Protecting the Brain as We Age

Supplements
#12

Probably more than you wanted to know:
As mentioned in another thread I do not use melatonin for sleep purposes.
This a self-experiment based on John Hemmings’s experience. He takes very high doses and is still alive :smile: and book I read a long time ago:
“Melatonin: Breakthrough Discoveries That Can Help You Combat Aging, Boost Your Immune System, Reduce Your Risk of Cancer and Heart Disease, Get a Better Night’s Sleep Paperback – July 1, 1996 by Russel J. Reiter (Author), Jo Robinson (Author)”
and on a recent Kindle book:
" Extreme Dose! Melatonin The Miracle Anti-Aging Hormone Anti-Alzheimer’s Hormone Anti-Baldness Hormone Menopause Reversal Hormone Kindle Edition"
These two books tend to be mostly anecdotal and are not based on good scientific studies.
That is why I say it’s a self-experiment.

There are more recent studies indicating the benefits and safety of high-dose melatonin.

“Beyond its sleep and chronobiotic properties, melatonin is a potent antioxidant9 and has the ability to cross the blood-brain barrier,10 with suggested anti-amyloid properties. Due to this, melatonin has been increasingly investigated in many varying conditions, including cancer, cardiometabolic conditions and neurodegenerative diseases at higher doses, where there is less documentation of its safety. Doses ranging from 30 to 100 mg are being suggested or tested for effectiveness in a range of conditions and ages”

“Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.”

There is some evidence of high-dose melatonin improving insulin sensitivity, etc.
A recent meta-analysis concluded:

“Conclusions: Our results showed that melatonin supplementation was useful for reducing diabetes parameters when compared to placebo.”

“Melatonin is a potent natural antioxidant and anti-inflammatory agent that protects against toxic side effects of radiation and chemotherapy”

"Safety of higher doses of melatonin in adults: A systematic review and meta- analysis

https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12782

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#13

The various reports on Melatonin are quite helpful. It really makes a difference, but it is not a complete solution.

I think I have a complete solution (or something close to this) now, but I do end up taking a lot of melatonin during the night and currently over 80 capsules of various supplements during the day as well as other things (including intermittent rapamycin) from time to time.

When I say a complete solution I think it improves healthspan, but I am not yet persuaded that it improves lifespan in a material manner. (as in being more healthy will make you live a bit longer, but the max probably won’t shift).

#14

"For your consideration” (yes, I am shamelessly using this line.

Research Hot Spots and Trends on Melatonin From 2000 to 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669723/#:~:text=Contributions%20of%20Authors%20to%20Melatonin%20Research&text=Russel%20J%20Reiter%20(638)%20was,121)%20(%20Table%203%20).

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#15

Good find. “To our surprise, the results also indicated that melatonin has the potential to treat osteoporosis” Didn’t catch that one before.

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#16

" I am not yet persuaded that it improves lifespan in a material manner"
As far as I am aware there is nothing that has been proven to extend lifespan in humans, only healthspan.

#17

FWIW

Russel Reiter, the world’s leading researcher melatonin.

And I am not meaning his general consumer book published in the mid 90.

He is around 88, take/taking 180mg{yes 180mg] every day for decades.

There is also Pierpaoli work.

We discussed this in another thread a few months ago .

Review;

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#18

I probably take more on average than RR and he is good on the research, but it is not a whole solution.

#19

My understanding is smaller melatonin doses are more suitable for older adults.

#20

Timing is critical as there are melatonin receptors on lots of things. Do you have a reference? I have taken doses Generally considered to be excessive for about 3 years.

#21

Have anyone tried sustained release versions and noticed any differences?

#22

There are two suppliers of suppositories that run at 200 and 400mg, but they release quite quickly in my experience. The sustained release versions around are OK to take before going to sleep, but again they release quite quickly. I saw this on a dexcom CGM as it kicked down the blood glucose whilst I was asleep which is a proxy for melatonin levels.

I have experimented with DR capsules in a russian doll style and use this for my wife who has delayed release melatonin inside 5 capsules (000,00,0,1 and 2). That works to a point, but still does not delay as much as I would like.

