Great video Michael! Your trial and error approach is paying off. You are on the way yo beating death,longer life age. Congratulations on all your hard work and efforts. You Are More Natural than some of the others.
Thanks @thomastoadally! I've got some more hypothesis-focused videos like this coming sooner rather than later, especially a potential way to increase NAD without niacin, NMN, NR, or tryptophan...
@@conqueragingordietrying123 WOW Michael than is inspiring news. You are very good at doing natural. What our bodies absorb is the key to your whole premise. I am waiting for you new findings and reports. Thank you for all you do 💞🙏 you are the best!!
Just ordered Iollo (annual). Look forward to what the data tells me. BTW, Prof. Michael Snyder, a co-founder of Iollo just gave a good talk on the NUS Medicine channel about healthcare and deep data.
Beautiful. I feel like we're watching a black-and-white TV, but the color ones are just a matter of time. I'm saying some more tweaking and a bit more complexity involved here will lead to some breakthroughs.
technically, increased glutamate levels could also be an indicator for ineffective/incomplete glutathione synthesis (maybe?) - since glutathione is glutamate + cysteine + glycine creatine is also on the right side (somewhat surprisingly so, but if it only contributes igf-1 raising properties (if the GSH synthesis pathway is trashed) then its probably net negative i guess(?)) and ATP (which it provides) is also required for GSH generation but ive no actual clue, just my confused thoughts 😂
@@conqueragingordietrying123 And the vitamin D association? It's fairly common for "health enthusiasts" to load up on both creatine and vitamin D supplements.
@@conqueragingordietrying123 At least to what I understand, creatine is made mostly in the kidney, liver & pancreas and is then transported to the muscle through the circulation. Since the paper was doing metabolomics on serum, this seems like a transport block in the muscle cells themselves. We know the cellular transport network does break down with aging. If they were doing metabolomics on muscles cells perhaps the creatine association would be reversed.
@@jackbuaer3828 Neither vit D [or creatine for that matter] replicated in the second cohort in that paper, so you could ignore those if you like. For vitamin D you usually need to adjust for season and they didn't mention that....
I wonder about these implications, especially when it comes to neuro degeneration. ALS, Alzheimer's, Parkinson's, etc. Think about how many of these diseases manifest as low NAD, high glutamate. Important content as usual, keep up the great work
Interesting…also dopamine stimulates glutamate production, and as stimulatory neurotransmitter its overabundance can lead to anxiety, hyperactivity, ocd. So NAC helps to regulate glutamate, I take it for glutathione but it is also calming because of that, and helps with sleep for me. So this is my strategy to counteract glutamate I guess…
You are right,... Just, the context you describe is taking place in the brain... in the liver and the muscles the issue of anxiety is not that prominent...
Great content Michael, thank you for this. Did you consider taking Niacinamide instead of Niacin, Shouldn't it have similar "positive" effects without the flush?
Perhaps, but as we saw in last week's video, niacinamide raises homocysteine, which is already on the high side. I'll have another potential way to increase NAD, and without NMN, NR, niacin, or tryptophan in an upcoming video...
These metabolomic studies are always interesting. The field is still in its early stages and I only know of 3 or so reasonable ACM studies so far. Focussing on the factors that have been identified across studies would be a good way to make sure we are addressing relevant pathways. These are the ones that have been identified in more than 1 study of middle aged individuals: Positive metabolites: Histidine, Leucine, Valine, Asparagine, Ergothioneine Negative metabolites: Isoleucine, Dimethylglycine, N2,N2-Dimethylguanosine, 7-Methylguanine, Homocitrulline That at least narrows it down to a reasonable set to monitor, do some pathway research on and perhaps follow the correlations.
Yep, good point on validation. The metabolites that I highlighted in the video are significantly associated with age, too, in a study that I'm analyzing for my academic work. So there is replication...
There seems to be methionine and the oxidised form with positive and negative hazard ratios. Since that reaction is reversible we could guess factors associated with aging are increasing methionine-S-oxide at the expense of methionine levels.
Aha, good catch@@jamesgilmore8192! I hadn't considered that methionine sulfoxide and methionine were on opposite sides of risk. I may cover that in a short video!
Thanks @Icarianbrother. Potentially useful based on published studies, and if one takes it, measuring objective biomarkers to see if has an effect (positive, negative, or neutral).
