Category Archives: vasopressin

Mutual influence of sleep and circadian clocks on physiology and cognition

“The 24-hour sleep-wake cycle is one of the most prominent outputs of the circadian clock systems (Heyde et al., 2018)”

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Sleep disruption and circadian arrhythmia induce metabolic, cognitive, and immunological impairments. Is it causal? YES.

 

 

Sleep is highly conserved across the animal kingdom, since the dawn of time.

Interesting comparison: unlike hibernation or a coma, sleep is highly reversible. Lots of rebound regulation: lots of wakefulness makes you tired; lots of sleep leads to increased wakefulness.

Studies have shown improved memory performance after naps and extended sleep durations. Imo, you don’t need to go from 6 to 9.5 hours overnight, but keep that “9.5” on your radar.

Diet is easy, just eat like an adult. You can go 10 days without even eating! Try that with sleep. No, don’t try that. Most definitely incompatible with survival. Sleep deprivation impairs cognitive functions.

As a marker of health: cognitive function >>> how many reps you can do at the gym.

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If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE.

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. recommend Lion’s Mane for the brain and Reishi for everything else.

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It STARTS with Sleep.

 

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Circadian rhythms, sleep deprivation, and human performance

“Much of the current science on, and mathematical modeling of, dynamic changes in human performance within and between days is dominated by the two-process model of sleep-wake regulation, which posits a neurobiological drive for sleep that varies homeostatically (increasing as a saturating exponential during wakefulness and decreasing in a like manner during sleep), and a circadian process that neurobiologically modulates both the homeostatic drive for sleep and waking alertness and performance (Goel et al., 2013).”

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Acute and chronic sleep restriction degrade neurobehavioral functions, attention, cognitive speed, and memory. Strictly according to the studies (not your n=1), < 5.5 hours is bad, < 7 hours is suboptimal, and ~ 9.5 hours may be optimal. Seems like a lot; who has time to sleep 9.5 hours?!

Above image shows cerebral blood flow (orange) in the same person’s brain during a Psychomotor Vigilance Test performed in the morning and afternoon. Interestingly, most participants perform better in the afternoon and this is associated with more blood going to a different part of the brain.

“Sleep is a ubiquitous biological imperative that appears to be evolutionarily conserved across species.” Mandatory for optimal attention and cognitive performance.

To get the rest of this article (it doesn’t suck, I promise) or if you just like what I do and want to support it, head over to Patreon! Five bucks a month and there are many other options. It’s ad-free and you can cancel any time.

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Affiliate links: still looking for a pair of hot blue blockers? Carbonshade and TrueDark are offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERE.
If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE.

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. recommend Lion’s Mane for the brain and Reishi for everything else.

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It STARTS with Sleep.

Social jet lag.

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Start paying attention to REV-ERB alpha

Hey team, remember when I was making wild predictions about REV-ERB alpha?

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“Food for thought: an endogenous ligand of Rev-erb is heme (the iron-binding element in red blood cells). Heme is degraded into bilirubin.  Elevated levels of bilirubin cause jaundice. A treatment of neonatal jaundice is exposure to blue light. Blue light is a major regulator of circadian rhythms and Rev-erb is an executive-level player in this game. The primary mechanisms of blue light appear unrelated in these two models (melanopsin activation vs. bilirubin photoisomerization), but seem intertwined, because heme activates Rev-erb.  Cool.” (From HERE)

and statements:

“Pharmaceutical-grade circadian augmentation = unwittingly better-timed meals? Improved body composition? …they were eating more and moving less. … One possible mechanistic explanation comes from mice lacking Rev-erb in skeletal muscle (Woldt et al., 2013). Mitochondrial biogenesis was impaired and exercise tolerance was reduced in these mice. Spontaneous physical activity was lower; thus, it stands to reason that Rev-erb agonism may improve skeletal muscle mitochondrial function. This isn’t entirely consistent with the drug study, but pretty close.” (From HERE)

 

REV-ERB is really really good for skeletal muscle.

Beta-hydroxybutyrate inhibits activation of the NLRP3 inflammasome.

 

 

Well, so does REV-ERB alpha! In a new study, knocking down REV-ERB alpha jacked up NLRP3 and pharmacologically enhancing it attenuated NLRP3 (Pourcet et al., 2017). The consequence of this in REV-ERB KO mice injected with LPS was hyper-inflation. No bueno. Mice given the commercially-available REV-ERB alpha agonist “Stenabolic” were protected.

I’m geeking out about REV-ERB alpha & SR9009. And fwiw, I don’t think anything will actually fully replace the benefits from actual physical activity and/or exercise, although it’s very hard for some people; eg, COPD, CHD, etc. In those populations, if they can’t exercise enough to really improve their condition, something like this might help. But I’m sure perfectly healthy people are going to try it. If you do, let us know in the comments!

