Circadian Rhythmicity - Intermittent Fasting (Re-)Sets the Peripheral Clock: Macros, Body & Liver Fat, AMPK & More

Fridge raiding in the middle of the night is just a side issue in today's installment of the Circadian Rhtythmicity Series that revolves around Intermittent Fasting with different macronutrient ratios and its effects on body weight, body fat, liver fat and the expression of circadian clock genes.

Everyone who's also following my posts on facebook will probably be aware that (a) I don't miss a single opportunity to kiddingly refer to scientists and journalists reading this series, whenever I point you towards a new paper or news item about circadian rhythmicity. He (or she) will yet also be aware that (b) one of the studies, I actually postponed to this installment of the series, made the rounds as of late, as the ScienceDaily piece on it - which was basically a "copy & paste job" of the EurekaAlert! press release - gave the impression that a "time-restricted" (others would call it "intermittent fasting") high fat diet would be superior to the carbohydrate-laden standard rodent chow, as far as the body compositional outcomes are concerned. I wrote and talked about this on facebook, as well as the SuppVersity Science News Roundup on Super Human Radio, last Thursday. Anyways,... today, I am going to deliver on my promise from two weeks ago and will eventually  discuss the results of the Sherman study (Sherman. 2012) and the influence of nutrient timing and composition on the  mammalian circadian rhythm in detail.

To fast or not to fast, this is not a question, anymore

As I have already pointed out in the "Break-Fast Installment" of this series, it is, at least from a circadian perspective, actually not a question of whether or not you should "fast", but more or less only one of how long this fast should last. An exact answer to this question has not yet been found, though, and I would even bet money that it never will, simply because it depends on too many confounding and highly individual (epi-)genetic and lifestyle factors. And still, based on what we know now, one thing can be said for sure: If you are standing up in the middle of the night either voluntarily or because whatever pathology may be driving you and have a protein shake or ransack the fridge, you have a problem. A psychological one in the first case, a physiological and probably clock-gene related one in the latter case.

*Always keep in mind: Mice are nocturnal animals, they start to party with pubertal humans (though this is meant as a joke, I suggest you take a look at my additions to figure 5, before you totally discard it as insignificant), when the lights go out. It is therefore only natural to restricting their food-intake to the so-called dark-phase - just as natural as not ransacking the fridge in the middle of the night would be for a normal human being!

That said, I don't think that the ad libitum (=whenever they wanted) fed mice in the Sherman study did have a fridge.  What's certain though is that the simple restriction of their food-access to a 4h time window that opened with the light being switched off* did have profound effects on the body composition of the mice in both, the low fat as well as the high fat groups. It did not, however, totally blunt the negative effects the above all energetically dense "high fat diet" had on the gynoid fat pads and the hepatic lipid content and thus sooner or later the liver function of the four-week-old male C57BL/6 mice (Sherman. 2012):

"[...] although body weight and epididymal fat mass were 20 and 48% lower, respectively, in the RF-HF group than in the AL-HF group, liver lipid content was not significantly different between these groups."

In view of the role a "fatty" and thus malfunctioning liver plays in the etiology of the metabolic syndrome, it can therefore not be said that the high fat diet, respectively the incarnation of the latter that was used in the study at hand, is either healthy or anti-obesogenic. After all, the increase in visceral and liver fat, of which only the former was slightly blunted in the study at hand, usually precede the development of the other classic features of a conglomerate of metabolic ailments, we usually refer to as "metabolic syndrome".

Less body weight, more liver fat - a pretty poor trade, I would say

Against that background, it is of questionable value that the overall body weight of the "intermittendly fasted" (=restricted feeding, short RF) rodents on the intentionally fattening "high fat diet" (HF) that contained 42% of the energy in the form of soybean oil and palm sterate, was lower than that of their peers on the ad-libitum (AL) high or low fat diets (AL-LF, AL-HF).

Figure 1: Comparison of gynoid (=epididymal) and liver fat (left) and body weight development (right) of male mice on ad-libitum (AL) or (time-)restricted (RF) low (LF) and high fat (HF) diets (based on Sherman. 2012)

Moreover, the significance of these allegedly "beneficial" effects, of which the author of the ScienceDaily article falsely states that they would also entail that the mice "on the scheduled high-fat diet [...] had a lower final body weight than the mice that ate an unscheduled low-fat diet" (Hebrew University. 2012), become even more questionable if we also take into account that ...

• the mice in the AL-LF (ad libitum, low fat) group consumed 6% more energy than their peers in the RF-HF group (restricted feeding, high fat) and
• the overall reduced body weight is unlikely to be solely the resul of lower body fat levels - specifically in the RF-HF group, where the fat is already beginning to clog the liver

And while the macronutrient and fatty acid composition of the diets does not allow for any definitive statements assertions about the value of real low carb diets with ~80% of the energy from fat, the data in figure 2 illustrates a couple of metabolically relevant differences that arose as a result of the different macronutrient composition of the diets (please remember that I plotted only values with significant inter-group differences between low and high fat groups, yet not those difference, which are attributable solely to the intermittent feeding / fasting regimen and have no relation to the macronutrient composition).

Figure 2: Metabolically relevant serum markers with statistically significant differences that can be attributed to the differences in macronutrient composition of the diets; arrows indicate changes that are more or less characteristic for "fasting" as in "not eating" or being in a energy deficit (data expressed rleative to AL-LF group; based on Sherman. 2012)

If you take a closer look at the data in figure 2 you will probably realize that the classic effects of fasting, i.e. a reduction in leptin, a reduction in insulin, a reduction in glucose, a reduction in triglycerides and increases in glucocorticoids (to squeeze the fat out of the cells and catabolize amino acids in order to stabilize the blood sugar via gluconeogenesis) and the "hunger hormone" ghrelin are either mitigated or almost blunted by the "high fat" approach to intermittent fasting (I repeat this once more: the "high fat" diet in this study has more in common with the standard American diet than with a ketogenic diet). This raises the question: Is this a good or a bad thing? Or, put another way: If this does not look like fasting does it have the same effects on the circadian clock as "real" fasting would? The study results suggest that this is the case - albeit with a small, but potentially relevant quantitative difference in the fasting induced phase shifts:

Figure 3: The RF-HF mice were the almost twice as active as the AL-HF mice and 42% more active than the RF-HF animals (of whom Sherman et al. write that they were about as active as the AL-LF mice)

• the casein kinase Iε (CkIε) oszillated robustly only in the low fat groups 
• "high fat" fasting reversed the phase advance of the circadian expression of Per1 and produced a phase advance of the previously phase-delayed expression of the Cry1 and Ror genes
• "low fat" fasting induced a phase advance in all measured clock genes
• compared to the high fat restricted feeding regimen the low fat restricted feeding group exhibited a phase delay with respect to the Bmal1 and Cry 1 genes

While the overall image that emerges here, i.e. the ability of a timed feeding regimen (aka intermittent fasting) to rectify and/or advance the peripheral (here, hepatic) shifts induced by the HF diet, is pretty obvious, our understanding of the interactions of the individual clock genes is still too premature to say something definitive about the implications of the registered changes.

"So what's that supposed to mean, now? Is fasting good? Is fat bad? ... or what?"

No effect of macros? In as much as these observations support that restricted feeding aka intermittent fasting alone can reverse the majority of negative effects on the peripheral expression of clock genes, it says nothing about their central expression (all values here were measured in the liver!) and the effects on body composition. The increase in pAMPK, for example speaks in favor of the low fat diet. The same is true for the potential longevity effects. Plus, it is essentially pointless to speculate about the best macronutrient ratios, as long as a clone of the fattening standard American diet, of which I do simply assume no one of you will truly believe that it would deliver better results than a low fat diet in a rodent model, is all we can compare the low fat approach to intermittent fasting to (read more on the practical side of things in the next installment).

