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So I've been really appreciating your videos, except you don't answer the question in this video unfortunately. When it comes to Circ rhythms, nocturnal animals are unfortunately far more difficult to translate to humans. There are studies (I wish I had the links) - that show NAD+ actually peaks at 11:00 AM, and NAMPT peaks at 6:00 PM - which is curious because you would think they would align - but not according to multiple studies. Clearing this up with the most accurate data should be a new video - I've studied biochem journals intensively for 2 years and I can tell you few things are as complex, confusing, and important as circadian rhythm in the context of anti-aging therapies; NAD, sirt, time restricted feeding (including leptin release), BAT thermogenesis, temperature hormesis, macro-nurtrient intake, hormones, among numerous other factors. Indeed I am one of those who truly believe the most confounding factor in all clinical molecular studies is the time of administration (which will have total different affects in a mouse than a human due from separate clock functions - some of them overlap with humans, some of them do not), along with of course the hours of feeding. What we need to discover is the circ rhythm in regards to NAD/NAMPT/TOR/AUTOPHAGY in particular - and if this implies eating between 6:00 PM-8:00 PM - if ice baths should be done in the morning/day time or in the evening "cooling down" period, etc.; Also another question is that Norepinephrine which seems to be conducive to mitochrondrial fusion (and one of the benefits of cold therapy, apart from UCP1 and HSP) - is also a glucocorticoid stress hormone?? Wouldn't this keep us awake at night? Also it seems there are studies that TOR2 activation is actually necessary to get the benefits of calorie restriction. Vegetables have an extremely high protein to carb ratio compared to most foods - 1 to 3; except it tends to be very high in fiber - so maybe the benefits is biome-SCFA based? Fruit has the best carb to protein ratio (100%) - but fructose is absolutely horrible for the body. Arachidonic Acid is central to the Cell Membrane Theory of Aging - along with cell membrane fluidity - except it also seems central to inflammation/cancer pathologies - while it has both anti-inflammatory transformations as well. Otherwise I love your video and hope we can cover the above topics - or I've given you some ideas!
Thanks! And as annoying as this may sound, your question is something that has just been under-researched at present but i think would be very important to understand!
@@TheSheekeyScienceShow Very much under-researched indeed! I'm currently doing some desk research on sirtuin activation timing, SIRT1 in particular. There are more factors that come into play when it comes to supplement timing, like activity levels throughout the day. Perhaps we can share some ideas on this some time, for now, I'll make sure to subscribe :)
Great video. Thanks🤗 Is there any correlation between appetite and nad+ levels? It seems logical that there should be both drivers and limiters that would mediate the body’s need for nad+.
Is the circadian rhythm linked to the day/night rhythm or is it individual? Or is it more related to light/darkness? For example, is it bad if I sleep from 4 am to 12, but have a good sleep and am not exposed to any light while sleeping?
Another great video, many thanks. I know you are a scientist, so you don't like to guess, but...you know whats coming next... Would you 'guess' that for a human our highest peak for NAD (if we mimic the mouse and dawn was at 0600 and dusk was at 1800) would be at around mid-day? As we age our NAD levels drop, it would be nice to know if they drop equally across the whole circadian clock [so if you could research that ASP, that would be great ;-) ] let's say they do, I guess it would be better to mirror the clock and boost it where it would normally be high, I think it is high there for a reason (our body does the most important NAD heavy processes there?), so we should boost it there and not where it is low for a reason?
Thank you! Yes, you are right, I do not like to guess, but in theory the oscillation in NAD+ would be the same as mice, but 12 hours out (nocturnal vs. diurnal). In terms of how NAD+ levels would be affected by age throughout the day is also complicated by the fact that the circadian rhythm weakens as you age as well (I think I discuss this is another video), so you would see less overall and less variation throughout the day. In this case, yes it would seem mimicking the clock NAD+ fluctuations would be most effective BUT, the difficulty with this is getting the timing right since it would depend on how fast the NAD supplements are metabolised in the body, timings for which I don't know. Basically, I think it is important to think about and hope that more research looks into it. Hope that helps :)
@@TheSheekeyScienceShow Thanks very much for the reply and venturing an opinion. You are right there is a lot we still don't know about NAD levels in humans and varying levels throughout the day and a lifetime. I was going to split my dose of NMN and take it at 0600 and 1300, I think I may try 1300 and 2000 and see what happens, the other key issue you rightly mention is how long it takes to metabolise. Any way thanks for you your answers and thanks for the content, great channel.