Ideally I would like to work with some form of pharmaceutical company to design a release pattern that works with the two compartment model as otherwise it involves holding melatonin sublingually in a way which controls release. However, this is not a personal priority as I am quite happy with how everything works. Last night I slept solidly for about 6 hours (probably because I was reasonably drunk - not so drunk that I forgot to measure my biomarkers before going to sleep (weight, bp, hr) - but quite drunk. When I woke up I took a total of 110mg of melatonin partly because I didn’t take DHM and Pantethine whilst drinking (intentionally - I am monitoring the alcohol rebound) and hence had a bit of a hangover which has now subsided. I will go to the pub to have my regular breakfast (without alcohol) at about 9am. For people in the UK the pub is part of the Wetherspoons chain.

Incidentally I am pretty certain that pantethine in accelerating the metabolism of acetaldehyde brings forward the alcohol rebound, but I continue to keep an eye on this.

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#23

I assume you decided that galantamine was not something you want to take on a regular basis? On the other hand, what about melatonin? If you’re taking or are going to be taking higher doses, do you have any type of schedule for what dose to take and when to take it? Thanks

#24

John_Hemming, With your large doses of melatonin, do you have any type of schedule for what dose you take and when you take it? Thanks

#25

Its not really a schedule. It is more that I time things in a way which I find best enables me to extend my sleep. Sleep is very complex and the interplay with the HPA ultradian cycle and melatonin is quite complex. My own protocol increases the energy state of my cells (levels of Acetyl-CoA via ACLY and ACCS2) with a view to increasing gene expression. This has the effect of increasing cytosolic ROS - depending on other factors like NF kappa b. I am running a particularly intense form of the protocol at the moment and a side effect is an increase in visible inflammation. Melatonin helps to keep this under control. Because melatonin has a relatively short half life (about 30 mins) I might take 10mg every 10 minutes or every 5 minutes to maintain a vaguely constant serum level.

Obviously if I don’t wake up in the middle of the night all I can do is to take some melatonin when I wake.

#26

I am not sure one way or another, as most studies see effects at very lose doses, so that’s why I was asking why they use such high doses. In adults, studies have found the benefits from melatonin are for people who have sleeping problems related to delayed sleep-wake phase disorder and jet lag. Evidence in small studies have indicated that melatonin may be useful in children with certain conditions including epilepsy and some neurodevelopmental disorders such as autism spectrum disorder and Angelman’s syndrome. High doses of melatonin increase sleep duration during nighttime and daytime sleep episodes in older adults.

In my understanding, we do see some age related decrease in melatonin synthesis, but the literature is mixed on this. I am fortunate to be able to learn from a great group of circadian rhythm field experts such as , Dr. Gianluca Tosini, who is a pioneer in the melatonin/circadian rhythm field. I talked to him about this issue before as we know the SCN and retina from older mice and humans a show a decrease in responsiveness to melatonin, and he said that as we age, it less so the effect of melatonin synthesis decreasing and more so the effect of melatonin receptor responsiveness decreasing that leads to disruption of sleep as we age. We also talked about melatonin’s antiaging effects, and the one study he knew of claimed to help in anti-aging and in the paper it was shown that if you give exogenous melatonin only at night, you can extend lifespan in mice. But his issue with the paper is that it is hard to distinguish between the effects of melatonin or if it is sleep that is causing this extension of lifespan.

There is a really good review on the aging clock that I will attach:
https://www.jci.org/articles/view/90328

What was interesting was their talk on melatonin:
" However, other evidence suggests that a “young” melatonin rhythm is in fact preserved in very healthy older adults, and a reduction in peak melatonin may occur only in older individuals whose total melatonin levels are at the lower end of the population distribution. For example, a 6-year longitudinal study found no evidence of a decrease in total melatonin secretion in healthy older adults (ages ranging from 55 to 74 years). This discrepancy in findings may suggest that a reduction in the melatonin rhythm is not a feature of a healthy aging process, and in fact may signal underlying pathology. To this end, Waller and colleagues reported a lower nightly melatonin peak in middle-aged men (mean age of 57 years) with cognitive impairment compared with age-matched healthy controls. Furthermore, significant reductions in melatonin synthesis and expression of melatonin receptors in the SCN have been documented in individuals with neurodegenerative diseases such as Alzheimer’s or Parkinson’s, or those with prodromal symptoms. "