If we use the results of Um et al., who found in 2007, already, that the expression of the aforementioned casein kinase Iε (CKIε) gene and its negative feedback mechanism on another clock gene, namely mPER2, are triggered by the AMPK promoting effects of the "wonder-drug" metformin (Um. 2007), the following observations Sherman made with respect to the expression of AMPK and other proteins that are involved in the fatty acid and glucose metabolism begin to make some sense:

• The RF-LF diet led to increased levels of pAMPK and pACC, indicating intracellular low energy levels, inhibition of fatty acid synthesis and increased fatty acid oxidation. 
• The AL-HF diet down-regulated AMPK, ACC and SIRT1 daily protein levels by 50% compared with AL-LF mice.
• The timed HF diet led to 37% lower levels of pAMPK than those in the RF-LF group and 62% increased pACC levels compared with the AL-LF group, indicating adequate energy levels but reduced fatty acid synthesis .
• The RF-HF diet also increased daily levels of PPARα mRNA.

The overall effect on the expression of AMPK, Sirt1 and ACC, i.e. the reversal of most of the negative effects of the high fat diet in response to the intermittent feeding regimen, is thus very similar to what we have seen in the case of the the clock genes (see previous list). Reason enough for Sherman et al. to conclude that "[t]hese results demonstrate again the dominance of the timed feeding over the HF diet." (Sherman. 2012) - or, as a take home message for you:

At least with respect to the circadian rhythm, it appears that...
when you eat is of greater importance, than what you eat!

Central vs. peripheral, master vs. slave, light vs. food - every orchestrate needs a director

Now that we have gained insight into the priority of when you eat over what you eat as far as their ability to correct, readjust and resynchronize the peripheral circadian clock are concerned, we are facing another, a follow up question that reads "Is when you eat also more important than what the light cues are telling your suprachiasmatic nucleus?" [(re-)read Part I & Part II of this series to learn all about the importance of light exposure]
 

Figure 5: Regardless of the model you prefer, the central clock and with it its exclusive direct regulator will always be the most important factor in the circadian master/slave or orchestrate system (based on Richard. 2012. Fig. 3)

In one of the most recent reviews of the currently available literature on circadian rhythmicity, Richard & Gymz write about the relation of central (=brain) and peripheral (=organs) aspects:

On a basic level, the circadian clock can be divided into 2 parts: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system tested. Light enters through the retina of the eye, causing electrical signals to pass through the retinal hypothalamic tract, which are converted to chemical signals in the SCN. Light signals and other physiological factors, such as feeding cues, entrain the central circadian clock. There has been much debate among chronobiologists about the relationship between the central clock and the peripheral clock with 2 major theories emerging.

These two theories scientists have come up with do explain the complex interrelation between the mostly light-driven central and the various peripheral clocks based on either a ...

• "master-slave" model which gives complete synchronization power to the central clock and thus assumes that all peripheral clocks are centrally synchronized in the brain, or an
• "orchestra" model according to which the multiple peripheral clocks are like the members of an orchestra, with each of them playing its own "instrument"

If you don't want the metabolic concert of your body to end up as a cacophonous cat's concert as in "David Teniers the Younger Cat concert" (see image), you better make sure that all the member's of it's orchestrate are in time with the director, the central and light dependent circadian clock in the suprachiasmatic nucleus of your hypothalamus.

The "orchestra" model has the beauty of ascribing greater importance to the previously discussed effects of feeding-times and (macro-)nutrient composition - a position that is backed up by the majority of recent studies, by the way (Richard. 2012).

"Thus, each peripheral clock can adapt to its own external and internal stimuli, such as feeding cues for the liver, kidney, and pancreas, but is "conducted" by the light-dark cues sensed by the central clock." (Richard. 2012, my emphases)

In other words, while your "peripheral clock", e.g. the clock of your fatty acid metabolism in your liver can go wrong, you better make sure that it does not, because in the end, it does not really matter how "independent" each of the members of an orchestra may be. When they start playing, their synchronization by the director, or, analogously, appropriate light cues determines whether the overall outcome of this intricate metabolic concert is a symphony and their concert hall, i.e. you(!) lean & healthy or a cacophonous mess that's making you fat & sick!

Light over Food Timing & Food Timing over Food Types.
On that note: Screens out for today, folks!

References:

• Hebrew University of Jerusalem. "A carefully scheduled high-fat diet resets metabolism and prevents obesity, researchers find." ScienceDaily, 12 Sep. 2012. Web. 16 Sep. 2012.
• Richards J, Gumz ML. Advances in understanding the peripheral circadian clocks. FASEB J. 2012 Sep;26(9):3602-13. Epub 2012 Jun 1.
• Sherman H, Genzer Y, Cohen R, Chapnik N, Madar Z, Froy O. Timed high-fat diet resets circadian metabolism and prevents obesity. FASEB J. 2012 Aug;26(8):3493-502.
• Um, J. H., Yang, S., Yamazaki, S., Kang, H., Viollet, B., Foretz, M., and Chung, J. H. (2007) Activation of 5=-AMP-activated kinase with diabetes drug metformin induces casein kinase Iε
  (CKIε)-dependent degradation of clock protein mPER2. J. Biol. hem. 282, 20794–20798

Circadian Rhythmicity: Retinol (Vitamin A) & Caffeine and Their Effects on the Central & Peripheral Clocks of the Body

Image 1: Is it a bad idea to "wake yourself up" with a pot of coffee in the morning, I mean from a circadian rhythm perspective?

In the last installment of this series we have been dealing with breakfast. Now, if you are following the mainstream advice neither of the two subjects of this installment should actually be a staple of it. Vitamin A, in its active form, retinol, is "bad and dangerous" and only present in such "evil cholesterol laden foods" such as eggs. And since coffee will sure give you a heart attack, you better stick to your calcium fortified orange juice, a minimal amount of white water, ah.. I mean low fat "milk" (learn more about the difference between white water and milk in "Mutant Milk!? New Research Fuels the Flames on Hushed Up Concerns About Ill Health Effects of Homogenized Milk") and - of course - "healthy cereals". And while you will hardly be able to argue that skipping a breakfast like that is probably the best you can do for your health, this was the topic of the last installment, while vitamin A and caffeine, will be what this episode of the Circadian Rhythmicity Series will be all about.

Vitamin A the circadian vitamin?

Only recently (officially, at least; preliminary results have been published ahead of print in March 2012, already; cf. Golini. 2012) a group of researchers from the Multidisciplinary Institute of Biological Research San Luis (IMIBIO-SL), at the National University of San Luis in Argentina found that contrary to the peripheral clock gene expression in the liver, which does not appear to be disturbed by vitamin A deficiency (Shirai. 2006), the superordinate (=master) clock gene expression in the hippocampus of rats housed at a regular 12h-light/dark interval gets profoundly compromised, when the rodents are fed a vitamin A (retinol, not beta carotene!) deficient diet (Navigatore-Fonzo. 2012). According to Navigatore-Fonzo et al. the effects are mediated by modified temporal patterns of the retinoic acid receptor in the hippocampus, which plays an essential role in the activation of a whole set of clock-genes that, in turn, have been implicated - among others in the anti-cancer effects of vitamin A, you've read about at the SuppVersity not too long ago!

In the light of these recent results many previously observed, but not fully understood effects of vitamin A deficiency, such as the permanent memory impairments (Etchamendy. 2003) and its repeatedly suggested involvement as a signaling molecule (and as it now turns out potential zeitgeber) in physiological (synaptic plasticity, learning and memory, sleep), as well as pathological (schizophrenia, depression, Parkinson disease, and Alzheimer disease) neurological conditions (cf. Tafti. 2007).

The fact retinol availability is so tightly regulated alone tells us something about its importance

Is there a fluctuation in serum retinol levels as well or is vitamin A only a prerequesite for the circadian rhythm to function normally? With the activity level of vitamin A depending on both the availability as well as the release and binding of retinoic acid from the stores (mostly) in the liver and to the respective binding proteins, which are also produced in the liver, it is obvious that the liver is the most important regulator of vitamin A metabolism (Buzio. 1989). Maybe this is also why it is protected against circadian disturbances subsequent to vitamin A deficiency.

Unfortunately, our understanding of the exact function of the retinol binding proteins is still very limited, what we do know, however, is that their release and renal clearance show a distinct circadian rhythm which is synchronized to meal ingestion and the excretion of (Buzio. 1989). Our understanding of these mechanisms is yet still too preliminary to make any supplement recommendations besides "don't avoid the full-fat vitamin A rich foods, we have been eating for ages!". This is all the more true, since the range, within which beneficial effects can be seen is not just very narrow, but will also depend on (a) your baseline vitamin A status and (b) the way your body metabolizes dietary and supplemental vitamin A, the latter of which usually comes in the form of retinyl palmitate.

