Pharmaceutical-grade circadian enhancement?

Is it possible to improve the amplitude and resiliency of your circadian rhythms?  Is this desirable?  Yes and yes, I think.

Go the fuck to sleep.png


Introducing, the aMUPA mice (Froy et al., 2006).  What you need to know about ’em: they have very robust circadian rhythms.  How is this assessed?  Take some mice acclimated to their normal 12 hour light-dark cycle (LD) and place them in constant darkness (DD).  Then take liver biopsies and measure circadian genes to see how well they still oscillate throughout the dark day; this is also known as the free-running clock, and it craps out differently in different tissues depending on a variety of factors.  Most of the time, however, it’ll run for a few days in the absence of light.  Circadian meal timing also helps to hasten re-entrainment.



Note in the figure below: 1) there are two distinct lines of aMUPA mice; and 2) both exhibit a greater amplitude in circadian oscillations during free-running, or DD conditions.

strong circadian rhythms


Same is true for body temperature.  Similar to humans, mice run slightly warmer during their active phase.  This is exaggerated in aMUPAs.  And instead of grazing, their food intake seems to be divided into two discrete “meals:” a big breakfast at the start of the active phase, and a small dinner about 12 hours later.  They have stronger circadian rhythms, and this is how they eat (make a mental note of this)… cause/effect?


body temperature and meal timing



Curve ball: circadian mismatch… what happens when you switch mice from LD to LDLDLD?  That is, shortening their normal 12-hour light-dark cycle down to 8-hours.  For normal mice: no bueno.  Food intake creeps up, and body weight along with it.  Not so much for aMUPA; stronger baseline circadian rhythms = better able to cope with mismatch.


circadian mismatch weight gain


Remember the food-entrainable oscillator?  It’s one way to kickstart your circadian rhythms.  It’s not known if the genetic alteration in aMUPA causes a change in meal timing which improves circadian rhythmicity, or the strong circadian rhythm chooses a big breakfast, but I’m all about hedging bets… do like the animals with strong circadian rhythms do: breakfast, in the morning; discrete meals, no grazing.

… and at least one other researcher thinks capitalizing on the food-entrainable oscillator to kickstart circadian rhythms might be a good way to stave off disease later in life (Kent 2014).  There are two entrainable oscillators (food and light); we should use both accordingly.


circadian entrainment and longevity



Part II: how to “strengthen” (or fix) circadian rhythms?

Disclaimer: I think circadian biohacks, in general, are better at repairing mismatches than making you superhuman.

In no particular order:

1) Be young 🙂  one study examined the effects of chronic jet lag, advancing or delaying the photoperiod by 6 hours every week, in young and old mice (Davidson et al., 2006).  Young mice did fine.  Old mice died.


phase shifts and mortality


Sirt1 agonists may help with this (Chang and Guarente, 2013)… until they figure out the proper ligand of Sirt1, red wine will have to suffice *sigh* :s

2. “Voluntary” exercise: works in mice and men, but as mentioned previously, if circadian mismatched to begin with, might want to try out some of the other methods because exercise can be painful, or at least less efficient, in this condition.

Exercise timing is negotiable, but I think it’s a good idea to time it around your biggest meals… naïve exercisers are stronger in the afternoon, but this is a highly adaptable system: a few AM training sessions abolishes this difference (eg, Sedliak et al., 2009).

3. Meal timing: eat more when the circadian regulation of insulin sensitivity in skeletal muscle and adipose tissue favors nutrient partitioning – in the morning. This is how aMUPA mice behave, and they fare quite well… they even live longer!!  Food-entrainable oscillator.

4. Mineral balance?  there might be a blood pressure hack out there, involving angiotensin or vasopressin, but I haven’t figured it out [yet]… pickles don’t shift my phase one iota.

5. Light: the other major entrainer.

5a. Avoid tech gadgets, blue light, etc. after sunset.  Duh.  Or at least rock a pair of hot blue blockers.  Anecdotally, blue blockers may be used to phase change, intentionally… eg, put them on earlier if you want to go to bed & wake-up earlier.

5b. Sunlight in the morning.  Lots of it.  Or at least a bright light device.

Piece of advice: don’t go too far from the natural, seasonal photoperiod as I suspect this may share some characteristics with chronic jet lag / circadian arrhythmia:  Impaired neurogenesis and cognitive deficitsCancerNutrient anti-partitioning.