My question to you is, what should be my take away from this in terms of both dosage timing and frequency of NMN/NR, to keep in sync with Circadian related NAD fluctuation?
Thanks for the comment and aha, that is a question i get asked a lot! There isn't enough evidence for me to feel comfortable suggesting a right "time" due to variations in eating/sleeping patterns, physical activity and pharmacokinetics of the supplement. The main take home of the video was to raise awareness that "when" is important to consider and to try and raise a conversation. The good news is that new research comes out as time goes on; in fact i am prepping a video currently on NAD+ and its impact on driving the circadian rhythm via SIRT1 activity. Although done in mouse, i hope it will go in more detail then this one. Hope that helps!
Back in the early 00's I started taking B vitamins pre cardio workout and noticed some good effects (perky skin, improved mood) and some bad effects (nausea). I separated out the B's and noticed niacinamide was the thing that gave me the good effects. That was before all the NAD+ stuff came to light. Of course, many say NAM is not the thing to do. I typically train fasted first thing in the morning. If there is a threshold phenomenon it seems like you want to bump up the peak. Post work out I take luteolin as it is a mast cell stabilizer (I have mast cell activation symptoms, started a couple of years ago, probably a post-infection thing; I expect more people will have this as a post-covid syndrome), after the workout since some histamine release is needed for exercise adaptations. Luteolin is also a CD38 inhibitor, so perhaps it blunts the troughs? ~ I would really appreciate ES's thoughts (or anyone else's) on the following articles: Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells pubmed.ncbi.nlm.nih.gov/28417163/ Quantitative Analysis of NAD Synthesis-Breakdown Fluxes pubmed.ncbi.nlm.nih.gov/29685734/ Despite thinking 250 mg NAM is okay, just in case I'm wrong, I am going to switch to NR soon and am considering NMN if I can find a reputable and not too expensive source. ~ I also have a question regarding butyrate. Butyrate has been found to extend life in some animal models, but it is considered to be a general HDAC inhibitor - so I'm assuming that includes SIRT1. What's up with that?
After posting this YT recommended an interview with Charles Brenner (the NR guy) wherein he addressed the Liu et al. (2018) paper: ruclips.net/video/u_KBthslx3Q/видео.html Sometimes the YT algorithm actually works. Would still appreciate opinions on the article.
NAM is unpatentable so it will never be promoted by scientists. Dr William Kaufman used upto 4 grams per day on patients with severe arthritis. They all reported feeling and looking younger so it is a great supplement.
I think perhaps the NAD+ synthesis at night is driven by sirtuin activity, whereas the peak during the day is a result of NADH being being released through activity. What's your thought?
Firstly, i agree that the bimodal pattern is really interesting! Since the two main usages of NAD+ are in redox reactions/metabolism or by NAD+-consuming enzymes, i think there is some truth in your comment; less activity at night would suggest that the peak is more important for the NAD+-consuming enzymes. However, sirtuins use up NAD+, not produce it, and so one could argue that an increase in NAD+ levels at night is due to the fact that there is less activity in the body and therefore less usage of NAD+. Moreover, in this video i only really focused on NAD+ production from NAM-->NMN-->NAD+, yet there are other pathways of NAD+ synthesis (ruclips.net/video/9nJl6EDFShc/видео.html). I honestly think the one way we will get to answer these questions is through computer simulations/machine learning to input all the different levels of regulation and to see the outcome.
@@TheSheekeyScienceShow Perhaps you're right and machine learning will provide us with more answers... Until then I'll do my best to interpret the research with the evidence we've got :p I did find some evidence suggesting an indirect increase in NAD+, triggered by active SIRT1, might be possible through AMPK signaling: www.sciencedirect.com/science/article/pii/S155041311200143X However, the pathway is hardly explained in this article, or other literature...
@@fitiwthw thanks for the paper! Am currently also prepping a video on this topic as some new research has come out, hopefully will release by tomorrow
*Get 10% off at DoNotAge using my discount code "SHEEKEY"*
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Disclaimer - using this discount will provide the channel with a small commission, so only use if you want to support the channel! :)
So I've been really appreciating your videos, except you don't answer the question in this video unfortunately. When it comes to Circ rhythms, nocturnal animals are unfortunately far more difficult to translate to humans.
There are studies (I wish I had the links) - that show NAD+ actually peaks at 11:00 AM, and NAMPT peaks at 6:00 PM - which is curious because you would think they would align - but not according to multiple studies.