At doses in the <10,000IU/day range vitamin A is regarded as totally benign, but even doubling that dosage, which was basically what Behr et al. did for their recently published paper on the potential anti-oxidant effects of vitamin A on menopausal increases in oxidative brain damage, when they  supplemented the diets of ovariectomized rats with 1,500IU /kg retinol palmitate (human equivalent ~20,000IU) per day, can result in profound increases in cerebral oxidative damage (Behr. 2012 Jul).

In conjunction with vitamin A's beneficial effect on serum markers of oxidative damage Behr et al. had observed in a previous trial with 500IU/kg and 1,500IU/kg per day (human equivalent ~6,700IU / ~20,000IU) in the same ovariectomized rodent model of menopause (Behr. 2012 Apr), the latest results from the laboratories of the Center of Oxidative Stress Research, at the Federal University of Rio Grande do Sul in Rio Grande do Sul, Brazil, only contribute to the emerging image of the hitherto hardly understood "Dr. Jekyll and Mr. Hide nature" of the (imho) most underrated vitamin there is (sorry, for the rant, but I won't get tired of raising the awareness that retinoic acid is, contrary to its overrated cousin, "vitamin D", a "real vitamin", in the sense that it is a substance we must necessarily get from our diet, while "vitamin D" is nothing but a cholesterol metabolite we should actually be able to produce ourselves, if we just got enough dietary cholesterol and sun exposure).

Figure 1: The profound loss of the rhythmicity of clock gene expression (BMAL1, PER1, top)  subsequent to three months of a virtually retinol free diet could not be restored after only 15 days on the regular rodent chow (same as control). These changes coincide with a similar loss of / shift in the expression of the antioxidant enzymatic cascade (shown here is the GPx activity) and subsequent increases shifts (deficiency) and increases in malondeyaldehyde expression (vitamin A refed group; bottom right - based on Fonzo. 2009

A closer analysis of the expression of selected markers of antioxidant activity and oxidative damage in the brain of vitamin A deficient rodents (3 months on a virtually retinol free diet) and vitamin A replete animals, who were fed the control chow for only 15 days after the depletion phase appears to confirm some of these results (Fonzo. 2009):

As expected, temporal patterns of CAT and GPx activities observed in the rat hippocampus were consistent with the rhythm of lipoperoxidation. While the lowest CAT activity occurs during the light period and, at least in part, brings lipid peroxidation into the maximal level, highest CAT and GPx activities, practically concur with the nocturnal peak of lipoperoxidation. Thus, antioxidant enzymes would have a complementary and proper timing for protecting hippocampus against peroxides, maintaining lipoperoxidation at controlled fluctuating levels, with the lowest MDA concentration occurring during the diurnal, anabolic, period in rats [...] the location of enzymes activity peaks during the night-feeding-period, may suggest the influence of feeding cycle, and macro or micronutrients, such as proteins, carbohydrates, aspartate, glutamate or some vitamins, on those rhythms, [...] the nocturnal peaks of CAT and GPx antioxidant activity seen in the hippocampus of our control rats would be in phase with the best time for performing learning and memory tests."

In this context it is interesting to see that the peak of CAT and GPX (in figure 1, only GPx is shown) does still coincide with the nightly (remember, rats eat during the dark period!) drop in GPX activity. The daily (=sleep / low activity phase) steady decline of which Fonzo et al. state that in coincides with the variation in the expression and activity of the BMAL1:CLOCK and the PER1 protein activity with

• a peak in GPx and Cat activity following the the BMAL1 protein peak at the end-of-the-night/beginning-of-the-day in the control rats, and 
• a trough of the Cat and GPx experssion after the negative regulator, PER1 protein peaks at the end of the activity phase during the day,

on the other hand, is profoundly disturbed in the vitamin A deficient animals that present with a complete loss of the BMAL1 and PER1 rhythm (figure 1, top). It does therefore appear obvious that we are (once more) dealing with two controlling mechanism:

1. an "externally" modulated, food (in the widest sense) induced regulatory mechanism and 
2. a fundamental, time- or rather light-dependent, centrally mediated circadian rhythm 

And while the latter of the two can be partly restored by vitamin A repletion. The 15-day repletion phase in the study at hand was obviously not long enough for the GPx and lipid peroxidation levels (as measured in malondyaldehyde TBARs) to return to their pre-intervention levels. If this is, as the scientists argue a result of transcriptional changes in the vitamin A receptor (RXR) "sensitivity", it is however likely that both the GPx peak activity (which should increase) and the closely related formation of lipid oxidation byproducts (MDA) should return to baseline, as soon as the stores are fully replete and the RXR levels have recovered.

From vitamins to ergogenics, from chronic to acute, from retinol to caffeine

Contrary to the effects of vitamin A which can be stored and released whenever our bodies deem it necessary, the impact of caffeine on the circadian rhythm is by the very nature of its metabolism acute and relatively short lived. This is at least true as long as the caffeine-induced circadian shifts do not lead to permanent deteriorations of the circadian rhythm. Intuitively, we all believe that caffeine can effect the circadian rhythm (or what our mainstream understanding is telling us, the circadian rhythm would be). It's not by chance that millions (ab?)use coffee and caffeine beverages on a regular basis to get going in the morning or keep going in the evening - times when our natural, undisturbed circadian rhythm should be telling us that our bed is the place our body would prefer to be, now.

One of the more exercise specific studies on this matter comes from the Exercise Physiology Laboratory at the University of Castilla-La Mancha in Toledo, Spain, where Mora-Rodríguez and his colleagues investigated the effects of a standardized caffeine containing (6mg/kg) or caffeine-free breakfast (ingested at 9:15AM) on early morning (10:00AM) or late afternoon (18:00PM) workout performance.

Figure 2: Hormone levels, performance and catecholamine levels on AM during AM and PM training sessions with or without caffeine containing breakfast (red = AM breakfast contained 3mg/kg caffeine); * indicates significant difference to AM (Placebo), PM trials were always performed on separate days with regular breakfast (based on Mora-Rodríguez. 2012)

As the data in figure 2 goes to show the whopping dose of 225mg of caffeine (note: in the graphical summary the scientists write 6mg/kg, if this is correct and the 3mg/kg that are repeatedly being mentioned in the text, then the dosage would have been 450mg) the twelve highly resistance trained men (75kg body weight; age 20; body fat 11%) did compensate for the "early morning weakness" of the participants and increased their bench press and squat performance as well as their isokinetic leg extensor strength (not shown in figure 2) to late afternoon levels, without inducing statistically significant changes in any of the measured hormonal parameters (growth hormone, testosterone, cortisol) compared to the placebo trial.

Short-term stimulation is not (yet?) equivalent to changes in circadian rhythmicity

Hack your training, not your rhythm? If the chronic use of caffeine and other stims to increase your performance at times of the day, where your circadian rhythm does not allow for maximal performance, entails possible negative downstream effects on the regular expression of your clock-genes, why don't you just train by the clock, then? Basically this is also what Hayes et al. suggested in their 2010 paper in Chronobiology International, where they state that despite the higher testosterone levels in the morning "an increased resistance exercise-induced T response [...] in the late afternoon [would suggest a] greater responsiveness of the hypothalamo-pituitary-testicular axis" later in the day - that this is bullshit, is something you should be aware by now, as the increased expression of testosterone has, as Hayes et al. have to coincide little to no influence on the hypertrophy response to training. Rather than that, they do therefore suggest to obey to the "individual responsiveness" and train whenever you feel you perform best (without the use of stims).

At times, when this is not possible, the use of stims (esp. caffeine, which is still among the "less damaging" stimulants on the OTC market), can provide temporary relief - as soon as even  3 cups of coffee only make you sleepy it is more than high time to take a break from caffeine and high intensity training (see "Tapering & Detraining - When and How to Take a Break")

For Mora-Rodríguez et al. these observations are a clear-cut sign of "circadian rhythm effects", but are they really related to changes in circadian rhythmicity? They blunt the morning reduction in muscle performance due to circadian rhythm - there is no debating that, but the study does not provide convincing evidence that this is due to changes in the expression of zeitgeber proteins and thus a direct consequence of a shift in circadian rhythmicity. If we take another look at figure 2, we would thus expect to see similar hormonal expressions, as well. After all, both the spike in cortisol in the morning as well as the steady decline of testosterone and even steeper decline in cortisol that occurs in the course of the day are both mediated by the circadian rhythm. The adrenaline spike in response to the ingestion of caffeine, which is unquestionably responsible for the observed performance enhancing effects in the study at hand, on the other hand, has nothing to do with circadian rhythmicity.