For more about this fascinating research and how it can work for you (or if you just like what I do and want to support it), head over to Patreon! Five bucks a month gets you full access and there are many other options.

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UPDATED Affiliate links: still looking for a pair of hot blue blockers? Carbonshade  is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERE.
If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else

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Regulation of Circadian Behavior and Metabolism by Synthetic Rev-erb Agonists (Solt et al., 2013)

Rev-erb alpha modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy (Woldt et al., 2013)

SERcadian Rhythms

Seriphos

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Poor sleep, “dietary disinhibition,” and weight gain

“Dietary disinhibition”

In school, the concept was taught like this: recruit a bunch of people and tell them it’s for a cookie taste-testing project. Give them a form with a bunch of questions about cookie quality (taste, texture, sweetness, etc.) and a plate of cookies.

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SWITCHAROO!

They aren’t there for a cookie taste-test. It turns out that some people experience “dietary disinhibition” wherein if they eat one cookie, they think something like “well, I’ve blown my diet for the day, so might as well just eat the whole plate of cookies” (actually, I’m pretty sure it’s way more complicated than that, but I learned it in a nutrition class, not a psychology class).

It’s not a lot of people — most would just take a bite and fill out the questionnaire — but it’s been replicated in enough settings that it’s probably a real phenomenon.

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Sunlight is anti-cancer: get some

Some important points: there is a lot of evidence that low melatonin mediates the carcinogenic effects of circadian arrhythmia. One of the classical observations was that melatonin-depleted blood from women exposed to bright light promoted tumor growth in a model of human breast cancer and rat liver cancer (Blask et al., 2005). This is also the study that elucidated one possible mechanism: tumors take-up the n6-fatty acid linoleic acid and convert it to 13-HODE, which drives proliferation. Melatonin inhibits this (and more).

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There are also data in both humans and rodents that bright light exposure during the day protects nighttime melatonin secretion against artificial light-induced suppression (eg, Kozaki et al., 2016).

 

This was confirmed by showing bright daytime light exposure protected sleep quality in people exposed to artificial light at night (Rangtell et al., 2016).

FYI Rodents exposed to light at night are screwed (Blask et al., 2014):

 

 

 

So, daytime light preserves & protects nighttime melatonin secretion. Melatonin-replete blood inhibits tumor growth. And to connect all the dots: daytime light exposure inhibits tumor growth in some pre-clinical models cancer (eg, Dauchy et al., 2015).

 

And for all you Walburgers, melatonin inhibits aerobic glycolysis in tumors  (eg, Hevia et al., 2017 AND Mao et al., 2016)!

This isn’t a free pass for you to use artificial light at night. Ideally, you should use no artificial light at night. Or dim red ones. Or at least rock some hot blue blockers.

Nocturnal light pollution and underexposure to daytime sunlight: complementary mechanisms of circadian disruption and related diseases (Smolensky et al., 2015)

Doxorubicin resistance in breast cancer is driven by light at night-induced disruption of the circadian melatonin signal (Xiang et al., 2015) (same for tamoxifen [Dauchy et al., 2014])

 

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Affiliate discounts: if you’re still looking for a pair of hot blue blockers, Carbonshade is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERETrueDark is running a pretty big sale HEREIf you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else.

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SERcadian Rhythms

The amino acid L-serine may be the next melatonin. A new study showed administration of 3 grams ~30 minutes before bedtime advanced melatonin onset dramatically, almost instantly. It didn’t increase the concentration of melatonin, just onset (Yasuo et al., 2017). For a higher concentration, you’d need AM sunlight and PM blue blockers or actual mel supps (preferably the former) (eg, Burke et al., 2013).

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Important and interesting caveat in the L-serine story: it only worked if the participants received bright light in the morning.

 

In the figure below, “day 1” is no AM light and “day 2” is yes AM light. In both the L-serine and placebo groups, there is a phase advance on day 2 because of the AM light treatment. The advance is markedly greater when the participants received 3 grams of L-serine:

 

Using rodent models (which mimicked the human effect almost exactly), GABA-A receptors were implicated.

Interesting for a couple reasons.

 

 

GABAnergic agents like benzo’s and alcohol don’t really put you to sleep; they knock you out, which isn’t proper sleep. This suggests a non-circadian effect of L-serine; however: 1) GABA-A prevents light-induced SCN activation; and 2) serine advanced melatonin onset (specifically only when combined with light in the morning).

Anyone gonna try L-serine?

To learn more about this fascinating discovery or if you just like what I do and want to support it, head over to Patreon! Five bucks a month for full access to all articles and there are many other options. It’s ad-free and you can cancel if it sucks 🙂

Also, I’m open to suggestions so feel free to leave a comment or email me directly at drlagakos@gmail.com.