@@conqueragingordietrying123 For the negative ones there is a genetic disease that might be relevant called Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD), that can raise those long even acylcarnitines, which might implicate transport across the mitochrondrial membranes by analogy. But I have not the faintest idea on the positive ones, which are all odd, which is either a coincidence or something else is going on.
You used Niacin to raise your NAD+. I've been putting 500mg in my electrolyte drink for about the past 9 days. Whether it's NAD+ increase or something else but I have made significant changes in my energy level and brain function level. I haven't felt this good in years. Did you try Niacin and NMN together? I understand they use different pathways of boosting NAD+. Might be worth a look.
Hey @jdholbrook33, relatively high doses of nicotinic acid might be bad for my epigenetic pace of aging: ua-cam.com/video/SwggBuuamCk/v-deo.html In contrast, low-dose (60 mg/d) is better in my case
I think we all saw that pic of mice with / without CaAKG supplementation about a year ago. My ears pricked at 3:20 when you mentioned AKG downstream of a potential blockage..
wait, I take beta-alanine, not for sport, but to bind with histidine to make carnosine, in stead of buying very expensive carnosine... so is this a bad thing lowering my histidine ???
Based on the all-cause mortality data in the video, having low circulating levels of Histidine may not be good for health, so that's something to keep in mind.
I just buy the carnosine. I can't tell you if the paper cited below is accurate, but I recall that it influenced me to take carnosine over beta-alanine "The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) has been found to exert an anti-senescence effect when used as a dietary supplement. Carnosine clearly improved the external appearance of experimental animals and provided beneficial physiological effects, thus maintaining the animals in better condition than control animals receiving no carnosine or a mixture of beta-alanine and L-histidine. Gallant S, Semyonova M, Yuneva M. Carnosine as a potential anti-senescence drug. Biochemistry (Mosc). 2000 Jul
@@jamesgilmore8192 I don't think there is great evidence to support its use. It's mostly theoretical and speculative. However, since I am vegetarian, my diet is going to be low in carnosine to start with. I never did find negative info on Carnosine, though perhaps there is some out there. Two servings of red meat would provide 500 mg of carnosine. I supplement with 500mg twice daily, Greg Fahy seems to believe it has efficacy ua-cam.com/video/wFjxGX2dW_I/v-deo.html You can read the Life Extension Foundation propaganda by googling the article title "Anti-Aging Effects of Carnosine Report" LEF states among other things: "Protein degradation occurs as a result of cross-linking and the formation of advanced glycation end products (AGE). These changes figure prominently in the processes of aging and its typical signs such as skin wrinkling and brain degeneration.4,5 Studies show that carnosine is effective against cross-linking and the formation of advanced glycation end products (AGE).6,7 Glycated proteins produce 50-fold more free radicals than nonglycated proteins and carnosine may be the most effective anti-glycating agent known. An example of carnosine's defense against protein degradation is provided by MDA (malondialdehyde).8 MDA causes protein cross-linking and AGE formation. Carnosine has been shown to inhibit MDA-induced glycation in blood albumin and eye lens protein.9 Carnosine has also been shown to keep MDA from inducing protein cross-linking.10 One study showed that carnosine actually decreased MDA levels in mice." "Laboratory research suggests that carnosine has the ability to rejuvenate cells approaching the end of the life cycle of dividing cells, restoring normal appearance and extending cellular life span.13 When scientists transferred late-passage fibroblasts (a type of skin cell) to a culture medium containing carnosine, they exhibited a rejuvenated appearance and often an enhanced capacity to divide.14 The carnosine medium increased life span, even for old cells. Cells transferred to the carnosine medium attained a life span of 413 days, compared to 126 to 139 days for the control cells. This study showed that carnosine induced a remarkable 67% increase in cellular life span." "A study tested the effect of carnosine on life span and indicators of aging in senescence-accelerated mice. Carnosine extended the life span of the treated mice by 20% on average, compared to the mice not fed carnosine.15 The mice given carnosine were about twice as likely to reach the "ripe old age" of 12 months as untreated mice. Carnosine did not alter the 15 month maximum life span of the senescence-accelerated mouse strain, but it did significantly raise the number of mice surviving to old age. Carnosine distinctly improved the appearance of the aged mice, whose coat fullness and color remained much closer to that of young animals. Significantly more carnosine-treated mice had glossy coats (44% vs. 5%), while fewer had skin ulcers (14% vs. 36%)."
iollo doesn't deliver to Germany. It's hard to believe, that they do it for this price. I only found the prices of one German company, Biocrates, which show their prices. They ar between 6,000 and 8,000 Euro. It's hard to belive, which prices iollo offers.