Go the fuck to sleep.png


calories proper


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  • “Know what I noticed while doing just a quick scan, Bill Lagakos? These mice ate two meals, a large breakfast and a light dinner, and fasted between for 12 hours between breakfast and lunch… sounds exactly like what the 10 subjects who reversed Alzheimer’s and memory loss did in the recently reported study.” -Facebook comment 🙂

    • Justin

      You’re really killing me on this “breakfast as a circadian modulator,” Bill. Can’t I just IF in peace -__- .

      In all seriousness, two of my gymnastics practices are evening. So if I get home after sunset and plop on my sexy goggles and pass out, will recovery be ample from the next days breakfast so long as 24-hr intake is ok and calories are ample (and proper =P )?

      • Hahaha! 🙂

        I’d say it’s definitely OK to eat at night if that’s when your exercise session is. Also, if “24-hr intake” is on par, then you’re probably good to go as well, but I don’t think it’s a good idea to do fasted exercise and then not eat after… always eat either before or after exercise…

        • Dan Ordoins

          Lately I have been adding some movement activity/ exercise (short in duration) before my last meal of the night. Then my meal is smaller in portion around 3+ hours before bed. My meal is then rich in protein and fats (seafood based). I seem to sleep well with this and wake up lean and with lots of energy (I sleep in a colder dark room). I then fast until around noonish or later and do movement or a lifting workout before breaking the fast. And the meal when I break my fast is a larger one, protein rich…. I may have another small meal before my last or some times just the two meals. So fasting daily 16/8 – 20/4 depending on daily activities.

          So far that has seem to be having a great effect on energy levels and body composition….
          I also don’t do any carb refeeds and keep my diet epi-paleo ketosis based. Seafood daily.
          Just my n=1

        • Dan Ordoins

          Loving your blog and insights…

      • I’ve noticed for several months timing of eating powerfully influences the circadian rhythm.

        -Making a forced attempt to not snack/graze will organize my circadian rhythms. It doesn’t matter much if I eat 3 meals or 1, the act of consolidating eating to distinct periods will powerfully organize rhythm. Ghrelin is elevated fasting and eating suppresses it normally, which is a circadian zeigeiber just like light or dark (melatonin rhythms, serotonin , dopamine shifts…)

        -My experience with IF is that it acts just like melatonin. Meaning to say when you time your meal can phase advance or phase delay via ghrelin suppression. If you IF and eat late in day (big night meal) this makes phase delay. If you IF and eat relatively earlier, this make a phase advance.
        I suspect the natural human rhythm is to eat upon waking therefore whenever you time your meal = circadian zeitgeiber of waking/daytime. Eating at night, like light at night, promotes phase delay and this can be normalizing or depressant depending on baseline condition.

        -Organized meals with fasting periods is by FAR superior to grazing/lack of organized meals. The nature of your food pattern organization is much less important than simply organizing it somehow. So, IF with a nightly meal is superior to snacking ‘whenever” with random eating patterns, but eating eariler in day and less at night is superior to that. Note: I do not practice what I preach LOL, my biggest food intake pattern is late in day to help my body wind down for sleep.

        -I suspect the powerfully circadian modulating effect of meal timing and ghrellin oscillations is a reason obesity is often coupled with phase delay/atypical depression, and perhaps why manic/bipolar disorder may be triggered by diabetes. Other than HPA axis effects, the chronically elevated blood sugar and Ghrelin kaplowy is a circadian disruptor just like season change and light, which are notorious affective/bipolar triggers.

        I lean toward obesity being a cause of circadian disorganization, as well as a symptom. Chronic hyperinsulinemia destroys the ghrelin pacemaker of meal timing, chronically elevated blood sugar does as well.

        • Oh:
          -If my circadian rhythms are more organized (chronotherapies) it becomes much easier to organize my eating in turn. There is inputs both ways – a disorganized rhythm makes eating very random , and random eating further harms the circadian pacemaker.

          • this, too 🙂

            Capitalizing on the food-entrainable oscillator can help organize circadian rhythms; and bolstering circadian rhythms can help organize meal timing (possibly the case in aMUPA mice).

        • “the act of consolidating eating to distinct periods will powerfully organize rhythm”


          “I lean toward obesity being a cause of circadian disorganization, as well as a symptom.”

          THIS. All those timed feeding studies in rodents confirm this, and suggest improper meal timing may even be causal… I think it’s true!

