Have you tested 8 oxo g? Jinfiniti has a panel
I would guess that an HDAC inhibitor would work like an MTOR inhibitor. You don’t 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 haven’t 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 don’t 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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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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I’ll say! I’ve 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.
– 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.
–So, 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 it’s a very complicated system.
I think the nutritional HDAC inhibitors are just providing the raw materials for epigenetics to do it’s job and avoid a shortage in say the acetyl CoA pools but I don’t 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 determine… @John_Hemming ? any comment?
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As you can see it is complicated … but … 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.
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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 don’t disagree, but like Rapa, the “danger” 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.
I’m thinking a 1 week 50mg per day N1 for myself 
There seems to be a lot of interesting beneficial effects but here are the…
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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I’m 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 it’s 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
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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. I’m agnostic on the issue - apart from avoiding a keto diet. However, my perspective on ketosis is informed by nature and evolution’s 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, I’m still agnostic about this - I’m neither rushing to embrace ketosis, nor condemning it. Bottom line, it’s 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
“The L479 variant of CPT1a underwent one of the strongest known selective sweeps in human history and is specific to Inuit and Yu’pik 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.”
“A 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.”
“The 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]”
“A 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].”
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That’s an old comment I made and I’m 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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β-hydroxybutyrate is interesting because in ketosis it can be around at a millimolar level which has significant HDAC inhibitory effects (or perhaps more precisely KDAC). I have not myself seen the same argument made for acetoacetate or acetone.
Q re acetone
Q more generally
Interestingly acetoacetate appears to be a weaker KDAC inhibitor (If anyone is interested in this the second chatGPT is worth reading).
Acetate itself has interesting functions, but operates homeostasis within the cell which means it is not that good as an exogenous intervention (unlike citrate)
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Within the context of this KE4 is potentially an interesting supplement or any other ketone ester that produces beta hb.