I consume high protein. I never notice that level of sleep benefit from protein.
I’ll have to give tart cherry juice another go and see if it was just placebo.
What proportion of tryptophan?
I eat a lot of chicken, whey protein, legumes. Occasionally eat lamb/beef.
What proportion of tryptophan is in that?
I don’t think it’s tryptophan.
“Cherry juice increased sleep time and sleep efficiency. Cherry juice procyanidin B-2 inhibited IDO, increased tryptophan availability, reduced inflammation and may be partially responsible for improvement in insomnia.” - Pilot Study of Tart Cherry Juice for the Treatment of Insomnia and Investigation of Mechanisms Pilot Study of Tart Cherry Juice for the Treatment of Insomnia and Investigation of Mechanisms - PMC
Interesting to see this, as this relates to endogenous production of indolepropionamide.
Nitric oxide, and apparently tart cherry juice and other things, inhibit IDO and TDO which allows more tryptophan to be metabolized by gut bacteria instead of into the kynurenine pathway leading to more tryptophan metabolites, one of which is melatonin.
So it seems it’s not directly supplying melatonin instead it is increasing endogenous production.
It may indeed be different usage of tryptophan. Tryptophan is used for lots of things like serotonin, melatonin and NAD.
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I’m working on a protocol to increase the amount of tryptophan we have in our body.
While there are necessary and beneficial L-kynurenine metabolites; there are some that are harmful in excess, especially when they are not balanced out by L-tryptophan metabolites.
As people age there tends to be a skew towards L-kynurenine over L-tryptophan, and therefore this ratio should be researched as one biomarker of aging.
Relation of the kynurenine pathway with normal age: A systematic review
https://www.sciencedirect.com/science/article/pii/S0047637423001161
One branch of the pathway ultimately leads to de novo synthesis of nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential cofactor that plays a critical role in many enzymatic redox reactions and in mitochondrial energy production. NAD levels decrease with age in a variety of tissues. This decline has been implicated as a driving factor in the pathophysiology of several categories of age-associated disease. This review explores the complex interplay between kynurenine metabolism, NAD+ production, and mitochondrial function in the context of aging and age-associated disease.
I am not a NAD obsessive and I don’t supplement with NR or NMN (now). I take a little bit of B3 twice a week. (in the solgar multivitamin).
My impression of the kyenurenine pathway is that there is an enzyme that with age becomes insufficient and this causes the NAD deficiency.
I’m aware that kynurenine is necessary for NAD. That’s the annoying thing about biology, good and bad are combined very often. I think some tweak with that pathway is necessary for longevity.
Simplistically just maintaining the youthful ratio of tryptophan:kynurenine is the answer. Likely it will be more complicated than this.
There are numerous health benefits to inhibiting or diminishing the IDO and TDO enzymes. Strong anti-tumor activity for instance.
Maybe we need to go deeper and only inhibit certain parts of the kynurenine pathway. Maybe we replace the whole thing and supplement what is needed such as NAD.
The underlying question, however, is why these things change. Simply fixing the consequences of the changes is not as good as fixing the cause.
I asked a question of chatGPT about the potential variation from splicing changes (related to acetylation of splicing factors).
Bottom line
- Aberrant splicing does touch almost every enzyme of the kynurenine pathway, but most changes are subtle (ΔPSI 2–10 %) and tissue-specific rather than wholesale exon loss.
- Even modest isoform shifts matter, because the pathway is highly regulated and rate-limited at several steps (IDO1, KMO, KYNU).
- Current evidence suggests that the cumulative effect of age-related splice noise probably trims overall pathway throughput by a single-digit percent range, contributing to the well-documented rise in upstream Kyn and fall in NAD⁺ yet stopping short of catastrophic loss of function.
- Rigorous, isoform-resolved, age-series datasets—ideally at the proteomic level—are still needed to pin down exact quantitative impacts.
That sort of information I’m not aware of. We can manage these systems quite easily by maintaining nitric oxide production however.
The degradation of this and downstream effects are quite possibly the answer to why these change. If that is the case, it is very much in our control with incredibly cheap supplements and regimens such as L-citrulline, L-arginine, activated B-vitamins, regular exercise and potentially low dose tadalafil.