I also know of Melatonin disruption leading to health disorders such as obesity, type 2 diabetes, insulin resistance, etc. A variant in MTNR1B is associated with increased risk of type 2 diabetes and impaired early insulin secretion. There have been some studies talking about melatonin over signaling being a risk factor for type 2 diabetes. In insulin secreting cells, melatonin seemed to reduce cAMP levels and MTNR1B overexpression exaggerated the inhibition of insulin released exerted by melatonin.

Personally, I don’t see much benefit in taking large doses of melatonin until we get much much older, and even then I would weigh the risk/reward in relation to the benefits of melatonin dosing vs how much longer you think you have left. I don’t see the harm in taking a large dose if your 70-80+ and you more than likely are heading toward your marginal decades, but if your younger than that, I would wait to see more research come out.

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#27

It is worth remembering that the concentration in the CSF is much higher (factors) than in serum. Particularly in the third ventricle. Hence studies that look only at serum levels may miss changes that happen in the CSF. I would expect the metabolism in the CSF to be different to the serum.

However, in the end I am concerned primarily as to the impact on myself. I am a lot healthier now than a few years ago and I consider melatonin to be part of that.

I would be interested in studing the profile in serum of large doses. I would think a proportion is absorbed into cells quite quickly and possibly faster than an orthodox half life of 30 mins.

#28

Actually am going to take galantamine hydrobromide, 8mg daily, sublingually for some time to see if I can find any subjective positive effects or deduce any effects it might have on my biomarkers. I think I have already posted references to the positive effects attributed to galantamine, but here are some of the positive effects gleaned from several articles about galantamine:
Improving memory and cognitive function.
Slowing down the progression of Alzheimer’s symptoms.
Enhancing thinking, learning, and problem-solving abilities.
Relieving depression.
Improving sleep quality.

#29

I’m aware of the diabetes connection and agreed best to wait and see before supplementing or megadosing melatonin outside of say delayed sleep-wake phase since the safety of long-term exogenous melatonin use is not well documented, nor are side effects actually well established. “Melatonin dysfunction” doesn’t necessarily mean taking melatonin would do much if it is an epiphenomenon, as you already know. As an example, an iron chelator for newly diagnosed drug naive PD reduced iron in niagrostriatal pathways and ended up increasing progression of PD despite the characteristic “iron dysfunction”, suggesting an epiphenomenon.

There is only a small benefit for sleep onset and none for sleep maintenance with a statistically significant but small improvement in sleep latency and total sleep time which doesn’t seem to be clinically significant afaik. Would be interested if you’re aware of any increased REM and/or N3 without significantly compromising any other parts of sleep architecture. The only suggestive deal I have seen with better safety profile is low dose gabapentin especially more justified with anxiety disorder and gabapentin responder with only limited use due to “tolerance”.

Not sure about high doses, but generally I want a fairly well defined potential benefit and high enough safety profile (although it might be the case where melatonin megadosing could turn out to be “safe”) to really consider it, let alone megadosing anything.

I’m also interested in whether low dose (ie 300 mcg) sustained-release dosing could “augment” natural circadian alignment over the longer term, as you know - we are not quite on the 24 hr mark, so I’m not quite saying we shouldn’t bother using melatonin in the long term especially if individual variation brings it down, the purported high safety profile just isn’t actually proven or disproven. Just dunno how much it matters in efficacy either.

#30

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800004

I just switched to candesartan based on this article, Brain/Dementia benefits theorized. Go ahead, change my mind :grin:

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#31

Btw I use canagliflozin intermittently instead of continuously partly to indirectly lower serum urate to <5.8 despite adequate hydration and a low fructose diet etc with FHx of gout (bimodal curve).

The main issue I see is the difference in safety and risk profile in my specific situation (it’s a high safety profile in general so far but there are several caveats and rare but important issues, especially in the context of rapa), hence intermittent dosing.

There may be some theoretical vascular and brain SGLT1/2 related effect in case anyone is interested in looking further