#163

I have done some experiments with increasing acetylation at night. This has been complicated with a mixture of rapamycin and alcohol, but it appears that it is best for sleep to wait a bit before increasing acetylation. Say a couple of hours.

Adding a bit of an explanation. Alcohol results in a reasonably high level of acetate in blood serum (which is maintained for some hours). Some of this is absorbed into the cells and able to be converted to acetyl-CoA via ACCS2. At the same time (well when taken) citrate goes into the serum and from there for a period of time until it drops back to normal levels, a higher amount is transported via SLC13A2 and SLC13A3 into cells (it is also taken into hepatocytes via SLC13A5 and oxidised) that is then converted by ACLY into acetyl-CoA.

AIUI ACCS2 is part inhibited by acetylation of the histone. I have read somewhere that a similar effect happens for ACLY, but my experience is that the citrate supplementation has a far greater effect on acetylation than acetate supplementation (although having high acetate levels which when taking citrate will be to some extent enhancing).

Additionally it appears that autophagy interferes in some way with circadian proteins. This tends to hit me on the night when I take Rapamycin in the morning, but notwithstanding the long half life that issue tends to disappear reasonably quickly.

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#164

I have a lifelong sleep issue where I wake up in the middle of nearly every REM cycle (I presume, because I remember being in a dream clearly upon waking), about 4-5 times per night. This used to be so bad, before I went on an SSRI, that I wouldnā€™t be able to sleep after about 5-6 hours. Now, at least, I can generally get back to sleep.

Over time, I have noticed a subjective correlation between the number and intensity of my remembered dreams and how I feel the next day. I have found that the less I remember dreaming, the better I think and feel, so I tend to gravitate towards substances that tamp down my dreams, which I presume involves REM. This is why I think that the SSRI has not only helped my anxiety, but also contributes to improving my sleep, since they are known to decrease REM sleep chronically.

My main hypothesis has always been that I have some form of sleep apnea, but I have never been able to fall asleep at a sleep lab. Further, I suspect that I have an uncommon form of apnea due to airway blockage on exhalation at my soft palate, making my trials of CPAP ineffective. This, coupled with the fact that it seems that I only wake up due to increasing airway resistance during REM sleep ā€“ at least that is my hypothesis, due to the fact that I remember long portions of dreams right before and after I wake ā€“ means that I think that I am effectively chopping off the last bit of my sleep cycles; except for maybe the first two, since REM sleep is a smaller percentage of time.

So, since whatever this is isnā€™t impairing enough to completely disrupt my functioning like some people with sleep apnea, and the fact that CPAP doesnā€™t work for me and I canā€™t complete a sleep study, means that I have to experiment on myself and just do what works. And for me over the past two decades, less dreaming makes me feel better. In fact, if there werenā€™t so many risks with MAOIs, I would be inclined to try one, since Iā€™ve read that they suppress nearly all of REM sleep, seemingly without major consequences.

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#165

Interesting what do you mean by best for sleep?
We know alcohol disrupts sleep and puts your brain in a sedative-like state instead of sleep-like state, and not much has been done in terms of rapamycin effect on sleep(something I am interested in).
Unfortunately in the literature, not much has been done on sleep and histone acetylation. There was one paper a couple years talking about how a prolonged sleep phenotype is seen in HDAC4 mutants on the sleepy allele(although this paper was flawed in my opinion). Other papers have shown that HDAC inhibition helps protect against the consequences of memory loss after sleep deprivation. Focus has been on hippocampus, so hard to tell if the protection of negative effects of sleep deprivaiton is more to due with histone acetylations role with memory and learning in the hippocampus and less so to do with sleep deprivation itself.

I am currently publishing a paper on the effects of inhibiting ACSS2 and how it changes stress repsonses in mice that undergo social stress. Found that it actually is promoting antiaxioyltic effects immediately and long term after stress. Stress and sleep have a very close relationship. So hypothehtically if sleep is improved, a reason might be due to reduction in anxiety/stress effects that one might be experiencing through the day than actually altering sleep itself.

In my own research, I have some preliminary data indicating that actually reducing intracellular acetyl CoA during sleep deprivation might actually be enhancing sleep quality and recovery in mice(still in the process of analyzing data currently).