Clearing this up with the most accurate data should be a new video - I've studied biochem journals intensively for 2 years and I can tell you few things are as complex, confusing, and important as circadian rhythm in the context of anti-aging therapies; NAD, sirt, time restricted feeding (including leptin release), BAT thermogenesis, temperature hormesis, macro-nurtrient intake, hormones, among numerous other factors.
Indeed I am one of those who truly believe the most confounding factor in all clinical molecular studies is the time of administration (which will have total different affects in a mouse than a human due from separate clock functions - some of them overlap with humans, some of them do not), along with of course the hours of feeding.
What we need to discover is the circ rhythm in regards to NAD/NAMPT/TOR/AUTOPHAGY in particular - and if this implies eating between 6:00 PM-8:00 PM - if ice baths should be done in the morning/day time or in the evening "cooling down" period, etc.;
Also another question is that Norepinephrine which seems to be conducive to mitochrondrial fusion (and one of the benefits of cold therapy, apart from UCP1 and HSP) - is also a glucocorticoid stress hormone?? Wouldn't this keep us awake at night?
Also it seems there are studies that TOR2 activation is actually necessary to get the benefits of calorie restriction.
Vegetables have an extremely high protein to carb ratio compared to most foods - 1 to 3; except it tends to be very high in fiber - so maybe the benefits is biome-SCFA based?
Fruit has the best carb to protein ratio (100%) - but fructose is absolutely horrible for the body.
Arachidonic Acid is central to the Cell Membrane Theory of Aging - along with cell membrane fluidity - except it also seems central to inflammation/cancer pathologies - while it has both anti-inflammatory transformations as well.
Otherwise I love your video and hope we can cover the above topics - or I've given you some ideas!
Another excellent video and thanks for getting us a discount from DoNotAge! Much appreciated...
Nice video, do you think we should take our precursors at the peaks or at the troughs of that curve?
Thanks! And as annoying as this may sound, your question is something that has just been under-researched at present but i think would be very important to understand!
@@TheSheekeyScienceShow Very much under-researched indeed! I'm currently doing some desk research on sirtuin activation timing, SIRT1 in particular. There are more factors that come into play when it comes to supplement timing, like activity levels throughout the day. Perhaps we can share some ideas on this some time, for now, I'll make sure to subscribe :)
@@fitiwthw Thank you and sure, sounds good!
Superb 👍
Great video. Thanks🤗 Is there any correlation between appetite and nad+ levels? It seems logical that there should be both drivers and limiters that would mediate the body’s need for nad+.
Is the circadian rhythm linked to the day/night rhythm or is it individual? Or is it more related to light/darkness? For example, is it bad if I sleep from 4 am to 12, but have a good sleep and am not exposed to any light while sleeping?
Are mice nocturnal? If so, would humans who are awake during the day have to do the reverse (take NAD+ in the morning and/or afternoon)?
Wondering the same thing. Only one way to find out until studies come out.
Another great video, many thanks.
I know you are a scientist, so you don't like to guess, but...you know whats coming next...
Would you 'guess' that for a human our highest peak for NAD (if we mimic the mouse and dawn was at 0600 and dusk was at 1800) would be at around mid-day?
As we age our NAD levels drop, it would be nice to know if they drop equally across the whole circadian clock [so if you could research that ASP, that would be great ;-) ] let's say they do, I guess it would be better to mirror the clock and boost it where it would normally be high, I think it is high there for a reason (our body does the most important NAD heavy processes there?), so we should boost it there and not where it is low for a reason?
Thank you! Yes, you are right, I do not like to guess, but in theory the oscillation in NAD+ would be the same as mice, but 12 hours out (nocturnal vs. diurnal). In terms of how NAD+ levels would be affected by age throughout the day is also complicated by the fact that the circadian rhythm weakens as you age as well (I think I discuss this is another video), so you would see less overall and less variation throughout the day. In this case, yes it would seem mimicking the clock NAD+ fluctuations would be most effective BUT, the difficulty with this is getting the timing right since it would depend on how fast the NAD supplements are metabolised in the body, timings for which I don't know. Basically, I think it is important to think about and hope that more research looks into it. Hope that helps :)
@@TheSheekeyScienceShow Thanks very much for the reply and venturing an opinion.
You are right there is a lot we still don't know about NAD levels in humans and varying levels throughout the day and a lifetime.
I was going to split my dose of NMN and take it at 0600 and 1300, I think I may try 1300 and 2000 and see what happens, the other key issue you rightly mention is how long it takes to metabolise.
Any way thanks for you your answers and thanks for the content, great channel.