They will need to get through the approvals....it will take time. In the meantime you can probably measure many other things and start optimising those
@@jamesgilmore8192 I'm not sure, whether approvals are required in the US or in Europe. But it's strange - it is just 50 cent/measurement in the US and 16 Euro in Europe. There was a big scandal in Germany about a measurement device, which randomly generated "measurements" without really measuring. Does iollo really create 500 measurements each time? How can that be done? Each value has somehow to be created separately.
@@dirkh0 Its done through an automated pipeline using specialised equipment and yes 500 measurements are possible for a much lower price if the pipeline is efficient. Biocrates is aimed at research which is a different market. The price will surely come down.
Great video Michael! Your trial and error approach is paying off. You are on the way yo beating death,longer life age. Congratulations on all your hard work and efforts. You Are More Natural than some of the others.
Thanks @thomastoadally! I've got some more hypothesis-focused videos like this coming sooner rather than later, especially a potential way to increase NAD without niacin, NMN, NR, or tryptophan...
@@conqueragingordietrying123 WOW Michael than is inspiring news. You are very good at doing natural. What our bodies absorb is the key to your whole premise. I am waiting for you new findings and reports. Thank you for all you do 💞🙏 you are the best!!
Just ordered Iollo (annual). Look forward to what the data tells me. BTW, Prof. Michael Snyder, a co-founder of Iollo just gave a good talk on the NUS Medicine channel about healthcare and deep data.
Cool, enjoy @peterz53. I'm obviously a big fan of the iollo kit, and also Michael Snyder!
Beautiful. I feel like we're watching a black-and-white TV, but the color ones are just a matter of time. I'm saying some more tweaking and a bit more complexity involved here will lead to some breakthroughs.
technically, increased glutamate levels could also be an indicator for ineffective/incomplete glutathione synthesis (maybe?) - since glutathione is glutamate + cysteine + glycine
creatine is also on the right side (somewhat surprisingly so, but if it only contributes igf-1 raising properties (if the GSH synthesis pathway is trashed) then its probably net negative i guess(?)) and ATP (which it provides) is also required for GSH generation
but ive no actual clue, just my confused thoughts 😂
Good point about glutamate. I'm not sure what to make of the creatine association yet...
@@conqueragingordietrying123abundance mimetics
@@conqueragingordietrying123 And the vitamin D association? It's fairly common for "health enthusiasts" to load up on both creatine and vitamin D supplements.
@@conqueragingordietrying123 At least to what I understand, creatine is made mostly in the kidney, liver & pancreas and is then transported to the muscle through the circulation. Since the paper was doing metabolomics on serum, this seems like a transport block in the muscle cells themselves. We know the cellular transport network does break down with aging. If they were doing metabolomics on muscles cells perhaps the creatine association would be reversed.
@@jackbuaer3828 Neither vit D [or creatine for that matter] replicated in the second cohort in that paper, so you could ignore those if you like. For vitamin D you usually need to adjust for season and they didn't mention that....
Congratulations on the 20K subs Michael. Love this channel and your community.
Thanks KoiRun!
I wonder about these implications, especially when it comes to neuro degeneration. ALS, Alzheimer's, Parkinson's, etc. Think about how many of these diseases manifest as low NAD, high glutamate. Important content as usual, keep up the great work
Interesting…also dopamine stimulates glutamate production, and as stimulatory neurotransmitter its overabundance can lead to anxiety, hyperactivity, ocd. So NAC helps to regulate glutamate, I take it for glutathione but it is also calming because of that, and helps with sleep for me. So this is my strategy to counteract glutamate I guess…
You are right,... Just, the context you describe is taking place in the brain... in the liver and the muscles the issue of anxiety is not that prominent...
Great video! Love the inclusion of the mechanisms…..
Thanks @davidford8539!
Great content Michael, thank you for this. Did you consider taking Niacinamide instead of Niacin, Shouldn't it have similar "positive" effects without the flush?
Perhaps, but as we saw in last week's video, niacinamide raises homocysteine, which is already on the high side.
I'll have another potential way to increase NAD, and without NMN, NR, niacin, or tryptophan in an upcoming video...