“In vivo studies indicate that the nitric oxide (NO) produced by iNOS inhibits IDO activity by directly interacting with it and by promoting its degradation through the proteasome pathway.” - Interactions between nitric oxide and indoleamine 2,3-dioxygenase Interactions between nitric oxide and indoleamine 2,3-dioxygenase - PubMed
I’m also going to start taking L-tryptophan itself mixed into a special yogurt blend I take a night, which also includes lots of prebiotics. This will help gut microbiota flourish and create more beneficial tryptophan metabolites.
IMO no food or drink can make enough of an impact to fix a condition. My sleep issue for example is waking up at 2 AM and I doubt Chery juice would make a difference if even 100mg of melatonin don’t make a difference most nights lol. Having said that foods we eat and what we drink play a role in helping prevent certain medical conditions but cure them, I doubt. I’m always skeptical of claims ACV cured my arthritis, or EVOO cured this or that, etc… etc… BTW, i do intend of trying the tart juice just for the heck of it, but my expectation is very, very low.
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In my experience taking super high doses of melatonin has resulted in me waking up around that time as well. Have you tried extended release melatonin? This works better for me.
I’m very interested in your experience.
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I have tried all kinds of melatonin and at different times and doses. initially it made a difference but after a while it stopped working. Believe it or not the thing that made the most of a difference was a cup of coffee when I wake up. It usually has a calming effect of some sort, and it tends to help go back to sleep, not right away but maybe within 45-60 minutes after having it. Go figure, everyone says coffee is a big no no for sleep. and in my case tends to be the opposite.
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Strange but not unheard of. Some people have a paradoxical reaction to caffeine where it makes them tired.
Sounds like you’d benefit more from upregulating endogenous production of melatonin than supplementing it.
According to the study I linked up there on cherry juice that could help with that. Need to prevent tryptophan degradation into kynurenine. There is more to it than that for melatonin, it’s not something I’ve looked super deep into but I plan on going deep on tryptophan metabolites.
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LaraPo
#505
Coffee has exactly the same effect on me - I would get very sleepy some 30 min after having my first morning cup.
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This might have been posted before somewhere, but I don’t see it on this thread. It compares melatonin to MitoQ (a modified form of CoQ10 to more specifically target mitochondria, increasing absorption, penetration, and accumulation there by many times compared to CoQ10) and MitoE in a rat model of sepsis
characterized by inflammation, mitochondrial dysfunction and early organ damage.
The results from the study showed that:
MitoQ, MitoE, or melatonin had broadly similar protective effects with improved mitochondrial respiration (P <0.002), reduced oxidative stress (P <0.02), and decreased interleukin-6 levels (P =0.0001). Compared with control rats, antioxidant-treated rats had lower levels of biochemical markers of organ dysfunction, including plasma alanine amino-transferase activity (P =0.02) and creatinine concentrations (P <0.0001).
It makes me wonder what a head-to-head comparison would look like between these compounds in healthy humans.
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LaraPo
#507
How to explain that my deep sleep stage is two times longer without melatonin than with it?
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Odd, my tracker says the opposite. High dose, long deep sleep.
Are you taking anything else at the same time?
I asked Perplexity.ai, currently my first go-to AI.
One study showed no significant differences in sleep stages in high-dose vs low-dose.
The bottom line is that people are different. I also take 1.5 grams of tryptophan at the same time so that may be making a difference.
“On the baseline nights, we did not find any difference in sleep onset latency between the low and high dose groups, there were no significant differences in the duration of any sleep stage, and there were no differences in the number or average duration of awakenings”
"Studies indicate that while melatonin can increase total sleep time and non-REM sleep, it may also reduce the amount of deep (slow-wave) sleep in some individuals, especially at higher doses.
Individual responses to melatonin vary, which may explain why some people see shorter deep sleep times, while others see longer periods on their sleep trackers."
(High dose melatonin increases sleep duration during nighttime and daytime sleep episodes in older adults - PMC
Frontiers | Timing of Sleep and Its Relationship with the Endogenous Melatonin Rhythm)
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