Tag Archives: melatonin

Fasting, circadian biology, and epigenetics

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

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

SIRT1

 

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

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Circadian disruptions impact behavior and metabolism in a tissue-specific manner.

The control of circadian gene expression is complex, with layer upon layer of suppressors and enhancers, numerous transcription factors, and a lot of interactions.  A gross oversimplification: Clock and Bmal1 are positive regulators of circadian gene expression; Per and Cry are negative (you don’t really need to know any of this).

 

Some pretty cool progress has been made in examining the effects of global and tissue-specific deletion of circadian rhythm-related transcription factors.  Bear with me :)

For example, global Bmal1 knockout mice (ie, mice that don’t express Bmal1 anywhere in their whole body.  Zero Bmal1.  Nil.) (Lamia et al., 2008).  These mice are obese, and exhibit impaired glucose tolerance yet improved insulin sensitivity.

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Fiat lux

Humans have a peculiar relationship with light: differences in brightness, wavelength, and even circadian timing all have biologically meaningful effects.

The right combination of timed light exposure and hot Blue Blockers is probably not only the solution to jet lag, but also to a whole host of other health problems.  Maybe you can’t completely escape the bane of the modern condition, but there are some tools, widely available, accessible, and even free in some cases (eg, sun), that may be of benefit.  

The frequency of light impacts circadian rhythms. 

Wright showed this in 2004.  The subjects wore special glasses with LEDs that emitted light of varying frequency for 2 hours, from 6 to 8 in the morning (65 uW/cm2).  Salivary melatonin measurements commenced at 7 pm.  As seen in the figure below, blue but not red light induced a significant phase advance in melatonin onset:

AM blue light phase advance

And for the whole group:all colors

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The hot Blue Blocker Experiment

The eyes are the window through which light must pass, regardless of sightedness.

FACT: we don’t realize the importance of circadian biology.  Or at least we don’t act like it.  And we’re certainly not going to turn off our iPhones & laptops when we’re supposed to.  Potential intervention: hot Blue Blockers.  They’re a band-aid, no doubt, but they might help.  Jane Plain raised a potential concern with this here.  In brief, we can block blue light from molesting circadian biology with hot Blue Blockers, but extraocular light exposure could betray such feeble attempts.  I read something to a similar effect on Dr. Kruse’s blog.

It seems to be based, in part, on an experiment by Campbell & Murphy (1998).  They tried to experimentally screw circadia by exposing an isolated spot of skin on the back of the knee to 3 hours of bright light.  Melatonin data weren’t shown, but the authors said they mirrored body temperature:

Campbell Murphy

It worked (for body temperature, at least).

But FAR more interestingly, Czeisler showed bright light-induced melatonin suppression in blind people was reversed if they covered their eyes!!!Czeisler

This is wild.  Unless there is something CircadianlyMagical about the skin on the back of the knees, then these findings refute those of Campbell.  Czeisler’s findings were confirmed by Hatonen (1999) in sighted people: black circles = no light exposure; open squares = full-face light exposure with eyes closed (partially blunted melatonin secretion); and open circles = full-face light exposure with eyes open (fully blunted melatonin):Hatonen

Of note, blind eyes and closed eyes aren’t the same as covered eyes.  There were, however, 2 people who exhibited no melatonin inhibition with closed eyes.  Perhaps some are intrinsically more light-resistant, or have robust eyelids or something.


It seems as though we needn’t worry about Campbell’s findings after all because they were directly refuted by Hebert (1999):Hebert

The light exposure protocol in both of the studies was identical: 13000 lux to the back of the knees for 3 hours.

Print

Perhaps we should’ve demanded to see Campbell’s melatonin data?  Or not.  Lushington confirmed Hebert’s findings (albeit with only 11000 lux):Lushington

In 2000, Lindblom blasted 10000 lux at a much larger surface area – chest & abdomen – and found no effect on melatonin:Lindblom

The eyes are the window through which light must pass, regardless of sightedness.


