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NAD+ Levels and Circadian Rhythms (and Possible Implications for Supplement Timing)

nicotinamide riboside nicotinamide mononucleotide nad+ circadian rhythms

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#1 Michael

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Posted 24 November 2017 - 08:20 PM




 

How closely are NAD+ and circadian rhythm connected? Is there any evidence supporting taking NR only in the morning, or explicitly not taking it at night?


Normally we have a peak in NAD+ around noon, and second smaller one as we sleep.

Dr Brenner seems to think it isn't so important to supplement to match the nighttime peak and recommends to just take NR in the morning.

With a 8 hour delay to peak NAD+, that wouldn't quite match a noon peak (unless you get up early and take it at 4 am), but seems a reasonable compromise.

Of course you can always take a second dose in the evening, but I don't think there is any evidence whether or not that provides a benefit vs one dose a day.

None of this is actually clear. There have been quite a number of quite elegant studies showing connections between the NAD+ synthesis machinery and central regulators of circdian rhythms, but surprisingly, they have come to quite different findings as to how this impacts (or is driven by) circadian rhythms of NAD+ levels. I note with some head-scratching that in a 2013 paper, Joseph Bass' group found what appeared to be an anticipatory peak in NAD+ levels late in the light/rest phase (rodent "night:" rodents, like George Thorogood, party all night and sleep all day), with much lower levels throughout the dark/active period (rodent "day") (Fig. 1A). But in a previous 2009 report,(2) the same group showed peaks in the middles of both light/rest and dark/active periods, with the largest of all in the middle of the second dark/active period (Fig. 1D).

 

One difference between the two studies noted by the authors in personal correspondence is that in (2) the animals were fed ad libitum, whereas in the later study(1) the mice were fasted for 18 hours prior to each time point. The results in (2) might be driven by an endogenous clock-driven NAMPT rhythm,whereas (1) could reflect a peak driven by feeding/fasting driven changes in NAD+ synthesis or consumption. As they note, it would certainly be counterintuitive if a clock-driven NAD+ rhythm would oppose the food-driven one — especially, I would note, since a prolonged fast and feed is one of the fastest way to shift circadian rhythms (after changes in time zone, for instance). I personally wonder if the fact that it's an 18 hour fast doesn't mess up the clock by 6 hours, though of course neither man nor mouse would normally eat all of its food within a narrow 2 hour window every day (not that some don't as part of an intervention).

 

I also urge caution in this idea of an "8 hour delay" in peak NAD+: as discussed before, there's certainly a lot going on under the hood.

 

References

1: Peek CB, Affinati AH, Ramsey KM, Kuo HY, Yu W, Sena LA, Ilkayeva O, Marcheva B, Kobayashi Y, Omura C, Levine DC, Bacsik DJ, Gius D, Newgard CB, Goetzman E, Chandel NS, Denu JM, Mrksich M, Bass J. Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science. 2013 Nov 1;342(6158):1243417. doi: 10.1126/science.1243417. Epub 2013 Sep 19. PubMed PMID: 24051248; PubMed Central PMCID: PMC3963134.

 

2: Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009 May 1;324(5927):651-4. doi: 10.1126/science.1171641. Epub 2009 Mar 19. PubMed PMID: 19299583; PubMed Central PMCID: PMC2738420.

 

 


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#2 LawrenceW

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Posted 25 February 2018 - 12:05 AM

Has anyone seen any studies or research as to the baseline (without any supplementation) levels of NAD+ during a 24 cycle?  Does it fluctuate with peaks and valleys or does it stay at a constant level during a 24 hour cycle? If it does fluctuate, how many peaks during the 24 hour cycle?


Edited by LawrenceW, 25 February 2018 - 12:06 AM.

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#3 tunt01

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Posted 25 February 2018 - 01:18 AM

Has anyone seen any studies or research as to the baseline (without any supplementation) levels of NAD+ during a 24 cycle?  Does it fluctuate with peaks and valleys or does it stay at a constant level during a 24 hour cycle? If it does fluctuate, how many peaks during the 24 hour cycle?