Another problem comes from the fact that acetylation is involved in so many things, one being circadian rhythms(i.e. CLOCK ) so one component contributing to changes with sleep may be the circadian aspect, not so much sleep itself. Also since sleep is influenced by so many factors such as other organ input , effects could be through other pathways that influence sleep instead of a direct pathway.
It is also possible the timing of manipulating acetylation may cause different effects based on the gene population that might be targeted. Changing acetylation could either affect wake promoting genes or sleep promoting genes. More investigations need to conducted to figure out acetylations role in sleep.

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#166

Best for sleep for me personally is delivering refreshing sleep. My test is being fully functional the next day without needing a nap. That normally requires 6 hours of sleep measured on a fitbit. I sometimes now get over 7 hours sleep (going back a few years my sleep was dreadful - I am 63).

I am aware of the alcohol rebound.

My protocol has two main strands. One relates to improving transcription. That involves increasing the available cytosolic acetyl-CoA, increasing levels of HDAC inhibition (not separating out classes), increasing substrate availability for RNA and GSK3 inhibition through low levels of lithium. (higher levels inhibit the SLC13A2 and A3 citrate transporters something I particularly donā€™t want to do.

Because part of this is done by increasing serum citrate and the half life of citrate in serum is around 30 mins there is a timing issue.

If I wish to increase acetylation levels and improve transcription during sleep (the CLOCK genes for example) then I have to take citrate around the timing of going to bed. I have found if I wake say after about an hour or twos sleep and then take 5g of citrate that I sleep well following that.

I think there is an element to which transcription is sticky in that if genes are not successfully transcribed then methylation levels on the DNA increase which in itself causes problems with transcription. Hence there is aneed to encourage transcription to remove the methylation so that even with lower levels of cytosolic acetyl-CoA transcription functions at what would be considered normal levels (for a younger person).

Hence you are right that increasing acetylation could affect wake promoting genes or sleep promoting genes. However, from my perspective as someone whose genes were not working that well I wish to simply get the genome to function better. I had generally been doing this during the day, but I would like to do some of this at night as well.

As to the balance between sympathetic and parasympathetic activation that I can influence with melatonin.

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#167

I thought everyone awakens in the REM cycle. The problem is if it wakes you totally. I donā€™t know if I make sense, but when you come towards the end of REM are awake for a minuscule amount of time before you go to deeper sleep again. The more you are awake the more you remember your dreams, but if you remember being awake that is the problem.
I did not know you can decrease REM without any consequences. As I said I always thought that it is necessary for optimal sleep architecture and brain function. I will research this further. Last week I have the same problem, that every REM cycle after 2 AM wakes me up to the point I remember being awake. It is really not a restful sleep even if total duration of my sleep is around 8 hours.

This might be my current problem as well, I had a surgery that makes your soft palate swell for few weeks and I had terrible problems first two weeks after the surgery, now it is fourth week and it might still be problematic. For the first two weeks I had to sleep on my belly with one leg stretched the other bent to be able to breath out normally during sleep. I have resumed my normal sleeping positions, maybe it is my palate that wakes me up or the inability to breath out.

My palate will hopefully go back to normal in few weeks. But I was told that you can get injections to harden your upper palate (it is supposed to help with snoring). Do you think this would be an option for you? Maybe check it out if you havenā€™t already.

#168

This is true in typical sleep. The way our sleep cycles work typically are as follow:

You go from Wake to NREM sleep. From NREM sleep you enter either REM or you wake back up. In healthy sleep you can only enter REM sleep from NREM sleep. After REM you then would enter a brief wake period or light NREM sleep stage(N1,N2), before entering into NREM sleep again. People with Sleep disorders can enter REM from wake(narcolepsy), but this is not normal.
image
image

IN the images above you will see stage 3 sleep(known as slow wave NREM sleep) will dominate the first half of your sleep, then REM episodes are longest at the end of the night. You also will see that you must enter REM from NREM sleep.

Both stages of sleep are important for different reasons.
image

Sleep is homeostatically regulated meaning that when you deprive yourself of sleep, you compensate for that sleep loss by trying to recover the lost sleep(this is known as sleep rebound). Essentially the longer you deprive yourself of sleep, the greater your need for sleep is.
(Sleep drive is proportional to the duration of prior wakefulness). The thing is lost sleep is never completely recovered. It takes someone 1 day to ā€œrecoverā€ from 1 hour of sleep loss(i.e. if you lost 6 hours of sleep it would take you 6 days to ā€œrecoverā€ that sleep loss). I have recover in quotes, beacsue the meaning of recover in this sense is to go back to normal sleep cycles or that sleep homeostatis is regained.

