Fasting, circadian biology, and epigenetics

From the best I can gather, one of the more immediate players in circadian biology is the coenzyme nicotinamide adenine dinucleotide (NAD), which participates in a variety of redox reactions.  Fasting increases the intracellular NAD/NADH ratio, setting off a cascade of events involving epigenetics and the regulation of metabolism.  HT to Jack Kruse for really cracking into this nut.

NAD activates sirtuins, a family of deacetylase enzymes.  This is epigenetics.



SIRT1 regulates the activity of BMAL1 and CLOCK, two circadian transcription factors, which target NAMPT, an enzyme that synthesizes NAD.  And in a curious feed-forward mechanism, CLOCK and BMAL1 enhance SIRT1 expression… genetic deletion of any of these players induces insulin resistance (Zhou et al., 2014), and this can be recapitulated with constant darkness: reduced BMAL1 and SIRT1, hepatic insulin resistance; the latter can be reversed with resveratrol (which may or may not be acting through SIRT1; this is controversial).  While alcohol does no great favors for circadian biology, if you’re going to imbibe, perhaps a resveratrol-rich Argentinian malbec served, and this might be the important part, at night, when all of this stuff is going on… coincidentally [fortunately], that’s precisely when most choose to imbibe.

The downside of drinking alcohol [at night] is that ethanol metabolism consumes NAD, potentially throwing a wrench into the gears of this particular aspect.  Perhaps supplementing the NAD precursor, nicotinamide riboside, would be helpful?  “It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting” (Chi et al., 2013)…





fasting -> NAD -> SIRT1 -> BMAL1/CLOCK -> NAMPT -> NAD


Viewed this way, fasting could potentially be seen as a circadian reset biohack.  And in a sense, we already do this [when we’re supposed to]: while sleeping [at night].  SIRT1 also activates PGC1a in liver (Rehan et al., 2014), which enhances fatty acid oxidation, at a time when we need it: while sleeping, which [fortunately] occurs at night.

All of these coincidences… you might begin to think we’ve been formulated throughout all of evolution with daily light-dark cycles that fundamentally dictated how we now operate.

Some people supplement with the amino acid tryptophan at night to help them sleep.  Tryptophan is a precursor of melatonin, a sleep-inducing, energy-conserving hormone.  Tryptophan is also a precursor of NAD, and people take it at night, when the redox potential is expected to be biased toward NAD, because we’re fasting, because we’re sleeping…



This is epigenetics.

Part 2. Animals with disrupted circadian genes in just about any tissue or cell-type exhibit deranged metabolisms in one way or another (eg, muscle: Dyar et al., 2013; liver: Zhou et al., 2014; macrophages: Xu et al., 2014)… and given the circadian nature of the redox potential, and the observation that insulin sensitivity also shows a bona fide diurnal variation (eg, Shi et al., 2013, blogged about here), it’s really no surprise that restricted feeding windows can completely reverse diet-induced obesity and insulin resistance in animal models, and in some cases this is independent from other factors like food intake and physical activity (eg, Hatori et al., 2011Sherman et al., 2012; Shamsi et al., 2014).

Mind your rhythms.

calories proper

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  • libfree

    I sleep better with a night cap, I base that on next day wakefulness. It peaks at a martini to a martini and a half. I could do a spoonful of honey and get the same effect, I just prefer the vodka. I’m guessing that their might be some carbohydrate need while sleeping. I know a lot of people are claiming that honey before bed helps them sleep. Seth Roberts made the connection that we might eat deserts after dinner for that reason.

    • Jack Kruse

      A wrong connection…………

    • John Lushefski

      I get more REM or at least more vivid dreams with carbohydrate restriction. I remember one week I ate 3lbs/day of full fat Fage (before they lowered the fat content) and had some incredible sleeps. I’ve never been able to replicate this. I think some lactobacillus species promote GABA. Magnesium works okay too.

    • William Lagakos

      I’m not sure about the “need” for carbs at bedtime, but here’s some speculation about how it might work:

      • libfree

        cool, thanks for the link, that’s some more ideas worth looking into. I’ve been tracking my sleep regularly for about 5 years and have been experimenting hard for at least 10. I had undiagnosed sleep apnea for a very long time I guess. I couldn’t afford treatment even after I figured out what was wrong with me so I just tried as many things as I could. I did finally get treatment with CPAP which had a strong effect.

        1. Paleo caused weight loss was the strongest effect. I was able to give up the CPAP
        2. After starting a daily probiotic of Plantarum v299 along with a heavy fat meal, my sinuses, lungs and allergies cleared up. I don’t know why this happened but my nose went from constant congestion to clear in a few days and always coughing up phlem went away. Second strongest effect.
        3. honey or a liquor drink before bed. third strongest effect. 30% less likely to be yawing by 4PM without caffeine.
        4. Lower temperature while sleeping. 10 to 13 percent less likely to yawning at 4PM, without caffeine.
        5. Brown noise while sleeping, 12 percent less likely to be yawning by 4PM. This is highly dependent on how loud my roommates are. I found it to be more effective than trying to sound proof my room
        6. Eliminating light and reducing blue light after sunset. I couldn’t find any effect to it.

        I haven’t always been rigorous with my methods so I could be seeing overlapping effects or caused by something I didn’t know I was changing.

        • William Lagakos

          The n=1 or placebo effect can’t really be evaded during self-experimentation, but it seems like you’ve done some pretty impressive tracking. Kudos.

          “Time til yawning”

  • valerie

    Hi Bill,

    I am confused by the Sherman et al. 2012 you link to at the end of your post. If I understand correctly, they fed the mice during the time when they are supposed to sleep, and that made them healthier. Huh? I thought it was supposed to be the opposite.