 

It fluctuates.  The best studies on this AFAIK are from Imai, Sassone-Corsi, and Schroeder.

 

SIRT1 deacetylates CLOCK in an NAD+ dependent manner, which oscillates in a circadian rhythm.  NAD+ levels are highest during midday/late afternoon.

 

nihms-158172-f0001.jpg

Source:  Imai 2010

 

nihms-158172-f0003.jpg

Source:  Imai 2010

 

 

 

 

And given that SIRT1 opposes p53 and other important metabolic/cancer checkpoints, the idea of continuous dosing of NAD+ precursors at a high level, seems really dangerous to me. 

 

 

Imai S. “Clocks” in the NAD World: NAD as a Metabolic Oscillator for the Regulation of Metabolism and Aging. Biochimica et biophysica acta. 2010;1804(8):1584-1590. doi:10.1016/j.bbapap.2009.10.024.

 

Sassone-Corsi P. Minireview: NAD+, a Circadian Metabolite with an Epigenetic Twist. Endocrinology. 2012;153(1):1-5. doi:10.1210/en.2011-1535.

 

Schroeder AM, Colwell CS. How to fix a broken clock. Trends in pharmacological sciences. 2013;34(11):10.1016/j.tips.2013.09.002. doi:10.1016/j.tips.2013.09.002.


Edited by prophets, 25 February 2018 - 01:23 AM.

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#4 LawrenceW

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Posted 25 February 2018 - 01:38 AM

I am not a scientist, so please excuse me if the following is asked incorrectly.

 

Is using NR to max out NAD+ levels 24 hours per day contrary to the daily fluctuations that biology seems to prefer? Does NMN dosing peak NAD+ for short periods after administration and therefore appear to mimic the fluctuations that biology prefers?  My understanding is that the peak levels of NAD+ in our older years is roughly half what they were in our youth, therefore would it be advantageous to time the NMN dosing with the peak levels of NAD+ to get NAD+ to peak levels that we last experienced in our youth? 

 

 


Edited by LawrenceW, 25 February 2018 - 01:41 AM.

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#5 tunt01

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Posted 25 February 2018 - 02:03 AM

I am not a scientist, so please excuse me if the following is asked incorrectly.

 

Is using NR to max out NAD+ levels 24 hours per day contrary to the daily fluctuations that biology seems to prefer? Does NMN dosing peak NAD+ for short periods after administration and therefore appear to mimic the fluctuations that biology prefers?  My understanding is that the peak levels of NAD+ in our older years is roughly half what they were in our youth, therefore would it be advantageous to time the NMN dosing with the peak levels of NAD+ to get NAD+ to peak levels that we last experienced in our youth? 

 

I'm not a scientist either but I spent a fair bit of time thinking about this matter and my personal viewpoint to your questions is as follows:

 

1.  It's basically insane to 'max out NAD+ levels 24 hrs a day'.

 

2.  I've no idea on the pharmacokinetics of NMN, but when I was looking at NR the viewpoint I came to was that I should fast in the AM (skip breakfast) and take NR around 8-10 AM, in the morning.  Then I would eat lunch around 12-1 PM.  If you look at the guidelines provided by Elysium, they basically suggest taking their product in the AM.

 

3.  NAD+ administration should be pulsatile, IMO.  I think NAD+ supplementation should be viewed as an exercise mimetic and dosage pulsatile in fashion, rather than some constant administration level.


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#6 MikeDC

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Posted 25 February 2018 - 03:16 AM

Brenner mentioned that NAD+ is highest in the morning. So they recommend taking Niagen first thing in the morning to fit into the clock. The Washington study used 2g per day and caused elevated NAD+ levels upto 24 hours. At 250mg dose, it will trend down through the day.

#7 Mind

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Posted 25 February 2018 - 08:25 PM

Anecdotally, NR seems to affect my sleep negatively.


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#8 Harkijn

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Posted 26 February 2018 - 11:08 AM

For more info on the diurnal NAD+cycle in human mother's milk, see also:

http://www.longecity...-types-of-milk/


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