Did I mention that results from in-vitro studies suggest that cortisol spikes, esp. the huge spike in the morning, could act as a "reset switch" for the circadian clock? (cf. Balsalobre. 2000)

If anything, we could - based on the acute catecholamine response in the Mora-Rodíguez study, that chronic morning caffeine consumption could lead to subsequent downstream changes in the expression of zeitgeber genes, which would in turn trigger a 12h shift in circadian rhythmicity with low morning and high evening cortisol levels that would basically reverse the natural pattern as it was observed in the AM/PM(Placebo) trials.That this would entail a whole host of negative health effects is something you should by now be familiar and renders the (long-term) use of caffeine to "avoid the morning reduction in muscle performance due to circadian rhythm" at least highly questionable, as it would go- in the most fundamental sense of the word - against our nature. If chronic caffeine consumption did actually induce the aforementioned changes in circadian rhythmicity. So, the next question would be...

Are the effects of caffeine even of circadian origin / does it affect circadian rhythms?

The answer to this question is not exactly easy to find, as most studies follow the flawed assumption that "being more awake" would equal "being able to hack the circadian rhythm", when it could just as well be nothing more (and nothing less) than a highly effective way to outwit the latter. Against that background it's strange that Oike et al. were the only scientists I found that explicitly mention that it "remains unknown" "whether or not [caffeine] affects mammalian circadian clocks remains unknown" (Oike. 2011).

Figure 3: The in-vitro exposure of human osteosarcoma cells (a common model used in gene essays) messes with the previously mentioned clock genes Per2 and  Bmal1 genes (left) and the in vivo ingestion of coffee / administration of caffeine in drinking water did increase the locomotor activity period length of mice after normal lighting conditions (first two weeks lower panel) and constant darkness (upper panel, right; based on Oike. 2011).

Luckily Oike at el. did not just nag at the absence of reliable evidence for / against the effects of caffeine on circadian rhythmicity, but also conducted a couple of in vitro and in vivo studies, in the course of which they were able to show that notwithstanding it's disturbing effects in on clock gene expression in the petri dish (figure 3, left), the "real-world" test with coffee and caffeine did

• lengthen the circadian rhythm of reporter gene expression in liver explants of the rodents, without affecting the time of the rhythm peak in the liver explants (not shown), while
• left the period length in the likewise explanted suprachiasmatic nuclei unchanged, but delayed the peak time of the rhythm

the real world results of these somewhat schizophrenic modulatory effect of caffeine on the peripheral (liver) and central (suprachiasmatic nucleus) rhythm is an increased length of the circadian pattern in dark-exposed (=constant day for mice!) mice, without affecting the locomotor activity in the presence of appropriate light cues!

In other words: The effects of caffeine will only mess with your circadian rhythm if they are not overridden by appropriate light cues!

Similar results have been reported by Sherman et al. who made an even more complex experiment which the results of which will be part of the next installment of this series, as the inclusion of a restricted feeding regimen a la intermittent fasting with a minimalist 3h feeding window segues quite nicely into the discussion of the metabolic implications of caffeine and nutrient (esp. glucose) availability, we will take up in the next installment of the Circadian Rhythmicity Series.

Image 2: I admit that all this is not easy to understand and many of the implications on our everyday lives are yet not clear, either. I still hope you don't feel you have wasted your valuable time with this post.

Before I let you go, I do yet still want to give you the elevator pitch on this long and allegedly very complicated post. While much of what we have been studying today must still be considered preliminary (also on the expert level) there are three important and theoretically, as well as experimentally relatively well certain take home messages. The first pertains to the importance of light cues as the main regulators of the central clock gene expression in the brain, the second relates to the vital, hence "vitamin", importance of vitamin A for the integrity of the central clock, and the third relates to the modulatory effect certain molecules, such as caffeine, can have on the peripheral clocks.

The practical implications of these insights, on the other hand are pretty straight forward and for most of you probably no real news, anyway:

1. stick to the "natural" dark/light cycle - reread episodes one and two of the series for tips on how you can make do so in our "light polluted" world
2. get adequate amounts of vitamin A in your diet - there is no need to supplement, your body manges the levels of vitamin A very effectively, so that a piece of liver once in a while is a way better choice than a vitamin pill every day
3. don't be scared of coffee - as long as you still stick to the natural cycle (see first point), your circadian rhythm may exhibit slight shift, it will yet only break if you use caffeine + light as in popping a caffeine pill and surfing on the Internet with your melatonin suppressing iPad (see episode I) in the middle of the night

Now, before you switch off your iPad and go to bed today, I suggest you check out the SuppVersity Facebook Wall, for the latest news - it is no coincidence that an item about the -57% reduced Parkinson's risk in habitual coffee drinkers who consume at least three or more cups per day, as well as a reference to the latest confirmation of the liver protecting effects of coffee there... ah, and by the way, it could be that we will be able to track those back to circadian gene expression (peripherally, obviously ;-) in the next installment, as well...

References:

• Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 2000;289:2344–7
• Behr GA, Schnorr CE, Moreira JC. Increased blood oxidative stress in experimental menopause rat model: the effects of vitamin A low-dose supplementation upon antioxidant status in bilateral ovariectomized rats. Fundam Clin Pharmacol. 2012 Apr;26(2):235-49.
• Behr GA, Schnorr CE, Simões-Pires A, da Motta LL, Frey BN, Moreira JC. Increased cerebral oxidative damage and decreased antioxidant defenses in ovariectomized and sham-operated rats supplemented with vitamin A. Cell Biol Toxicol. 2012 Jul 18.  
• Buzio C, Mutti A, Capani F, Andrulli S, Perazzoli F, Alinovi R, Negro A, Rustichelli R. Circadian rhythm of proteinuria: effects of an evening meat meal. Nephrol Dial Transplant. 1989;4(4):266-70.
• Fonzo LS, Golini RS, Delgado SM, Ponce IT, Bonomi MR, Rezza IG, Gimenez MS, Anzulovich AC. Temporal patterns of lipoperoxidation and antioxidant enzymes are modified in the hippocampus of vitamin A-deficient rats. Hippocampus. 2009 Sep;19(9):869-80.
• Golini RS, Delgado SM, Navigatore Fonzo LS, Ponce IT, Lacoste MG, Anzulovich AC. Daily patterns of clock and cognition-related factors are modified in the hippocampus of vitamin A-deficient rats. Hippocampus. 2012 Aug;22(8):1720-32. 
• Hammouda O, Chtourou H, Chahed H, Ferchichi S, Chaouachi A, Kallel C, Miled A, Chamari K, Souissi N. High Intensity Exercise Affects Diurnal Variation of Some Biological Markers in Trained Subjects. Int J Sports Med. 2012 Jul 12.
• Mora-Rodríguez R, García Pallarés J, López-Samanes Á, Ortega JF, Fernández-Elías VE. Caffeine ingestion reverses the circadian rhythm effects on neuromuscular performance in highly resistance-trained men. PLoS One. 2012;7(4):e33807. Epub 2012 Apr 4. 
• Navigatore-Fonzo LS, Golini RL, Ponce IT, Delgado SM, Plateo-Pignatari MG, Gimenez MS, Anzulovich AC. Retinoic acid receptors move in time with the clock in the hippocampus. Effect of a vitamin-A-deficient diet. J Nutr Biochem. 2012 Aug 16.
• Oike H, Kobori M, Suzuki T, Ishida N. Caffeine lengthens circadian rhythms in mice. Biochem Biophys Res Commun. 2011 Jul 8;410(3):654-8. Epub 2011 Jun 13.
• Shirai H, Oishi K, Ishida N. Circadian expression of clock genes is maintained in the liver of Vitamin A-deficient mice. Neurosci Lett. 2006 May 1;398(1-2):69-72.
• Tafti M, Ghyselinck NB. Functional implication of the vitamin A signaling pathway in the brain. Arch Neurol. 2007 Dec;64(12):1706-11.