How about if you used niacinamide together the substance of homocysteine remedy
These metabolomic studies are always interesting. The field is still in its early stages and I only know of 3 or so reasonable ACM studies so far. Focussing on the factors that have been identified across studies would be a good way to make sure we are addressing relevant pathways. These are the ones that have been identified in more than 1 study of middle aged individuals:
Positive metabolites: Histidine, Leucine, Valine, Asparagine, Ergothioneine
Negative metabolites: Isoleucine, Dimethylglycine, N2,N2-Dimethylguanosine, 7-Methylguanine, Homocitrulline
That at least narrows it down to a reasonable set to monitor, do some pathway research on and perhaps follow the correlations.
Yep, good point on validation. The metabolites that I highlighted in the video are significantly associated with age, too, in a study that I'm analyzing for my academic work. So there is replication...
@@conqueragingordietrying123 Yes there is definitely more than one way to validate things.
Outstanding!
1:00 surprising that methionine shows up on the left side 🤔
Maybe the animal studies won't translate to people...
There seems to be methionine and the oxidised form with positive and negative hazard ratios. Since that reaction is reversible we could guess factors associated with aging are increasing methionine-S-oxide at the expense of methionine levels.
Aha, good catch@@jamesgilmore8192! I hadn't considered that methionine sulfoxide and methionine were on opposite sides of risk. I may cover that in a short video!
Thank you for another great video! What is your opinion on creatine monohydrate?
Thanks @Icarianbrother. Potentially useful based on published studies, and if one takes it, measuring objective biomarkers to see if has an effect (positive, negative, or neutral).
Thank you! I know that you are right about having blood tests. I will eventually start doing that. @@conqueragingordietrying123
this metabolimics stuff is meta, i just hope iollo is accurate in mesuring them
The fatty acid story with carnitine is interesting here. Lots of +ves and -ves.
Agreed. Sorting out which species are consistently "bad" is what's slowing down a video on acylcarnitines, as they don't all go in the same direction.
@@conqueragingordietrying123 For the negative ones there is a genetic disease that might be relevant called Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD), that can raise those long even acylcarnitines, which might implicate transport across the mitochrondrial membranes by analogy. But I have not the faintest idea on the positive ones, which are all odd, which is either a coincidence or something else is going on.
Is NAD good for benzo withdrawal, since it is said that glutamate storms cause withdrawal symptoms?
You used Niacin to raise your NAD+. I've been putting 500mg in my electrolyte drink for about the past 9 days.
Whether it's NAD+ increase or something else but I have made significant changes in my energy level and brain function level. I haven't felt this good in years.
Did you try Niacin and NMN together? I understand they use different pathways of boosting NAD+. Might be worth a look.
Hey @jdholbrook33, relatively high doses of nicotinic acid might be bad for my epigenetic pace of aging:
ua-cam.com/video/SwggBuuamCk/v-deo.html
In contrast, low-dose (60 mg/d) is better in my case
you just added to my poor understanding of the benefits of AKG supplementation
AKG supplementation could be a positive, especially if NAD is low-I considered expanding the video to include more on AKG, perhaps in another video!
I just started taking CaAKG and I notice that the skin on my face is looking better.
I think we all saw that pic of mice with / without CaAKG supplementation about a year ago. My ears pricked at 3:20 when you mentioned AKG downstream of a potential blockage..
Thanks!
Thanks for the support @christianravera6768!
What is the optimal NAD+ level per decade (I am 63 on 1gr of NMN)
That's a great question, which depends on many factors-I'll have more insight in an upcoming video, and also using metabolomic analysis.
@@conqueragingordietrying123 is there a NAD+ level overdose ? could you become Superhuman on overdose?
ahhh... a cliffhanger :))
IOLLO is not avail in europe, unfortunately
Ah, sorry to hear that. Probably in time, they'll ship to Europe
@@conqueragingordietrying123 they should hurry before I start that business here :)
wait, I take beta-alanine, not for sport, but to bind with histidine to make carnosine, in stead of buying very expensive carnosine... so is this a bad thing lowering my histidine ???
Based on the all-cause mortality data in the video, having low circulating levels of Histidine may not be good for health, so that's something to keep in mind.
I just buy the carnosine. I can't tell you if the paper cited below is accurate, but I recall that it influenced me to take carnosine over beta-alanine
"The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) has been found to exert an anti-senescence effect when used as a dietary supplement. Carnosine clearly improved the external appearance of experimental animals and provided beneficial physiological effects, thus maintaining the animals in better condition than control animals receiving no carnosine or a mixture of beta-alanine and L-histidine.