Affiliate discounts: if you’re still looking for a pair of hot blue blockers, Carbonshade is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERE. If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like the taste, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else.

 

 

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Two important blog posts which may hint at how this happened: LIGHT timing for circadian entrainment and Melatonin sensitizes the system.

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This study on melatonin supps proves everything about LIGHT is true

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Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening (Rubio-Sastre et al., 2014)

If you like what I do and want to support it, consider becoming a Patron! Five bucks a month for full access and there are many other options. It’s ad-free and you can cancel if it sucks 🙂

Also, I’m open to suggestions so feel free to leave a comment or email me directly at drlagakos@gmail.com.

Affiliate discounts: if you’re still looking for a pair of hot blue blockers, Carbonshade is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERETrueDark is running a pretty big sale HEREIf you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else.

 

 

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Breast Cancer Awareness Month

“LIGHT for thought”

There are some things you can control and many more you can’t (eg, circadian disruption, alcohol, BRCA, etc.). It’s impossible to know how much circadian arrhythmia contributes to cancer risk, but the epidemiology is strong and some of the mechanistic work makes sense. It has to do with LIGHT and melatonin.

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Tl;dr: a robust circadian rhythm and proper melatonin peak at night mitigate a lot of other factors. If there’s artificial light at night, then there’s no melatonin, and that’s like, SHIELDS ARE DOWN! And it doesn’t take a lot to shut ‘em down.

There’s also a dietary angle, but it’s borderline one of those things you can’t change (unless you try really really hard) (more on this below), or at least not nearly as fast as you can fix melatonin (see HERE).

 

In 1978, Cohen and colleagues made a few seminal observations (Cohen et al., 1978). In their words,

“(1) Pineal calcification is commonest in countries with high rates of breast cancer and lowest in areas with a low incidence; the incidences of pineal calcification and of breast cancer are moderate among the black population in the United States.

(2) Chlorpromazine raises serum-melatonin; there are reports that psychiatric patients taking chlorpromazine have a lower incidence of breast cancer.

(3) Although information is lacking on breast cancer, the pineal and melatonin may influence tumour induction and growth in experimental animals.

(4) The demonstration of a melatonin receptor in human ovary suggests a direct influence of this hormone on the ovarian function, and possibly oestrogen production.

(5) Impaired pineal secretion is believed to be an important factor triggering puberty (early menarche is a risk factor for breast cancer).”

 

The dark side of light at night: physiological, epidemiological, and ecological consequences (Navara and Nelson, 2007)

 

 

And further observations, for example, that urinary melatonin is prospectively inversely associated with breast cancer (Schernhammer et al., 2008) and total blindness is protective against breast cancer (Flynn-Evans et al., 2009). Total visual blindness is associated with a variety of other problems, but they’re less likely to succumb to artificial light at night-induced melatonin suppression.

 

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Efficacy of a wide range of things, from sleep & diet to supps & meds, may depend on timing

A study on epilepsy was published comparing gene expression in parts of the brain where seizures developed with adjacent healthy tissue (Li et al., 2017). It was in humans, so they couldn’t really have proper controls, because what healthy person would volunteer to have some of their brain chopped out?

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They found the core circadian rhythm gene CLOCK was reduced in epileptogenic regions of the brain compared to healthy nearby tissue. It could be that this is just the way it is in healthy people, or that the seizure itself reduced CLOCK not vice versa. But the researchers followed-up with animal models lacking CLOCK in either inhibitory or excitatory neurons and showed mice lacking CLOCK in excitatory neurons had a lower seizure threshold and a more severe condition (suggests causation). They had worse seizures in the dark phase, similar to the findings in humans.

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Fixing your rhythms makes everything better. Here’s how.

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What’s more anti-cancer than ‘shrooms and isothiocyanates?

CIRCADIAN RHYTHMS

Affiliate discounts: if you’re still looking for a pair of hot blue blockers, Carbonshade  is offering 15% off with the coupon code LAGAKOS and Spectra479 is offering 15% off HERE. If you have no idea what I’m talking about, read this then this.

20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like the taste, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS.

Caffeine, large meals, and bright light in the evening induce circadian misalignment. That’s why these are better suited earlier in the day.

Caffeine reduces sleep pressure (which is supposed to start low in the morning and peak shortly after sunset) and delays melatonin onset (Burke et al., 2015). After dinner, make it a decaf or just pass.

 

Caffeine is an adenosine antagonist, and the accumulation of adenosine in the brain throughout the day is thought to be a chemical mediator of sleep pressure. Caffeine also delays and reduces melatonin, which increases your sleep needs, or at least time in bed/darkness.

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