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
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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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@AlexKChen kindly pointed this out to me. I had missed it when it came out in April.
Open access:
The mammalian longevity associated acetylome
Despite extensive studies at the genomic, transcriptomic and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. To further explore the role of acetylation, we develop the PHARAOH computational tool based on the 100-fold differences in longevity within the mammalian class. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695 significant longevity-associated acetylated lysine residues in mice and humans, respectively. These sites include acetylated lysines in short-lived mammals that are replaced by permanent acetylation or deacetylation mimickers, glutamine or arginine, respectively, in long-lived mammals. Conversely, glutamine or arginine residues in short-lived mammals are replaced by reversibly acetylated lysine in long-lived mammals. Pathway analyses highlight the involvement of mitochondrial translation, cell cycle, fatty acid oxidation, transsulfuration, DNA repair and others in longevity. A validation assay shows that substituting lysine 386 with arginine in mouse cystathionine beta synthase, to attain the human sequence, increases the pro-longevity activity of this enzyme. Likewise, replacing the human ubiquitin-specific peptidase 10 acetylated lysine 714 with arginine as in short-lived mammals, reduces its anti-neoplastic function. Overall, in this work we propose a link between the conservation of protein acetylation and mammalian longevity.
https://www.nature.com/articles/s41467-025-58762-x
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I was wondering about this HDAC inhibitor. I wonder if low dose cycles may be of benefit to otherwise healthy people
Vorinostat
Chemistry
Vorinostat also known as suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable inhibitor of class I and II HDACs.
It is very strong. I am not myself persuaded that one as strong as that is a safe option.
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I donāt disagree, but like Rapa, the ādangerā may be in the dose and duration.
The dose commonly used for cancer is 400mg daily. People who have issues at that level go down to 300mg and the issues go away. I am considering that these are people who are fighting cancer so they may need the highest tolerable dose and for a specific duration.
Iām thinking a 1 week 50mg per day N1 for myself 
There seems to be a lot of interesting beneficial effects but here are theā¦
Adverse effects
Toxicities with Vorinostat were seen when the dosing exceeded 400 mg a day, rendering the clinical benefits of dose escalation very minimal. With the FDA-approved dosing the most common side effects encountered include fatigue, diarrhea and nausea. These side effects were usually mild to moderate needing no intervention or non-invasive intervention. Other side effects that were life threatening and required hospitalization included thrombocytopenia, dehydration,[37] pulmonary embolism, squamous cell carcinoma and severe anemia. There have also been reports of QTc-interval prolongation in some patients taking Vorinostat.[38] Therefore, it is advisable that patients who are on anti-arrhythmic drugs should undergo a regular screening when on Vorinostat. Vorinostat is a category D drug in pregnancy. A study in animals found that Vorinostat crosses the placenta and may harm the developing fetus.[39] The most common developmental defects seen were low fetal birth weight and incomplete ossification of the skull, vertebrae, and other bones of the axial skeleton.
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It operates in the nanomolar range whilst the ones people normally take (curcurmin, quercetin) operate in the micromolar range.
I have not thought of taking it myself.
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Iām more tempted to try low dose Vorinostat LoL!
This result is of great importance because of several reasons: i) such effect was never evidenced for any drug to our knowledge, ii) the depletion occurred at low dose of vorinostat which did not induce AcH3, which suggest a non-histone 3 regulation, iii) the effect appeared to be very sensitive because itās occur since the lowest dose, concomitantly with tubulin acetylation for U87-MG / U87 Sh0/ShEB1 and GBM6 cells and before tubulin acetylation in murine GL261 cells, iv) the effect appeared linked to EB1 expression level, v) the effect is proteasome-independent and only affect endogenous EB1 suggesting a direct transcriptional effect on EB1 expression via HDAC6 epigenetic regulation [39]. Interestingly, we found a mirror regulation of EB2 expression but not EB3 suggesting that EB1 and EB2 are regulated in an opposite way by vorinostat.
Just a general overview of HDAC inhibition potential for longevity
https://www.embopress.org/doi/full/10.15252/emmm.201809854
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There is a complication about HDACs in that they are sometimes called KDACs because they deacetylate Lysine in various places, but that can also be on other non-histone proteins such as splicing factors. Hence if you inhibit the deacetylation of the histone you may also inhibit the deacetylation of other things.
As far as I personally am concerned, however, we have considerable experience with some HDAC inhibitors.
Vorinostat is one with less experience.
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All you hear about, especially from influencers, is how beneficial are ketones and ketosis. Iām agnostic on the issue - apart from avoiding a keto diet. However, my perspective on ketosis is informed by nature and evolutionās great experiment. The result of that experiment is to avoid chronic ketosis by any means possible. Perhaps ketosis is an adaptive mechanism for short term stress and so is a health positive, but as a permanent state, nature avoids it. If nature selects against it in free standing populations, the evolutionary process eliminated those individuals who were on permanent ketosis, instead favoring those who evolved a gene to limit entering ketosis in the first place. Make of it what you will. But does that mean that ketosis itself is a health negative? Not necessarily. Perhaps there are other mechanisms that result in the byproduct of lack of ketosis in these populations compared to a state that would result in ketosis in populations that did not undergo such a genetic shift. This is why ultimately, Iām still agnostic about this - Iām neither rushing to embrace ketosis, nor condemning it. Bottom line, itās very complicated and I would not rush to conclusions.
Inuit metabolism revisited: what drove the selective sweep of CPT1a L479?
https://www.sciencedirect.com/science/article/abs/pii/S1096719220300329
āThe L479 variant of CPT1a underwent one of the strongest known selective sweeps in human history and is specific to Inuit and Yuāpik populations. Recent hypotheses predict that this variant may have been selected in response to possible detrimental effects of chronic ketosis in communities with very low carbohydrate consumption.ā
āA high intake of n-3 fatty acids may be linked to selection through the mitigation of a detrimental effect of the mutation that arises in the fasted state.ā
āThe first hypothesis suggests that L479 offers an evolutionary advantage by conserving glucose during a very low carbohydrate (but not necessarily ketogenic) diet, increasing its availability for processes linked to evolutionary fitness [72]ā
āA second hypothesis, which may be complimentary to or even synergistic with the glucose conservation hypothesis, suggests that L479 provides an evolutionary advantage in cold adaptation [50].ā
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Thatās an old comment I made and Iām just curious what is the relation to ketosis from you answer?
Because ketone bodies are HDAC inhibitors and you referenced HDAC inhibitors.
@cl-user made a post re: ketones
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