    Did I get this right? If so, as far as you know, it this the usual outcome? Or is it species specific? Or diet specific?

    Also, could you explain where the epigenetics happen? I thought epigenetics were alterations of gene acticity without changing the DNA bases. I don’t see anything close to that in your description. Could you elaborate a bit for those of us without much biochemistry background?



    • William Lagakos

      Hi Valerie,

      Epigenetics: for example, CLOCK and SIRT1 impact gene expression via the addition and removal of acetyl groups.

      In the Sherman study, the feeding window was out of sync but very short – 4 hours – so reduced food intake contributed to the outcome.
      Check out the Hatori paper, it’s a better example of this phenomenon.
      And one last note, from my experience, animal studies like these can be very fickle; so while these few examples seem to make sense, I wouldn’t be surprised if subtle inconsistencies arise due to subtle variations in study design (eg, Sherman study: interaction between out of sync feeding and reduced feeding window?)…

      • Jack Kruse

        Remember aging is also associated with poor redox: 9% drop per decade leading to DNA repair. Why is this big? DNA repair machinery (PARPs) also draws down on NAD+ and it is therefore in short supply with aging. So older folks may benefit from ketosis of from the use of Nicotinamide Mononucleotide (NMN) NMN also increases NAD+. NAD+ is a cofactor for both Sirtuins(and all the various PARP’s). There are 7 Sirtuins and over 30 different PARPs. NAD+ is an “on switch” for part of the mitochondrial encoded genes required for Complex II and Complex IV in the mitochondrial electron transfer chain. If you can not make them you can not tunnel electrons from your food and this destroys energy and circadian signaling.

        • William Lagakos

          NAD+ and sirtuins in aging and disease.
          Nicotinamide adenine dinucleotide (NAD+) is a classical coenzyme mediating many redox reactions. NAD+ also plays an important role in the regulation of NAD+-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD+biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD+ levels decline during the aging process and may be an Achilles’ heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD+ by supplementing NAD+ intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD+ intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.

    • Matus Sotak

      Hatori paper seems to be better designed and more consistent. Also it studied more factors.
      Anyway it is interesting that reverse-feeding high fat diet had better outcome that ad libitum high-fat diet. Maybe at least “some” diet intake regularity is better than none.

  • JAA

    “The downside of drinking alcohol [at night] is that ethanol
    metabolism consumes NAD, potentially throwing a wrench into the gears of this particular aspect. Perhaps supplementing the NAD precursor, nicotinamide riboside, would be helpful? ”

    Alcohol dehydrogenase converts NAD+ to NADH, but NADH is quickly converted back to NAD+ by reducing oxygen.

    Also, the number of moles of ethanol in a glass of wine is far beyond the number of moles of NAD or precursor you would take in a supplement.


    • William Lagakos

      …with that logic, a gram or two of nicotinamide riboside daily should have zero biological impact. This compound hasn’t been very extensively clinically studied (to my knowledge), but I don’t think that’s the case.

      this is biology not mathematics!

      • Jack Kruse

        Modern blue light is a form of non native EMF, in case you were wondering. We are only designed to see blue light in sunlight, and its power varies with the seasons we are in. I told people in Brain gut 11 that humans have 48 % of their neural circuits dedicated to light. Now you might begin to realize why. These circuits link the brain to the mitochondrial proteins by way of the leptin receptor. The leptin receptor accounts for the electrons and the mitochondrial harvest of light released to the cytochrome proteins. The water micelles surrounding the mitochondria accept the photon light and distribute that power to proteins all over the body because every protein is covered by a water hydration shell. Fundamentally, water is a chameleon. It is globally elastic and locally fragile because it can act in many different forms. Water can organize itself differently when it is adjacent to different materials, allowing it to be the perfect chemical for interactions with the electromagnetic force. Sun light is part of the electromagnetic spectrum.

        Carbs are a direct product of the power of the sun’s light and, therefore, are the most SEASONAL OF FOODS. Carbs have a lot more blue light photons in them which is why they enter cytochrome one and not cytochrome two. We need more proteins to harvest them of their photonic power. This is why high powered UVB light makes Vitamin D. More cytochromes are used to move the electron down to the ground state while taking the photon’s energy into water of the hydration shell/micelle around the mitochondria. Remember that water absorbs best at 270 nm according to Pollack’s work on water chemistry. It is also why all fruit has a naturally high water content, too. This is why we make 147 ATP from beta oxidation of fats and only 36 ATP from carbohydrate metabolism. This difference is not just a calculation of ATP stoichiometry, it is a function of the electromagnetic photons during the seasons present on Earth as they change. Therefore, the electromagnetic spectrum of the sun carries information and energies of these seasonal factors directly to mitochondria.When you have too much blue light and/or too little water within the system, it can short out. You know, this might be interesting for biology researchers when they eventually realize the benefit of a high fat and low carb diet on a fundamental quantum basis. A high fat diet is protective to shorting out the system that is blue light toxic. When you are blue light toxic, your vitamin D falls in a big way, and you will find supplementing with D3 won’t allow it to rise. The brain will protect itself for as long as it can. Carbohydrates speed up our circadian clocks, shortening our telomeres and depleting stem cells. The electrons of carbs have more blue light in their photons because they grow in more powered seasons by the sun’s light. So how would you slow down a fast clock??? You would use something that lowers the charge on the input to mitochondria. Charge is called the delta psi on the inner mitochondrial membrane. Fats lower the delta psi best of all foods because they have lower powered photons in their electrons. They just provide more electrons. This is why they enter at cytochrome 2 and not cytochrome 1. This is why a ketogenic diet helps any short circuited mitochondrion. Pretty simple concept, no? Ketosis recycles NAD+ so that you can properly sense the seasons .