Was all of this blog post irrelevant until now?  Maybe. (sorry)

Sasseville compared bright light-induced melatonin suppression in people wearing boring shades (top graph) or hot Blue Blockers (SolarShield Orange Lenses) (bottom graph):

Sasseville

The orange lenses transmit slightly less light than the boring ones (32 vs. 52%), so they accounted for this by hitting the hot Blue Blockers with more lux (4000 vs. 2200… this is directly in their faces, so it couldn’t be >10000 lux like in the previous studies)… this still resulted in more irradiance hitting the hot Blue Blockers, so the odds were stacked against them (I think, #physics).

Lux: luminous flux per unit area
Irradiance: electromagnetic radiation per unit area

Melatonin suppression is important, but what we’re really talking about here is SLEEP.  And in 2009, Burkhart showed just that.  When assigned to hot Blue Blockers (NoIR Polycarbonate Lasershields), sleep quality markedly improved:

Burkhart

(granted, randomization was horribly bollixed, but it is what it is).


Sasseville came through again in 2009, this time for shift workers.  Their subjects had to wear hot Blue Blockers (Uvex Skypers) when they were leaving work [in the morning].   It worked.

Sasseville II

In sum, don’t sweat extraocular light exposure, and anyone with a metabolic disturbance who lives a remotely modernized existance, paleo or otherwise, might benefit from these.

calories proper

hot Blue Blocker experiment: expectations = none.  I’m a “non-responder.”  This might not be the best time of year to conduct such an experiment, but the combination of high motivation and low patience prevailed.  And I still use my computer a lot at night.

This is a diary of sorts.
day 1: initial observations.
Started wearing them about 2 hours before sunset.  Outside sky prior to dusk looks like insane alien invasion.  But creepy red bathroom light looks exactly the same.  #physics.

Morning of day 2: Usually wake once or twice in the middle of the night, but didn’t…

Evening of day 2: Started rocking the shades 2 hrs prior to bedtime.  Same awesome yellow-ness and crisp resolution of the sunset.  It really looks like another planet.  I also could’ve probably stared directly at the sun with impunity (but didn’t).

Morning of day 3:  new conclusion: I think I usually wake up a few hours prior to dawn, but hot Blue Blockers prior has shifted this to a few hours earlier.

Morning of day 4:  same!  Hot Blue Blockers make me need to pee 4 hours sooner after falling asleep <– I’m a “responder!”
Mood, sleep quality, & energy levels stable <– “non-responder,” but willing to give it more time.  Burkhart’s study showed a near doubling of sleep quality, but it took 3 weeks.

P.S. FWIW, I’m wearing these, so definitely not going out in public places.

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Paleo breeding: mating in the wild.

I’ve adapted much of this chart from Howell-Skalla (2002)  and Tsubota (1998).

Canadian polar bears: bona fide seasonal breeders.circannual hormones

The light cycle increases until June, then decreases until December.  Melatonin goes in the exact opposite direction. Testosterone peaks around the onset of breeding season (springtime, April/May), coinciding with LH (as expected). There is also a lot of bear-on-bear violence at this time due to: 1) testosterone-induced aggression; and 2) the high female:male ratio –-> females rear their cubs and are thus out of the game for about 3 years, but males like to breed every year.

Females followed a similar pattern, with estrogen peaking around breeding season and prolactin following the light cycle.

The authors mentioned that prolactin levels mirrored day length, and according to Wiley this would be the prolactin peak that normally occurs when you’re sleeping, but has spilled over into the daytime due to short sleep / long light cycle… not total prolactin levels (24h AUC?), which should be highest in winter (see below).

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The incredible camping experiment, circadian proper

Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle (Wright et al., 2013)

Abstract (edited): The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle, and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise

In other words, they compared circadian events during 2 weeks of normal life to 2 weeks of 100% camping.  And camping won.

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