Circadian Rhythmicity - "Breakfast" or "Breaking the Fast"? Fasting as Zeitgeber & All About King, Prince & Pauper

Image 1: What would a King say if you served him that for breakfast?

When it comes to the regulation of circadian rhythms by nutrient intakes (and vice versa) the first thing we have to consider is the relation of the day-/night-cycle as discussed in the previous installments of this series and our (historical) ability to hunt and gather food. With our pathetic visual acuity in the dark and our laughable odor sensitivity and sense of hearing, our food intake has always been closely in tune with the light-controlled circadian rhythm. Without the "paleolithic" requirements of gathering and hunting, however, our eating time and frequency is either consciously controlled (e.g. "intermittent fasting") or behaviorally entrained, respectively learned via socialization.

While our sleep/wake cycle is very rigid, our feeding cycle gives us a lot of leeway 

Everyone of you who has ever tried to change a previously learned eating habit or (en-)train a child who is used to be fed whenever it gets hungry to switch to your dietary habits, will be aware of the resistance of these entrained rhythms towards change. Someone, who comes home from his last appointment with his Dr where he was told that "you have to have breakfast", because as we all know "it is the most important meal of the day", is guaranteed to have a hard time switching from coffee-to-go to the "healthy breakfast cereals" his Dr wants him to eat ;-) Mr. Kellog's Honeypops, on the other hand, will certainly be thinking about his beloved breakfast cereals all morning, when his progressive nutrition code wants him to start intermittent fasting.

More than with our sleep cycle which has at least in the broad scope of our evolutionary history always been very stable, the variations in nutrient availability on the large (e.g. seasons), but also on the small scale (e.g. bad luck hunting), are probably the reason that we have a lot more leeway with respect to our eating habits. And still, the well-documented existence of the aforementioned entrainments, and their metabolic and endocrine consequences, of which the correspondence between the release of the "hunger hormone" ghrelin  and our habitual feeding hours is probably the best-established one (suggested read: "Ghrelin Boosting Fats for Intermittent Fasting" for more on why ghrelin is not simply a "hunger hormone").

In a 2008 study, Frecka et al., for example, were able to show that ghrelin rises according to the habitual feeding patterns in both obese and lean subjects (18-50y) - contrary to what the (misplaced) appellation "hunger hormone" would suggest, however, without any significant correlation to subsequent food intake! In other words: While the subjects felt that "it's about time to eat", higher ghrelin levels, as they were observed in those with a lower meal frequency (5.5-6.5h vs. 2.5-3.5h between lunch and breakfast), did not correspond to higher food intakes during lunch - at least as long, as the 2nd meal coincided with the entrained rhythm. What the study does yet not address are the consequences of deviations (short and long term) from this rhythm and the question whether a "natural", i.e. our genetically determined and/or sunlight mediated rhythm exists.

Rise and shine... and eat?

Image 2. Firstly, no king would eat junk like that for breakfast and secondly the saying "have breakfast like a king" should actually read "beak your fast like a king".

When you think about it from an evolutionary perspective, the idea of "having to wait for a meal",  especially the first one of the day, is actually so intuitively logical that it is somewhat tragic that people misunderstand the statement that "breakfast is the most important meal of the day" as an invitation to start binging the very moment the get up, instead of waiting for lunch or even dinner to begin stuffing junk down their pie-holes. Actually this is quite ironic, because if we take a look at the etymological origins of the word "breakfast", it's plain obvious that this is not - as in Germany, where it is called "Frühstück" = "the first piece", the first meal of the day, but the meal that breaks the fast!Unfortunately, though, fasting, has become something, the average TV watching couch-potato of the Western hemisphere is a total foreigner to.

Most of us have become so alienated to the natural 12h+ fast which has once been an obligatory consequence of long winter-nights, food seeking and game that did not willingly surrender to its fate of becoming "breakfast", lunch or dinner, that many of us even have to take specific precautions in order to make sure that they are actually "fasted", when they go to the Dr. to get blood drawn early in the morning. On regular work-days, on the other hand, our tummies, which are designed to work short-time over night, oftentimes haven't even fully digested the remainder from our 16-20h binge of the previous day, in the course of the insufficient 6h of sleep we have gotten before the alarm clock rang. No wonder many people wake up "not feeling like having breakfast" and simply ignore the advice of their doctor has given them, grab a cup of coffee and head to work. Now, this may make their doctors' toenails curl in horror, but it is actually evidence that despite being misaligned (in the eyes of their docs), their feeding pattern does still have some sort of circadian rhythmicity, which would easily be lost once they switch from an early morning fast to the 24/7 binge regimen McDonald's, Burger King & Co are long catering to (see image 2).

When you didn't fast you cannot have breakfast

The answer to the endlessly debated question of whether or not you should have breakfast is - as long as we understand "breakfast" correctly, i.e. as "breaking the fast" - stupidly simple: Without fasting there is no "break(ing the)fast"! Our diurnal metabolic rhythm is geared towards cyclic fasting and feeding patterns, where the feeding hours have always been shorter than the fasting hours.

Figure 1: Are there many ways to Rome? If so, they all have one thing in common achieving an intermediate "fasting state" (green: low energy; orange: medium energy; red: high energy meal)

Obviously, this does not mean that you cannot have breakfast! Rather the opposite is the case, if you recall my hint at the weight loss intervention of the Stadtwerke Cologne (cf. "Carbs Past 6PM"), you will also remember that the most important principle of this dietary intervention is not to have dinner (or at least minimize the energy intake in the evening). And the success obese and chubby and even normal weight bus drivers, administrative officials and all sorts of other employees had with this regimen exemplifies that people can actually have breakfast in the common sense, as long as they've already had their share of (overnight) fasting and are actually breaking a fast.

Did you know that Ratcliff et al. have shown that consuming eggs for breakfast (CHO/fat/protein = 22:55:23) instead of a bagel (CHO/fat/protein = 72:12:16) will reduce the insulin and glucose response, lead to longer satiety and suppress appetite and reduce 24h energy intake (Ratcliff. 2010)? But how can that be? It must be the protein, right? Not really - it's rather the low carbohydrate content which will not totally compromise the increase in FFA levels during fasting, which is characteristic of "being in fat burning mode" - not the least to the morningly rise in cortisol, by the way ;-)

The obese Israeli police officers in the treatment group of the Sofer study (cf. "Carbs Past 6PM"), on the other hand, were just about to begin "fasting" (in the sense of "running" solely on stored fuel), when they woke up at 6AM, after all they did not just have all of their carbohydrates but at the same time ~80%+ of their daily caloric intake less than 12h ago (while the "official" time was past 6PM it is reasonable to assume that dinner was not due before 8PM for most of them). That said, their low calorie, almost-no-carbohydrate "breakfast" was effectively a means to support, not to break the fast. With the caffeine from their artificially sweetened coffee and the slowly digesting combination of fat, small amount of protein and minimal amounts of carbs in the nuts, they kept fueling the lion's share of their metabolic demands from the same stores the Stadwerke employees have tapped into extensively during the evening hours an the night of the previous day.

The "carbohydrate fast", the Israeli police officers were practicing did, if you will, put them in something that would be accurately described as a "semi-fasted" state, where the small and macronutrient specific influx of energy is insufficient to replenish the ATP stores, so that the constant or even slowly declining ADP/ATP ratios will trigger the the same (at least qualitatively) increase in p-AMPK, Sirt1 and downstream PGC1-alpha expression, as regular fasting (cf. Draznin B. 2012).

We are adaptive machines: Many regimens work, as long as they don't lack tact

If thus obviously having, not having or modifying your breakfast can work, it is actually not very surprising that a closer look at the existing research on the issue of whether you fare better or with breakfast, is inconclusive to say the least. Studies such as Astbury et al. with "regular breakfast eaters" as subjects, for example, show that the regular hormonal response was disrupted (stop for a second and think about what "regular" is measured against, here... ok, now go on), when the normalweight healthy men skip their breakfast (Astbury. 2012).

Figure 2: Visual summary of some of the results and weaknesses of the Astbury study.

