrients with 500 mg, NOW with 200 mg, and other brands I don't recognize. Thanks,
Chris

LG1 wrote:I'm about 30 minutes into the podcast where Peter Attia interviews David Sinclair. They speak about this and more at length. I’m already into online rabbit holes researching Horvath's methylation clock and Zymo, the company that uses his research to offer the testing. Totally nerding out on this. This is exciting, incredible stuff. Just WoW!!!


Chris, I believe Masterjohn recommends a micronized version such as this one:
https://revgenetics.co.uk/collections/m ... esveratrol

Did you see Dr. Rhonda Patrick has a new blog post on resveratrol?
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Re: Epigenetics - can we really turn APOE4 off?

Postby BrianR » Sun Sep 29, 2019 8:43 am

LG1 wrote:I'm about 30 minutes into the podcast where Peter Attia interviews David Sinclair. They speak about this and more at length. I’m already into online rabbit holes researching Horvath's methylation clock and Zymo, the company that uses his research to offer the testing. Totally nerding out on this. This is exciting, incredible stuff. Just WoW!!!

Hi @LG1, you might be interested in Peter Attia's new commentary on the study showing reversal of aging with hGH, metformin, DHEA, D3 and zinc. (Which uses the GrimAge Horvath Clock as evidence.)

https://peterattiamd.com/190929/

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Re: Epigenetics - can we really turn APOE4 off?

Postby Indywoman » Sun Sep 29, 2019 2:08 pm

BrianR wrote:Hi @LG1, you might be interested in Peter Attia's new commentary on the study showing reversal of aging with hGH, metformin, DHEA, D3 and zinc. (Which uses the GrimAge Horvath Clock as evidence.)

https://peterattiamd.com/190929/


What I absolutely love about Peter Attia is his unbridled enthusiasm and curiosity about new research and ways of approaching our health and longevity. What I also absolutely love about Peter Attia is his unswerving commitment to slowing us from running down a path without fully understanding the questions we all need to ask of a study, trial, etc. Please read the whole commentary that BrianR posted, noting that Attia writes:

This study does not convince me to put even one of my patients on the cocktail of hGH, metformin, and DHEA used in this study, despite how many have asked. This is a small, short, and uncontrolled preliminary study that can’t determine cause-and-effect between the many independent variables in the study and a reversal of aging represented by epigenetic clocks (that are solely estimating at one specific blood cell type in isolation). Time may prove me overly cautious, which would be wonderful, but not today.


For those of us who want to better understand studies and their strengths and limitations, start with Peter Attia's "Studying Studies: Part 1
https://peterattiamd.com/ns001/ and move on to https://peterattiamd.com/category/under ... g-science/
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Re: Epigenetics - can we really turn APOE4 off?

Postby Fiver » Mon Sep 30, 2019 7:47 am

In terms of how expression of the apoe4 gene could be manipulated the options would be indirect (changing methylation of nearby DNA or acetylation of nearby histones, small RNA which are poorly understood) or direct (anti-sense DNA silencing, RNA destruction, protein destruction). But it's still not clear if it is better to have more or less apoe4 expression. The answer might be different for 4/4s compared to 3/4s and be different at different ages and stages. I tend to be convinced by cell culture and mouse studies showing that altering histone acetylation status can repair the garbage recycling systems of brain cells that do not work well because of apoe4. That seems promising.
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