Protein dilemma ~ sleepy or smart. #Gelatin

Gelatin and glycine have bounced around the blogosphere for quite some time.  Coming from a nutrition-centric place: you say gelatin, I think tryptophan (or lack thereof) and glycine.  Others think:

Jane Plain discusses positive mental effects of gelatin and pimps Pro-Stat (good source of glycine).  Chris Masterjohn discusses glycine and in typical WAP fashion seems to favor bone broth (20% off Kettle & Fire’s awesome broths HERE!).  Knox gelatin didn’t help Michael Allen Smith sleep better, and he apparently tracks sleep quality quite well.  However, Sondra Rose thinks it improves sleep harmony, and gelatin simply blows Dana Carpender’s mind.

bones

 

Tryptophan-rich proteins like those found in whey and egg whites will elevate blood levels of tryptophan relative to other large neutral amino acids (Trp:LNAA ratio), leading to higher brain uptake and subsequent serotonin synthesis.  Tryptophan-poor proteins like gelatin do the opposite, and impair memory.  But the high glycine content in gelatin improves sleep quality.*  Glycine powder might be able to get around this, it’s dirt cheap and it seems to have the opposite effect on brain serotonin, albeit at a much higher dose (and in rats).

 

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Ketosis: anti-brain fog. Neurotransmitters, dietary protein, and the gut microbiome.

Treatment for dietary protein-induced brain fog: dark chocolate with 3% GOS and 10% MCTs.  Who’s in?

#IntermediaryMetabolism (bear with me here)
Ketosis from liver’s perspective:  increased fatty acid influx & [partial] oxidation causes acetyl-CoA levels to rise dramatically.  Concomitantly, gluconeogenesis redirects oxaloacetate (OAA) away from combining with acetyl-CoA via TCA cycle citrate synthesis and toward gluconeogenesis.  Since the acetyl-CoA doesn’t have much OAA with which to couple, it does itself to make acetoacetate.  Ergo, ketosis, and fortunately liver lacks ketolytic apparatus.

ketosis

 

Brain is singing a different tune.  Ketones provide ample acetyl-CoA and are efficiently metabolized in the TCA cycle.  Ketolysis is not ketogenesis in reverse, else liver would consume ketones.keto metabolism

Teleologically speaking (and I don’t really know what that word means), ketones are meant to spare glucose for the brain by replacing glucose as a fuel for peripheral tissues like skeletal muscle and displacing some brain glucose utilization.  The former is vital as one of the few sources of “new” glucose is skeletal muscle amino acids, and they would be exhausted in a short amount of time if skeletal muscle kept burning glucose –> incompatible with survival.  Getting some of that fuel from fatty acids, ie, ketones, is just way better.  Thus, the “glucose sparing effect of fat-derived fuel.”  And by “glucose,” I mean “muscle;” and by “fat-derived fuel,” I mean “ketones.”  There are numerous intracellular signaling events and biochemical pathways pwned, but that’s the gist of it.

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Circadian biology: jet lag, mood, & potential role of BP regulatory peptides

There are enough connections here to suggest it’s an interesting rabbit hole.  Besides the effects of ARBs & desmopressin on mood and cognition, blood pressure regulation is not interesting <– fact.  But if it ties into fertility, circadian biology, and seasonal changes in how we should be doing things…

Way back in 1998 when I was graduating high school, Murphy and colleagues were screwing with “light-entrainable” and “food-entrainable” oscillators of circadian rhythmicity (1998).  They did this in two lines of rats, one with intact vasopressin signaling and one without.  With little mechanistic work, they showed vasopressin mediates circadian effects driven by light; and rats without vasopressin were more entrainable by meal timing.  N.B. in addition to the posterior pituitary, vasopressin is also found in the famous circadian light-regulated SCN neurons (Rosving 2010).

While it is speculated to play a role in social behaviors and sexual motivation, vasopressin is primarily known for its anti-hypotensive effects.  When plasma volume drops, vasopressin is secreted to decrease urinary water loss and increase blood pressure.  This is antagonized by alcohol, which is thought to be one reason why alcohol can dehydrate you.

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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.  

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.

Flash forward to 2017… Circadian rhythms: blocking the blues. AND THE GREENS

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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.

It’s paleo: Hypothyroidism impairs reproductive success in bitches.

Kisspeptin was discovered in Hershey, Pennsylvania, and was named after Hershey’s Kisses.  It has 776 pubmed citations going back to 2001, and may (or may not) play a key part integrating circannual reproduction patterns and seasonal thyroid function.

Kisspeptin was originally identified as a protein that inhibited breast cancer and melanoma.  This might also provide insight into the WHO’s recent declaration of shift work as a “probable” carcinogen.

Exhibit A. TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin (Klosen 2013)

In this study, TSH infusion in short-day adapted hamsters (who are in winter non-breeding mode) induced summer phenotype & kisspeptin.  It also fattened them up a bit.  These TSH secreting neurons express melatonin receptors, but not those for TRH or T3 (Klosen 2002), so it is said to go something like this:Kisspeptin feedback diagram

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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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Summer is fattening. Don’t do it in winter.

Seasonal eating proper

More on seasonal eating in what appears to be the primary model for its justification for use in humans – hibernating mammals.