Unfortunately, the Astbury study is in a way exemplary of much of the research that is / has been done in this area: Many of the studies have either methodological issues / shortcomings and/or present very biased and often even unwarranted interpretations of selected data.

Image 3: Another day at the SuppVersity and yet another thing learned, right? Come on, don't tell me you knew that it was the US nutritionist Adelle Davis who coined the (in-)famous advice to "breakfast like a king, lunch like a prince and dine like a pauper"...

In the Astbury study, for example, the provision of a 2nd breakfast-like liquid "preloading" meal before the launch is a major drawback to the real-world significance of their results. Serving their subjects Kellog's Krispies with skim milk, on the other hand, may be representative of the "fly-by" junk breakfast many people consume in the misplaced believe that it would be a "healthy breakfast", but has eventually little to do with the "long-term satiating breakfast of the kings", Adelle Davis (image 3) probably had in mind when she advised people to...

"BREAKFAST LIKE A KING, LUNCH LIKE A PRINCE, DINE LIKE A PAUPER" - Adelle Davis (1904-1974)

Moreover most of the promoters of this approach recommend to get at least (!) 25% of your day’s calories from breakfast - enough to keep you going right through till lunchtime, both physically and mentally". The sugary junk breakfast in the Astbury study, however, was not just fat free (something Adelle's milk in image 3 certainly wasn't!), it contained also no more than 10% of the daily energy requirements and was thus 40% beyond the minimal prescription for a "king's breakfast".

"To say that obesity is caused by merely consuming too many calories is like saying that the only cause of the American Revolution was the Boston Tea Party." - Adelle Davis

What's even more hilarious, though, is that the scientists explicitly measure the statistically already hardly significant changes in hormonal patterns, specifically highlight the the +17% increase in caloric intake upon lunch, and don't waste a single word on the important fact that the the overall caloric intake in both conditions was identical, and the increased food intake during lunch did not even fully compensate for the calories the subjects missed during breakfast in the abstract to their paper.

Eating vs. not-eating and quantity over quality

Note: The aforementioned "calories don't cause obesity" statement is only valid within a relatively narrow margin of total caloric intake and there is NO - and I repeat NO - debating that a healthy human being can maintain it's body weight, let alone lose weight, when he or she is eating more than 50% above his / her maintenance threshold!

With the second of the afore-cited statements from Adelle Davis, who was incidentally also among the first prominent nutritionists to support the necessity of exercise, the dangers of vitamin deficiencies, and the imperative need to avoid hydrogenated fat and excess sugar consumption, we are getting back on track, now: "Obesity is not caused by consuming too many calories!"

If you look at the current "answers" to the ensuing question: "If it's not calories that cause obesity, what is it then?" You will find answers that range from insulin over leptin resistance to fructose and general carbohydrate overconsumption, right into the too much omega-6 fats argument and the whole litany. Each "expert" has his / her own hobbyhorse in his stable... they are like pieces to a puzzle, some of which do, some of which don't go well together.

Eating a high protein diet (40%+ from protein), while trying to reap the benefits from a "ketogenic diet", for example, is impossible, and one of the reasons people "just can't lose weight". To "breakfast like a king" and still adhere to the underlying principles of a "Berkhan-esque" Lean Gains regimen, on the other hand, is not as mutually exclusive as it may sound. After all, the "intermittent fast" which is at the heart of Berkhan's protocol does not have to take place in the morning (click here and read more about intermittent fasting).

Figure 3: The good old saying of the king, prince and pauper could actually become important again, when you break the fast early and thus stop eating "early". Why you want to do that at all? Well if you want your diet to have any priming effect on your circadian rhythm fasting is the best (and most natural) way to induce the zeitgeber gene response - here exemplified by the Per2 expression of mice in response to 8h (red) and 16h (green) fasts (data based on Hirao. 2010)

Compared to the "early fast" (=skipping breakfast and even lunch), which comes totally naturally as an extension of the (ideally) growth hormone mediated nightly shift into the fasted state, the "late fast" (=skipping dinner) does simply require some more tweaking on your part (see figure 3), because you will have to modulate your food intake in a way that allows for a similarly smooth transition into the fasted state, as the going to bed after a satisfactory last meal of the day and letting your body take care of the rest.

Low GI, low carb, damn ... didn't we hear that before?

Image 4: "If you had told me that this is all about low GI or low carb diets before I had taken a nap right away! Much better for my circadian rhythm than this!"

This is also, where macronutrient ratios come into play. The aforementioned egg breakfast from the Ratcliff study (see red box above), for example, would provide the advantage of minimizing the glucose and insulin spike compared to a "breakfast" with Rice Krispies, for example, and thus minimize the subsequent drop in blood glucose. That the latter is one of the fundamental determinants of our ability to appropriately control our food intake, was one of the findings of a 2002 study by Westerterp-Plantenga et al. who report that the frequency and extent of these events added significantly to the explanatory value of the meal frequency data they had collected from 20 healthy young (18-31 y) normal weight (BMI: 22.8+/-1.9 kg/m²) men.

Yet despite the fact that the conclusion the researchers from Maastricht University in the Netherlands make based on their data

"[h]abitual meal frequency is based upon a cluster of related factors including macronutrient composition of the food, sweetness perception, hunger suppression, blood glucose declines and average baseline blood glucose levels." (Westerterp-Plantenga. 2002)

may sound like yet another recitation of the "good" reasons why you should eat a low GI or low carb diet, the most important word, at least in the context of this series, is probably "habitual"!

Eating by the clock or setting the clock by eating?

Figure 4: Light is the master regulator, and integrated only via the suprachiasmatic nucleus; fasting and calorie restriction can strengthen or weaken this superordinate or central rhythmicity, of greater practical importance is yet probably their role in the subordinate system and specifically the peripheral organs, e.g. liver, muscle, fat, etc. (illustration based on Froy. 2007)

Exactly this previously mentioned habituation or "entrainment" effect, however, is a significant problem, when we are trying to interpret the already scarce research on "optimal" circadian feeding patterns: Imagine you invite a group of 8 breakfast eaters for two testing sessions into your lab, give them breakfast in one, let them "starve" in another. Two weeks later, you repeat the same experiment with Adelfo Cerame and 7 other people who fast for 16h+ every day... I guess I don't have to tell you that you cannot expect the breakfast eaters to show the same hormonal, metabolic and epigenetic response as the intermittent fasters.

Instead of following up on the exact timing questions, the next episode will therefore deal with the lower right part of figure 4, the few established effects of individual macro- and micronutrients, and just to make sure you come back next week, I'll drop three of them: glucose, caffeine and vitamin A

References:

• Astbury NM, Taylor MA, Macdonald IA. Breakfast consumption affects appetite, energy intake, and the metabolic and endocrine responses to foods consumed later in the day in male habitual breakfast eaters. J Nutr. 2011 Jul;141(7):1381-9. 
• Draznin B, Wang C, Adochio R, Leitner JW, Cornier MA. Effect of Dietary Macronutrient Composition on AMPK and SIRT1 Expression and Activity in Human Skeletal Muscle. Horm Metab Res. 2012 Aug;44(9):650-5.
• Frecka JM, Mattes RD. Possible entrainment of ghrelin to habitual meal patterns in humans. Am J Physiol Gastrointest Liver Physiol. 2008 Mar;294(3):G699-707.
• Froy O. The relationship between nutrition and circadian rhythms in mammals. Front Neuroendocrinol. 2007 Aug-Sep;28(2-3):61-71. Epub 2007 Mar 24.
• Halsey LG, Huber JW, Low T, Ibeawuchi C, Woodruff P, Reeves S. Does consuming breakfast influence activity levels? An experiment into the effect of breakfast consumption on eating habits and energy expenditure. Public Health Nutr. 2012 Feb;15(2):238-45.#
• Hirao A, Nagahama H, Tsuboi T, Hirao M, Tahara Y, Shibata S. Combination of  starvation interval and food volume determines the phase of liver circadian rhythm in Per2::Luc knock-in mice under two meals per day feeding. Am J Physiol Gastrointest Liver Physiol. 2010 Nov;299(5):G1045-53.
• Ratliff J, Leite JO, de Ogburn R, Puglisi MJ, VanHeest J, Fernandez ML. Consuming eggs for breakfast influences plasma glucose and ghrelin, while reducing energy intake during the next 24 hours in adult men. Nutr Res. 2010 Feb;30(2):96-103.
• Westerterp-Plantenga MS, Kovacs EM, Melanson KJ. Habitual meal frequency and energy intake regulation in partially temporally isolated men. Int J Obes Relat Metab Disord. 2002 Jan;26(1):102-10.

