medaura
#21
What do you make of this?
Apparently the opposite results.
There are several members of the HDAC family of enzymes, and their primary function is to modify histones - proteins around which DNA is spooled. These modifications control gene expression by blocking genes in certain stretches of DNA from being copied into RNA. In 2013, researchers linked HDAC1 to DNA repair in neurons. In the current paper, the researchers explored what happens when HDAC1-mediated repair fails to occur. To do that, they engineered mice in which they could knock out HDAC1 specifically in neurons and another type of brain cells called astrocytes.
For the first several months of the miceās lives, there were no discernable differences in their DNA damage levels or behavior, compared to normal mice. However, as the mice aged, differences became more apparent. DNA damage began to accumulate in the HDAC1-deficient mice, and they also lost some of their ability to modulate synaptic plasticity - changes in the strength of the connections between neurons. The older mice lacking HCAC1 also showed impairments in tests of memory and spatial navigation.
The researchers found that HDAC1 loss led to a specific type of DNA damage called 8-oxo-guanine lesions, which are a signature of oxidative DNA damage. Studies of Alzheimerās patients have also shown high levels of this type of DNA damage, which is often caused by accumulation of harmful metabolic byproducts. The brainās ability to clear these byproducts often diminishes with age. An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage, and the researchers found that HDAC1 is needed to activate OGG1. When HDAC1 is missing, OGG1 fails to turn on and DNA damage goes unrepaired. Many of the genes that the researchers found to be most susceptible to this type of damage encode ion channels, which are critical for the function of synapses.
Several years ago, researchers screened libraries of small molecules in search of potential drug compounds that activate or inhibit members of the HDAC family. In the new paper, researchers used one of these drugs, called exifone, to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1. The researchers used exifone to treat two different mouse models of Alzheimerās, as well as healthy older mice. In all cases, they found that the drug reduced the levels of oxidative DNA damage in the brain and improved the miceās cognitive functions, including memory. Exifone was approved in the 1980s in Europe to treat dementia but was later taken off the market because it caused liver damage in some patients. Researchers are optimistic that other, safer HDAC1-activating drugs could be worth pursuing as potential treatments for both age-related cognitive decline and Alzheimerās disease.
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I dont want to stop HDAC just the option of slowing it down a bit from time to time.
Have you tested 8 oxo g? Jinfiniti has a panel
ng0rge
#24
I would guess that an HDAC inhibitor would work like an MTOR inhibitor. You donāt want to eliminate it but just modulate it better - cycling on and off in the case of Rapamycin. Many of the supplements that we already take are good HDAC inhibitors - including Quercetin, Sulphoraphane, Resveratrol, Caffeine, Curcumin (in fact I think most or all polyphenols). So I think I get enough HDAC inhibition.
I havenāt tested 8-Oxoguanine. I glanced at the Jinfiniti website, but could not immediately find which panel this is.
The issue of how much HDAC inhibition is helpful is in theory really complex because there are different classes of HDAC and some inhibitors affect only a subset of classes.
The reason I think it helps is because it affects transcription. I have been experimenting with various levels, but I donāt think necessarily it is something that requires cycling.
Clearly the Queen Bee requires a large amount of HDAC inhibition, but the HDACi in royal jelly is relatively weak.
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Jonas
#27
Can you give both us a refresher of your HDAC inhibitors strategy? What are the top go to supplements and how are you spacing and dosing them? Is there biomarker you are aiming for? Thanks @ng0rge
I havent fully worked this out as yet. It is quite complicated. My core quartet remains curcumin, quercetin, pterosilbene and berberine.
There are, however, lots of subtleties with HDAC inhibition
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ng0rge
#29
Iāll say! Iāve been doing a deep dive into epigenetics, and histone acetylation and deacetylation, along with DNA methylation and demethylation are two of the main processes. So HAT acetylates histones and HDAC deacetylates them which controls (in part) gene expession.
ā Acetyl-CoA (acetyl coenzyme A) is the key molecule at the intersection of the citrate (TCA) cycle, epigenetics and cholesterol synthesis - so hugely important.
It is often presented that turning on genes (acetylation/demethylation) is good and turning them off is bad but there are many exceptions where the opposite is true.
āSo, as in the case @medaura presented above, sometimes activating HDAC to silence a gene is beneficial. And epigenetics is constantly turning genes off and on in response to many conditions (environmental, nutritional, disease, etc.) so itās a very complicated system.
I think the nutritional HDAC inhibitors are just providing the raw materials for epigenetics to do itās job and avoid a shortage in say the acetyl CoA pools but I donāt know that it up-regulates or down-regulates acetylation if no shortage exists.
No biomarkers that I know of, other than epigenetic clocks, but the correlation between your epigentic clock results and your intake of HDACi in your diet would likely be hard to determineā¦ @John_Hemming ? any comment?
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As you can see it is complicated ā¦ but ā¦ very important.
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