The same holds true for specific sleep stages.
Sleep loss promotes increase in sleep need, meaning you will see an increase in NREM and REM sleep rebound during sleep. Your body will first try to recover its NREM sleep need first, meaning you will undergo little to no REM sleep during your first few nights of sleep recovery. Then REM sleep recovery will occur. Only substantial sleep deprivation (12-24 hours) causes significant REM sleep rebound

Say someone undergoes 12 hours of sleep deprivation one night. When you enter sleep to recover after the sleep deprivation your body will try to recover NREM sleep first. After your body recovers its NREM sleep need, the subsequent nights you would experience an increase in REM duration and intensity. This is becasue your body is trying to recover the REM sleep loss it experienced(i.e. your dreams will be intense and occur frequently until your body has ā€œrecoveredā€ from the REM loss).

I hope this made some sort of sense, as this is really hard to explain over text.

I also want to add some facts about sleep loss , that I typically see individuals misunderstand about sleep:
-Individuals may vary somewhat in their tolerance to the effects of sleep loss, but are not able to accurately judge this themselves.
-Sleep needs are genetically determined and cannot be changed. i.e. you cannot ā€œlearnā€ to sleep less.
-Human beings do not ā€œadaptā€ to getting less sleep than they need.
-Although performance of tasks may improve somewhat with effort, optimal performance and consistency of performance do not! Studies show that sleepy people underestimate their level of sleepiness and overestimate their alertness.
-The sleepier you are, the less accurate your perception of degree of impairment.
-You can fall asleep briefly (ā€œmicrosleepsā€) without knowing it.
-Portions of your cortex can enter a sleep-like state during waking.

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#169

Thanks,
I am curious, how do you know you are actually increasing transcription?

#170

Its the macro changes that would imply this. Obviously I am not tracking mRNA creation, but if I am doing something that should result in the production of more proteins (a wider range particularly the longer ones) and at a macro level
a) I find improvements in muscle gain (anti-sarcopenia)
b) I find improvements in kidney function (reduction of Cystatin-C)
c) I get more hair growing etc etc.

Then there needs to be some low level change causing this. It is also dose dependent on tricarboxylate supplementation. Hence it links to that. (which it should).

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#171

A question about napping and nrem sleep. Apparently it takes 45" to enter nrem sleep. But I feel I enter a short nrem period within a 20" nap. A period of a sort of dream state. Is that possibly nrem sleep?

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#172

The deepest portion of NREM sleep(N3 or Slow wave sleep) takes about 30-45 minutes, but you enter lighter NREM stages (N1 and N2) immediately after you fall asleep. N1 happens the fastest and last the shortest ( wihtin minutes). N2 happens a bit later and lasts 10- 25 minutes.

Its normal to enter a short sleep cycle during a nap but depending on how long you are napping.
What exactly happens in a short duration is dependent on your sleep need.
For example if you slept less than 7 hours the night before, you would still have a sleep need that was not ā€œemptiedā€. So you would add additional sleep pressure to your waking day(see in the figure above that shows additional sleep pressure and circadian drive.) Your body could try to compensate for the that sleep loss in the form of a nap, so its possible to enter deep NREM sleep during a nap in a shorter amount of time since you need to recover that sleep.
I mentioned early that NREM sleep is the primary focus after sleep loss, REM sleep is recovered over time. Its possible you drank, had THC or deprived yourself of sleep a couple nights prior and now you are recovering some of that REM sleep during naps days later.

I didnā€™t mention this above, but you dream every night but most of the time you wont remember it. Same with brief periods of wake that occur. So its possible you could be dreaming and not realize it or that you are just in deep NREM sleep. Hard to tell unless we monitored your sleep and had an idea of how much sleep your getting, how good that sleep is.