Circadian Rhythmicity - Sunlight a La Carte: How to "Hack" Your Circadian Rhythm With 30min of Light Therapy Per Day

Image 1: The last installment was all about avoiding artificial  light, today we will use it to our advantage.

In the last installment of the SuppVersity Circadian Rhythm Series, we have taken a brief look at some of the physical aspects of light, in general, and how they relate to the physiological effects sunlight and artificial light exert on our biological clock. We have identified the omnipresence of unnatural "light" (in the broadest sense)  in our 24/7 x 365 world as one of the, if not the most important reason that our natural circadian rhythm and all the metabolic and endocrine parameters that depend on it got out of balance and we have discussed a couple of things that could be useful for anyone to either regain or retain the natural rhythm our genes have evolved with. In today's installment we are now (figuratively) turning back the time and take a look at the beneficial effects the same light(s) that keep(s) us awake, when we are long supposed to sleep, can have on the accuracy of our biological clock, earlier in the day.

Let the sun shine in your eyes to feel it in your heart ;-)

Now, that the day's are long and the sun is up or at least about to rise, when we are making our way to the bathroom to shower, brush our teeth, brew our coffee and grab something to eat (or continue our fast) before we pour ourselves into our daily business, many of you may already have forgotten those dark winter days, when you leave the house in darkness and sit in the office all day and are happy to see the last rays of the sun, when you jump into your car and head home, to the gym or to wherever you may be going on an "afternoon", your body can hardly distinguish from the darkest night.

Image 2: Selected physiological functions and their circadian pattern (Richter. 2011).

Scientists have long coined a specific term for this syndrome: Seasonal affective (SAD). Despite the fact that SAD has become more or less synonymous with the dreaded "winter blues", however, the depressive mood many people experience during the winter months, may be the most prominent, but certainly ain't the only symptom of a whole set of pathologies that are directly or indirectly related to a mismatch between your biological and social clocks. Against the background that the former controls a whole host of very important physiological processes (see image 2), it stands to reason that the consequences of this mismatch are not restricted to psychological problems. Moreover,  the number of patients and non-patients, i.e. people who simply regard symptoms such as...

• sleep problems - oversleeping but not refreshed, cannot get out of bed, napping in the afternoon
• overeating - carbohydrate craving leading to weight gain
• depression, despair, misery, guilt, anxiety - normal tasks become frustratingly difficult
• family / social problems - avoiding company, irritability, loss of libido, feeling emotionally 'numb'
• lethargy - too tired to cope, everything an effort
• physical symptoms - often joint pain or stomach problems, lowered resistance to infection
• behavioral problems - especially in young people

as part of their nature, for whom the occurrence of these problems is still seasonal, is constantly declining, so that what began as "seasonal affective disorder" has long lost both, its restriction to "affect" and its "season-"ality. A phenomenon, by the way, which should hardly surprise us. After all, we have done our very best to get rid of all kinds of all the inconvenient and unproductive seasonality in our lives, so that cynics would probable argue, that we are now paying the price for the 24/7 + 365-days-a-year availability of everything... 

From seasonal affective to circadian affective and physiological disorders

Before we are digressing any further into philosophical consideration, let's take a more scientific 2nd look at the enlightening (all puns intended) connection between the "winter blues", obviously a matter of circannual rhythmicity, and its high(er)-frequency equivalent the 'daily affective disorder'.

Figure 1: Circadian and circannual rhythm are both influenced by the sunlight and insufficient light exposure in the "high in intensity light hours" of the summer days can have the same detrimental effects on your psychological and physiological well-being as the dreaded "winter blues" aka "seasonal effective disorders" - no wonder they also respond to the same treatment strategies, i.e. dawn simulations and / or bright light therapy (respective data from Terman. 2006.)

The collage of data and illustrations I have come up with in figure 1 should actually make it pretty obvious: Despite the fact that the term 'circadian affective and physiological disorders' I have already used in the caption of this paragraph does not exist, the symptoms by which it makes itself felt, the sleep problems, the ravenousness, the depressive undertone, the lethargy, the tiredness, etc. are virtually identical.

Figure 2: Illustration of normal circadian rhythmicity (green), in seasonal affective disorders (SAD, red) and a circadian mismatch due to a phase-shift (violet); the units are more or less arbitrary.

In the end, you could probably argue that "SAD" is nothing but the "natural" accumulation of a light debt and results in a similar suppression of the natural amplitude (= degree of ups and downs, figure 2, green) of the circadian rhythm as a mismatch of the internal clock with external time emitters, above all the light of the sun.

How to "hack" your circadian rhythm

Despite the fact that the outcome of seasonal depressive disorders, on the one hand, and the downstream effects of permanent "social jet lag", or other misalignments of your biological clock and the "social time" you are living in, on the other hand, are in fact almost identical, the classic "winter blues" is the result of simple light deprivation, while the more complex pattern of circadian disorders has an intensity and a phase component and will necessarily have to be fixed differently.

What chronotype am I? Find out and become a part of a scientific study! While it is unquestionably possible to come up with an indefinite number of "classes" between the classic "early bird" (=person who raises with or before sun rise) and the "owl" (=person who rises, when the birds are having lunch), the scientific branch of chronotyping, which is occupied with the study of human rhythms in behavioral and cognitive functions, has come up with (you guessed it) a standardized questionnaire, the "Munich Chronotype Questionnaire", you can fill out here and will receive a "personal profil" via email.

Figure 4: Suggested starting times for 10,000-lux 30-minute session; timepoint is ~8.5h after the estimated melatonin onset (Termann. 2005)

If you don't want to wait or don't trust the German researchers, you can also download the modified Horne-Östberg Questionnaire, here. When you've filled it out, you will be able to calculate your "Morningness Eveningness Score." Based on that score you can then locate your suggested starting time in figure 4. The respective recommendations are based on a paper by Terman from 2005 and have been developed for SAD, so take them as what they are guidelines, not rules!

While research suggests that the correct timing of light exposure/therapy is of little or no importance as far as its beneficial effects on depression scores are concerned (Wirz-Justice. 1993), the so-called "circadian phase-delay", as scientists refer to the "time-shift" between natural and social clock (see figure 2, violet), must not be ignored if you intend to realign or protect yourself from future misalignment of your social and biological time domains.

The situation in figure 2 (violet), for example, depicts a ~4h phase shift, which would get you up and out of bed with the dreaded "2-AM wake-up call" (by the way pretty common in people who overtrain), 4h before your time!  

Now what can you do to battle this problem? Get out of bed switch on your 10,000 lux light therapy lamp, log on to facebook, check a couple of emails and sip a strong coffee? If you want to and can afford to be back to bed at 6 PM, go for it. If you don't you better stay in bed (and in the dark!), get up as you would "like" to and take a 30min "light shower" 1-2h after the time your morningness-eveningness score   would dictate (see infobox "What chronotype am I?") This will help you to push the onset of melatonin release gradually backwards until you reach the point, where it is ~8.5h before your "optimal" or necessary wake-up time.

For someone with an MEQ score of 45 who would ideally get up at 7 AM but won't make it to the office in time if he isn't up at least 1h "before his current time", on the other hand, a different strategy would be necessary.

Instead of turning around and sleeping the day away, he would set the alarm clock ahead by about 1h, jump out of bed at 5:00 AM, get his 30 min of bright light therapy in front of his 10,000 Lux lamp and do his regular morning routine afterwards. As soon as it becomes easier to get out of bed, it's time to set the alarm clock to 5:30 AM and eventually to 6:00AM.

It should be obvious, that even that will never be optimal for someone who is a born owl, i.e. a person whose genetic clock is set to wake him up, when the rest of the world has just had lunch. The daily and most importantly regular, early and intense light exposure in the morning is  going to help him to get out of bed easier and it will also increase his chances that the earlier onset of melatonin production combined with the tricks I have outlined in the last installment of this series allow him to fall asleep in time and get his 7-9h of sleep before the next light therapy session.