How it goes, or so they say: in summer, hibernators massively overeat, including carb-rich foods, in order to generate muscle and liver insulin resistance, so as to promote body fat growth.  The long light cycle reduces evening melatonin, which pushes back the usual nighttime peak in prolactin, which causes an abnormal resistance to leptin, which induces hypothalamic NPY and subsequent carbohydrate craving.  Ergo, summer is fattening.  In today’s day, increased artificial lights guarantee year-round pseudo-summer; and we no longer experience the benefits of the short light cycle: longer sleep times (akin to hibernation) and fasting – either complete fasting as in hibernation, or pseudo-fasting, ie, a ketogenic diet.

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Lights Out! Get your melatonin.

From T.S. Wiley’s website:
“People spent summers, before electric lights, sleeping less & eating heavily in preparation for winter because the light triggered the hunger for carbohydrates. Now, light is available 24 hours a day. Heating and air-conditioning climate control our hormonal responses to consume carbohydrates now available year round. This is the scenario for obesity, Type II diabetes, and depression… In Wiley’s opinion, sleep is the best medicine.”

And Wikipedia:
“Wiley’s main thesis in Lights Out is that light is a physiological trigger that controls dopamine and hormones like cortisol. Wiley posits that with the extension of the natural day through artificial lighting, rest at the hormonal level is rarely adequate for optimum biological needs of the body. In her view, this results in both fatigue and unnatural appetite, which leads to weight gain, exhaustion, and disease. Wiley theorizes that the body’s responses are cyclical, reflecting the seasons of the year, and that the body’s needs vary seasonally. According to Wiley, during the winter months the body needs more sleep, and carbohydrates should be restricted as they would have been naturally during hunter-gatherer times.”

melatonin

Most of the first third of Wiley’s book “Lights Out: Sleep, Sugar, and Survival” centers around light exposure, melatonin, and the many, many effects of a screwed up circadian cycle.  Jane Plain and Jack Kruse have written volumes on the subject, please see their websites for more in-depth analyses and practical applications…

Much of this blog post is my take on that first third (I couldn’t wait to finish it before writing about it), plus a little input from Google, Pubmed, et al; some commentary & pseudo-fact-checking as well.  I’m going to finish the book, and hopefully it will inspire a few more blog posts as opposed to a tin foil hat.  Most of the stuff in Lights Out makes incredibly good sense, but: 1) that doesn’t mean it’s true; and 2) the strings of logic are far too long to do a proper fact-check.  But really it’s how well it makes sense (mostly) that has me intrigued.

divide and conquer

Melatonin is a sleep-inducing hormone controlled by the light-dark cycle.  It is known.  On the day-to-day, melatonin increases at night and decreases during the daytime.  From Wiley: on a seasonal level, longer days during the summer meant less melatonin overall during these months.  Since melatonin suppresses sex hormones (inconsistent? Eg, Smith et al., 2013), summer is supposed to be breeding time, so the baby is born in spring when food is plenty (I’m OK with this now, but will certainly disagree come December).  Melatonin also suppresses metabolic rate, so the decreased daylight and thus increased melatonin during the winter months helped to survive on less food (supported by Marrin et al., 2013).

Disruptions in circadian rhythms royally screws us up.  According to Wikipedia, fireplaces/candles and incandescent bulbs produce less of the melatonin-suppressive blue lights… use these at night in winter?


Antidepressant and circadian phase-shifting effects of light. (Lewy et al., 1987)
Abstract: Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. This finding suggested that bright light may have other chronobiologic effects in humans as well. Eight patients who regularly became depressed in the winter (as day length shortens) significantly improved after 1 week of exposure to bright light in the morning (but not after 1 week of bright light in the evening). The antidepressant response to morning light was accompanied by an advance (shift to an earlier time) in the onset of nighttime melatonin production. These results suggest that timing may be critical for the antidepressant effects of bright light.

Next:  Prolactin inhibits sex hormones, and melatonin stimulates prolactin (supported by Gill-Sharma 2009Campino et al., 2008).  Thus, less melatonin in summer means less prolactin = more sex & fertility.  She also says day sex is more likely to result in conception compared to night sex for this reason (couldn’t find a reference for or against this).

Dopamine inhibits prolactin, whereas TRH & melatonin stimulate it.  Melatonin also blunts ACTH-induced cortisol secretion (supported by Torres-Farfan 2003Campino 2008).  Winter = high melatonin, prolactin, and low cortisol & dopamine.  Summer = high dopamine & cortisol, and low melatonin & prolactin.  Prolactin is supposed to be high in winter, during pregnancy; low dopamine would support this.

Circadian rhythm

Dopamine is a summer hormone?  Lu et al. (2006) showed high dopaminergic activity was associated with light and wakefulness (ie, summertime).  However, Venero (2002) showed melatonin stimulated dopamine synthesis in specific brain regions, and Eisenberg (2010) showed increased dopamine synthesis in fall & winter relative to spring and summer.  Two  possible confounding factors come to mind: 1) Location, location, location!  Some of these discrepancies may be due to brain region-specific dopamine metabolism… actually, Lu is the only odd-man out, so perhaps dopamine is a winter hormone?  And 2) Wiley’s main premise is that we pwned the light… epigenetics and the like mean that we, including the people in those studies, have deeply screwed up light/dark summer/winter metabolic programs on an epigenetic level, so it’s possible those studies are riddles with artefacts.  However, Wiley also says that people get sick because they live in perpetual summer (lights on all the time = high dopamine), and Markianos (2013) showed elevated dopamine metabolites in overweight patients; in my experience these studies usually continuously enroll patients, year-round.


I’m really just blazing through abstracts here – this is why I call it “pseudo-fact-checking;” not to be confused with any degree of academic rigor.

To be continued… (no tin foil hats, I promise) (not yet at least)

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