Gallant S, Semyonova M, Yuneva M. Carnosine as a potential anti-senescence drug. Biochemistry (Mosc). 2000 Jul
@@jackbuaer3828 Jack -- imho that's not a paper to be basing any decision on.
What is the evidence for supplementing/increasing carnosine?
@@jamesgilmore8192 I don't think there is great evidence to support its use. It's mostly theoretical and speculative. However, since I am vegetarian, my diet is going to be low in carnosine to start with.
I never did find negative info on Carnosine, though perhaps there is some out there.
Two servings of red meat would provide 500 mg of carnosine. I supplement with 500mg twice daily,
Greg Fahy seems to believe it has efficacy
ua-cam.com/video/wFjxGX2dW_I/v-deo.html
You can read the Life Extension Foundation propaganda by googling the article title
"Anti-Aging Effects of Carnosine Report"
LEF states among other things:
"Protein degradation occurs as a result of cross-linking and the formation of advanced glycation end products (AGE). These changes figure prominently in the processes of aging and its typical signs such as skin wrinkling and brain degeneration.4,5 Studies show that carnosine is effective against cross-linking and the formation of advanced glycation end products (AGE).6,7 Glycated proteins produce 50-fold more free radicals than nonglycated proteins and carnosine may be the most effective anti-glycating agent known.
An example of carnosine's defense against protein degradation is provided by MDA (malondialdehyde).8 MDA causes protein cross-linking and AGE formation. Carnosine has been shown to inhibit MDA-induced glycation in blood albumin and eye lens protein.9 Carnosine has also been shown to keep MDA from inducing protein cross-linking.10 One study showed that carnosine actually decreased MDA levels in mice."
"Laboratory research suggests that carnosine has the ability to rejuvenate cells approaching the end of the life cycle of dividing cells, restoring normal appearance and extending cellular life span.13 When scientists transferred late-passage fibroblasts (a type of skin cell) to a culture medium containing carnosine, they exhibited a rejuvenated appearance and often an enhanced capacity to divide.14 The carnosine medium increased life span, even for old cells. Cells transferred to the carnosine medium attained a life span of 413 days, compared to 126 to 139 days for the control cells. This study showed that carnosine induced a remarkable 67% increase in cellular life span."
"A study tested the effect of carnosine on life span and indicators of aging in senescence-accelerated mice. Carnosine extended the life span of the treated mice by 20% on average, compared to the mice not fed carnosine.15 The mice given carnosine were about twice as likely to reach the "ripe old age" of 12 months as untreated mice.
Carnosine did not alter the 15 month maximum life span of the senescence-accelerated mouse strain, but it did significantly raise the number of mice surviving to old age. Carnosine distinctly improved the appearance of the aged mice, whose coat fullness and color remained much closer to that of young animals. Significantly more carnosine-treated mice had glossy coats (44% vs. 5%), while fewer had skin ulcers (14% vs. 36%)."
This kinda sounds like we should consume more Glutamate to make sure the conversion to 2-oxogluterate takes place. Or am I wrong?
No, definitely not. If you supplement with glutamate and are low in NAD, that's bad news
@@conqueragingordietrying123What would be the effect of too much glutamate?
My iollo results showed a glutamate level of 0. Suggested I supplement with it. Not sure that is right call after watching this
0 seems unlikely-I'd reach out to iollo to maybe repeat the test...
Valeu!
Thanks for the support @danielcordeiro7048!
iollo doesn't deliver to Germany. It's hard to believe, that they do it for this price. I only found the prices of one German company, Biocrates, which show their prices. They ar between 6,000 and 8,000 Euro. It's hard to belive, which prices iollo offers.
European demand will likely push iollo to offer services there, so it's only a matter of time...
They will need to get through the approvals....it will take time. In the meantime you can probably measure many other things and start optimising those
@@jamesgilmore8192 I'm not sure, whether approvals are required in the US or in Europe. But it's strange - it is just 50 cent/measurement in the US and 16 Euro in Europe. There was a big scandal in Germany about a measurement device, which randomly generated "measurements" without really measuring. Does iollo really create 500 measurements each time? How can that be done? Each value has somehow to be created separately.
@@dirkh0 Its done through an automated pipeline using specialised equipment and yes 500 measurements are possible for a much lower price if the pipeline is efficient. Biocrates is aimed at research which is a different market. The price will surely come down.