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#173

Interesting, how has this faired for you?
Obviously, it seems acetylation is playing a role in aging. But do you feel the protective effects of adding acetyl-CoA/changing histone acetylation is to the general body of aging or more specific functions? I ask because HDAC inhibition literature is very interesting. HDAC inhibition is being investigated for therapeutic roles in stress responses, neurodegeneration, cancer, etc. What I find interesting though, the effects in some literature are stimulus dependent. Itā€™s the concept of epigenetic priming. Histone acetylation: molecular mnemonics on the chromatin - PubMed
So I wonder if beneftis from increasing acetate/citrate/acetyl-CoA come through other benefits such as changing metabolic pathways/products, Improving mitochondrial function, etc. https://www.frontiersin.org/articles/10.3389/fphys.2020.580167/full
I just ask because I wonder how much transcriptional change you are generally promoting with your routine Or is the bioavailability of these supplements so low that its not necessarily inducing a big change on the transcripitonal level.

#174

I am quite pleased with the outcome. I have posted quite a bit on twitter and in this forum.

My current view on aging is that the main causes of the phenotypes of aging are failures to produce the right proteins. Part of the cause lies in transcription and part in translation. Additionally there are issues with DNA damage, but I donā€™t think that is a major cause of aging.

When it comes to transcription you have the issue of a shortage of acetyl-CoA. Ac-CoA essentially indicates to the cell the availability of energy. Interestingly when a cell goes cancerous and moves away from producing energy in the mitochondria the citrate carrier no longer provides Ac-CoA to the cytosol.

Also with transcription there is the issue of HDAC inhibition. The Phenotype of the Queen of EUSocial Hymenoptera (not the queen of termites/isoptera, though) is created through the use of Royal Jelly which has both a HDACi operating in the millimolar range and also vitamin B5 (a CoA precursor in it). Hence the variation of the Queen Bee phenotype is caused both by additional acetyl-CoA and also by HDAC inhibition.

I have played around with HDAC inhibition and it seems to have subtly different effects to that of increasing acetyl-CoA levels.

Whichever way you look at it a shortage of acetyl-CoA causes spicing variants to occur.

I have also added in additional RNA as that has been shown on old papers (from the 1940s) to have longevity benefits and would help with transcription and low levels (about 50 microMolar) of Lithium.

It is of course, possible that the benefits I get from this protocol donā€™t operate though this particular mechanism, but it does fit in with the literature quite consistently.

It is worth noting that evolution has decided that there is a merit in soaking the zygote in citrate at least for mammals.

I am into seriously chugging citrate at the moment now I am managing to keep my blood pressure in a good range. I have about 14 HDAC inhibitors that I use when having a good go at that particular intervention. I also have a set of AMPK activators and ATP enhancers, but I want to give heavy citrate (over 20g a day) another set of test data for now.

You can see some of the data I have put on twitter here:

https://twitter.com/johnhemming4mp/media

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#175

Data Upload Failed. Post Deleted.

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#176

Has anyone here actually been able to find an intervention or supplement that significantly improves sleep efficiency (reducing awake/restless time and hence time in bed) and allows you to feel the same or better with fewer hours in bed?

Iā€™ve tried a ton of different things, but none have resulted in groundbreaking results as measured by sleep trackers. Iā€™m assuming many people here experiment with different changes and wear sleep trackers, so Iā€™d love to know if anything has worked well for you!

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#177

Vitamin D3 did that for me.

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#178

A new study by an interdisciplinary team of researchers at The University of Texas at Austin provides the most reliable validation to date of the connection between physical activity, sleep quality and psychological health.

The study found that physical activity lengthened REM latency ā€” that is, the time it takes to enter the REM stage. This may indicate that exercise helps consolidate deeper sleep stages before transitioning into REM sleep, which is when we tend to have vivid dreams and our brains seem to be as active as they are when weā€™re awake.

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#179

Taken at what time of the day? Thanks!

#180

Less important when you take it than that you take it with food that contains a source of fat.

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#181

This will probably be useless for you, but I am not a great sleeper so am always looking for an edge there. Melatonin helps me someā€¦Then I started using an oral chelator of lead. After doing an EDTA challenge and finding out I have a lot of lead. Then finding out what it costs to do the number of IV EDTA sessions to get rid of it. Add in the cost to drive 80 miles 1 way to do it. So I started using DMSA 2 days in a row every week. That stuff is great for sleep, I sleep like a kid and remember dreams and everything.

Testing the urine costs only $80 and you can do it yourself after using DMSA. Itā€™s a good thing to know and you get a good nightā€™s sleep. Lol, I should be selling this shit.

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#182

I use vitamin D3 oil drops, but Iā€™ve noticed that if I donā€™t take them in the morning, it significantly disrupts my sleep.

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