On this video, 00:00 represents dawn and not midnight.
Thx for doing up the vid.
This was great - thanks!
Is the fluctuation bimodal in humans as well as mice or just mice because they are nocturnal?
If NAD is low in the morning, then should not we eat in the evening and fast in the morning ? (I saw glucose decrease NAD level)
My question to you is, what should be my take away from this in terms of both dosage timing and frequency of NMN/NR, to keep in sync with Circadian related NAD fluctuation?
Thanks for the comment and aha, that is a question i get asked a lot! There isn't enough evidence for me to feel comfortable suggesting a right "time" due to variations in eating/sleeping patterns, physical activity and pharmacokinetics of the supplement. The main take home of the video was to raise awareness that "when" is important to consider and to try and raise a conversation. The good news is that new research comes out as time goes on; in fact i am prepping a video currently on NAD+ and its impact on driving the circadian rhythm via SIRT1 activity. Although done in mouse, i hope it will go in more detail then this one. Hope that helps!
Back in the early 00's I started taking B vitamins pre cardio workout and noticed some good effects (perky skin, improved mood) and some bad effects (nausea). I separated out the B's and noticed niacinamide was the thing that gave me the good effects. That was before all the NAD+ stuff came to light. Of course, many say NAM is not the thing to do. I typically train fasted first thing in the morning. If there is a threshold phenomenon it seems like you want to bump up the peak. Post work out I take luteolin as it is a mast cell stabilizer (I have mast cell activation symptoms, started a couple of years ago, probably a post-infection thing; I expect more people will have this as a post-covid syndrome), after the workout since some histamine release is needed for exercise adaptations. Luteolin is also a CD38 inhibitor, so perhaps it blunts the troughs?
~
I would really appreciate ES's thoughts (or anyone else's) on the following articles:
Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells
pubmed.ncbi.nlm.nih.gov/28417163/
Quantitative Analysis of NAD Synthesis-Breakdown Fluxes
pubmed.ncbi.nlm.nih.gov/29685734/
Despite thinking 250 mg NAM is okay, just in case I'm wrong, I am going to switch to NR soon and am considering NMN if I can find a reputable and not too expensive source.
~
I also have a question regarding butyrate. Butyrate has been found to extend life in some animal models, but it is considered to be a general HDAC inhibitor - so I'm assuming that includes SIRT1. What's up with that?
After posting this YT recommended an interview with Charles Brenner (the NR guy) wherein he addressed the Liu et al. (2018) paper:
ruclips.net/video/u_KBthslx3Q/видео.html
Sometimes the YT algorithm actually works.
Would still appreciate opinions on the article.
NAM is unpatentable so it will never be promoted by scientists. Dr William Kaufman used upto 4 grams per day on patients with severe arthritis. They all reported feeling and looking younger so it is a great supplement.
So, why the most effective time to take NDA+ supplement is during 12PM?
I think perhaps the NAD+ synthesis at night is driven by sirtuin activity, whereas the peak during the day is a result of NADH being being released through activity. What's your thought?
Firstly, i agree that the bimodal pattern is really interesting! Since the two main usages of NAD+ are in redox reactions/metabolism or by NAD+-consuming enzymes, i think there is some truth in your comment; less activity at night would suggest that the peak is more important for the NAD+-consuming enzymes. However, sirtuins use up NAD+, not produce it, and so one could argue that an increase in NAD+ levels at night is due to the fact that there is less activity in the body and therefore less usage of NAD+. Moreover, in this video i only really focused on NAD+ production from NAM-->NMN-->NAD+, yet there are other pathways of NAD+ synthesis (ruclips.net/video/9nJl6EDFShc/видео.html). I honestly think the one way we will get to answer these questions is through computer simulations/machine learning to input all the different levels of regulation and to see the outcome.
@@TheSheekeyScienceShow Perhaps you're right and machine learning will provide us with more answers... Until then I'll do my best to interpret the research with the evidence we've got :p I did find some evidence suggesting an indirect increase in NAD+, triggered by active SIRT1, might be possible through AMPK signaling: www.sciencedirect.com/science/article/pii/S155041311200143X
However, the pathway is hardly explained in this article, or other literature...
@@fitiwthw thanks for the paper! Am currently also prepping a video on this topic as some new research has come out, hopefully will release by tomorrow
@@fitiwthw Thanks very much for this - very useful information indeed!
Why the most effective time to take NDA+ supplement is @12pm?
Nice ....
Not get used to British accent.
Indeed, i am very British