  • Gerard Pinzone

    “Piece of advice: don’t go too far from the natural, seasonal photoperiod…” Hmmm… That’s highly variable depending on where you live. Never mind low carb, how did the Inuit deal with months of “too much” sunshine followed by months of darkness?

    • One guess: they didn’t go from the equator to the poles overnight… they gradually migrated over hundreds of generations, theoretically giving them ample time to adapt to the new circadian environment.

      But nowadays they do take steps to block out light at night during the light half of the year, etc.

      • Jack Kruse

        BOOM. Modern abilities cause massive mitochondrial issues in how we handle food electrons daily.

      • Paleo Osteo


  • Ken

    Another great article. Lovin’ the Circadian nutrient timing studies. Any thoughts on Circadian rhythm protein timing? Interesting stuff. I may start having larger protein doses around bedtime!

    • Thanks, Ken 🙂

      Some studies show that protein in the morning helps to control appetite throughout the day… and as per the studies you cited (thanks, btw), dinner is also a good time for protein.

      The Alves study also showed that protein for dinner (and avoidance of carbs at this time) was good for body comp (discussed in the comments here:

      • Ken

        Awesome, I’ll check your other article out!

  • rs711

    Those aMUPA mice are basically the envy of every WallStreet trader out there.

    What about the sleep pressure building up from the moment you are awake? What IS it? Is it simply an umbrella term for of a few different processes we think are involved in making you want to sleep or is it now quantifiable (by proxy)? [not an area I’m well read in, obviously]

    Fun read.

  • Biological rhythms during residence in polar regions.

    “Only small numbers of subjects have been studied intensively in polar regions; however, these observations suggest that suboptimal light conditions are deleterious to health.”

  • Jack Kruse


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  • Exercise upregulates key circadian rhythm genes: “Time- and exercise-dependent gene regulation in human skeletal muscle”

    BACKGROUND: Skeletal muscle remodeling is a critical component of an organism’s response to environmental changes. Exercise causes structural changes in muscle and can induce phase shifts in circadian rhythms, fluctuations in physiology and behavior with a period of around 24 hours that are maintained by a core clock mechanism. Both exercise-induced remodeling and circadian rhythms rely on the transcriptional regulation of key genes.

    RESULTS: We used DNA microarrays to determine the effects of resistance exercise (RE) on gene regulation in biopsy samples of human quadriceps muscle obtained 6 and 18 hours after an acute bout of isotonic exercise with one leg. We also profiled diurnal gene regulation at the same time points (2000 and 0800 hours) in the non-exercised leg. Comparison of our results with published circadian gene profiles in mice identified 44 putative genes that were regulated in a circadian fashion. We then used quantitative PCR to validate the circadian expression of selected gene orthologs in mouse skeletal muscle.

    CONCLUSIONS: The coordinated regulation of the circadian clock genes Cry1, Per2, and Bmal1 6 hours after RE and diurnal genes 18 hours after RE in the exercised leg suggest that RE may directly modulate circadian rhythms in human skeletal muscle.

  • James

    I generally go to bed at 1 AM and sleep till 10 or 11 AM (college student). However, while I’m sleeping, I sleep in a tent covered with aluminum foil, as well as covering my windows to black them out. Since I sleep in a pitch dark environment, will I still have a negative effect from being far from the natural photoperiod?

    • “Tent” …outdoors?

      In any case, it might not be 100% optimal, but the pitch dark environment is definitely a step in the right direction.

      • James

        No it’s a tent built for a bed (called a “Privacy Pop Bed Tent”)

        I have a pretty serious health condition called “Reactive Arthritis” which is quite possibly linked or caused by gut dysbiosis – is it super important that I’m on a natural circadian rhythm?

        • I’d say being on a “natural circadian rhythm” is important, but context matters… Shift workers usually experience some [negative] consequences down the line in the long run.
          And as mentioned above, the situation you described isn’t 100% optimal, but it isn’t going to kill you overnight.

    • Kasha

      Not necessarily, there are plenty of people who live on a schedule like yours. But when you wake up you need to immediately expose yourself to light. There are 2 ways to do that: immediately go outside for 15-30 minutes after getting up or use light therapy.

      • Good tip, Kasha. Might also be prudent to block out blue light if using tech (eg, computer, TV, smart phone, etc.) after sunset. Eg,

        • Kasha

          Agreed. I use f.lux, bug lights and Eagle Eyes at night to block blue light. Most people don’t have to be that hypervigilant though. I have a free-running circadian disorder. I would suggest adding one at a time and deciding what works best for you.