Warning: Guidelines and examples are no blueprints! These examples, as well as the figures in the infobox on chronotypes are very broad recommendations! You won't be able to avoid experimenting in order to pinpoint the optimal regimen for you.

Ok, I am convinced, what device shall I get?

What's that Valkee device? Is that any good? While there is a sponsored study on the efficiacy of the Valkee bright light device a "plug in your ear" light therapy device, the study is uncontrolled, which renders is more or less impossible to say how much of the observed beneficial effect the scientists measured by two different tests (HAMD-17 & BDI-21) were simply the result of a placebo effect (Timonen. 2012).

Figure 3: Comparison of BDI improvements of the Valkee device and classic light therapy (based on Timonen. 2012 and Meesters. 1993, respectively)

This does not mean that this device does not work, it just means that light therapy through the eyes is a well-established method not just to treat depressive disorders, but also to reprogram your circadian rhythm. The Valkee, on the other hand, could be a mobile and thus very convenient alternative (or adjunct) to the classic devices. It does yet still lack credible independent research that would prove its effectiveness - something like the 1993(!) study by Meesters et al. I picked as a comparison and in which only 4 days of light therapy with a classic 10,000 lux lamp had slightly more pronounced effects than the Valkee, even 10 days after the therapy had ended (see figure 3; note: It must be said that this is at best a binary comparison, because a quantitative comparison of the study outcomes from these studies can would at best serve as a basis for a hypothesis that would then have to be verified in a future trial).

The information we have compiled in the just mentioned last installment of this series does also come very handy, when you are clicking through the various product descriptions that will turn up when you enter the search token "light therapy lamp" into your favorite product search engine. Basically there are two different systems you can use if you want to try to "hack" (I know that this term is ludicrous, but I'll use it anyway, 'cause its also fashionable and would boost the sales if I ever intended to make an ebook out of this text ;-):

• a 10,000 lux full natural daylight spectrum white energy lamp or light therapy device, which will provide the full natural spectrum (you remember that's the sum of all frequency components of the sunlight, see  figure 2 in the last installment) without the potentially carcinogenic UV part - I don't have to tell you that this implies that you won't get tanned, right?
• a blue light that produces a light that has the same spectral composition as the blue sky on a summer day and is likewise devoid of the invisible high frequency ultraviolet part of the spectrum

According to the claims of the producers of such devices the blue light allows for shorter exposure times to achieve the desired effects.

This assumption does unquestionably seem reasonable, but the same is true for the hilarious notion that eating more protein will make you gain proportionally more muscle or that the presence of cholesterol in arterial plaque would verify that cholesterol is the cause of heart disease. Independent and controlled large(r) scale trials to support these claims are yet scarce and in the case of an even more innovative device, the fancy Valkee "brain stimulation set" that's supposed to shine light through your ears onto the recently discovered light sensitive proteins in your brain (for more info on the Valkee, check out the infobox on the right and the website of the producer), simply non-existent.

I personally did therefore decide to buy a classic white energy light system, also in view of the fact that you can simply place it right next to you at the breakfast table, the newspaper, your computer screen or wherever you want during your morning "circadian rhythm hacking sessions" *rofl* - this is by the way I use my device - at least if the weather / season / my wake-up time doesn't allow me to use the sun instead; and believe me, the blue light or Valkee could hardly be more convenient.

Side effects, summary & guide:

Bright light therapy guide

Intensity & wavelength requirements For white light pick a device that emits the full-spectrum of the visible light at 10,000 lux (measured at the level of the eyes of the user!)

Distance from light source Remain positioned at approximately 20–60 cm from the light source; don't stare directly into the light, the lamp just has to be in your field of view

Time of day for application In 90% of the cases the morning is the best time to apply light therapy; different rules do apply if you have to adapt your biological clock to a totally unnatural social rhythm, as it would for example be the case if you work night-shifts.

Dose 30 min at 10,000 lux, more does not necessarily help more, if you feel sleepy too early rather implement a second sitting

Onset of effect and maintenance 3–7 days till the effect sets in; if you use it to enforce an unnatural rhythm the effect will probably vanish shortly after discontinuation of therapy

In case of non-response double-dose, if you feel sleepy before your time; start earlier or add melatonin (3-10mg) before bed, if you can't get to bed in time.

In the end, it is still up to you, which device you want to buy. The guidelines in the overview on the right, which is based will probably work for the blue light systems and the Valkee, as well (assuming that those do work ;-). It is yet still by no means sure if and to which extend you can benefit and there are even occasional reports of allegedly mostly transient side effects, such as...

• hyperactivation and/or difficulty to fall asleep, which is by the way not just restricted to cases in which you apply the light too late in the day
• light headaches and/or nausea, which are particularly likely to occur in the transition periods or can be a simple consequence of starting starting out with a too hefty (=long) dose
• visual side effects, which are usually a result of staring into the light, which is not necessary for the light therapy to work, so don't do it

Other than that, Terman & Terman mention in a 2005 review paper that in their trials on patients with all sorts of serious psychological disorders, like manic depression or bipolar disorders, it was often necessary to increase the dosages, both time- and intensity-wise slowly to avoid flare-ups of these pre-existing problems. Compared to your average energy drink, let alone pill, the 30-min in front of a light therapy lamp are yet still child's play... its effects on the other hand are longer lasting and way more far-reaching.

A sneak peak on the next installment: In the next installment of the Circadian Rhythm Series we are going to leave the light out, only literally, of course, and devote ourselves to such profane things as food, what your biological clock tells you about when and what to eat and which effects this can have on your physique, performance and overall health.

References:

• Baroni BM, Leal Junior EC, Geremia JM, Diefenthaeler F, Vaz MA. Effect of light-emitting diodes therapy (LEDT) on knee extensor muscle fatigue. Photomed Laser Surg. 2010 Oct;28(5):653-8. Epub 2010 Jul 13.
• Blouin AG, Blouin JH, Iversen H, et al. Light therapy in bulimia nervosa: a double-blind, placebo controlled study. Psychiatry Res. 1996;60:1 9.
• Braun D, Sunday S, Fornari V, Halmi K. Bright light therapy decreases winter binge frequency in women with bulimia nervosa: a double-blind, placebo controlled study. Compr Psychiatry. 1999; 40:442-8.
• Howland RH. An overview of seasonal affective disorder and its treatment options. Phys Sportsmed. 2009 Dec;37(4):104-15.
• Lam RW, Goldner EM, Soplyom L, Remick RA. A controlled study of light therapy for bulimia nervosa. Am J Psychiatry. 1994;151: 744-9.
• Meesters Y, Jansen JH, Beersma DG, Bouhuys AL, van den Hoofdakker RH. Light therapy for seasonal affective disorder. The effects of timing. Br J Psychiatry. 1995 May;166(5):607-12. 
• Reiter RJ, Rosales-Corral S, Coto-Montes A, Boga JA, Tan DX, Davis JM, Konturek PC, Konturek SJ, Brzozowski T. The photoperiod, circadian regulation and chronodisruption: the requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin. J Physiol Pharmacol. 2011 Jun;62(3):269-74.
• Terman M, Terman JS. Light therapy. In: Kryger MH, Roth T,  Dement WC, eds. Principles and Practice of Sleep Medicine. 4th  ed. Philadelphia, Penn: Elsevier; 2005:1424-1442. 
• Terman M, Terman JS. Controlled Trial of Naturalistic Dawn Simulation and Negative Air Ionization for Seasonal Affective Disorder. Am J Psychiatry. 2006; 163:12.
• Timonen M, Nissilä J, Liettu A, Jokelainen J, Jurvelin H, Aunio A, Räsänen P, Takala T. Can transcranial brain-targeted bright light treatment via ear canals be effective in relieving symptoms in seasonal affective disorder? A pilot study. Med Hypotheses. 2012 Apr;78(4):511-5.
• Wirz-Justice A, Graw P, Kräuchi K, Gisin B, Jochum A, Arendt J, Fisch HU, Buddeberg C, Pöldinger W. Light therapy in seasonal affective disorder is independent of time of day or circadian phase. Arch Gen Psychiatry. 1993 Dec;50(12):929-37.