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.

Full article open to everyone over at Patreon! <- link

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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We don’t want more or less antioxidants. We want balance. #NRF2

“The goal is to maintain or improve brain function and physical performance. And not get cancer.”

Antioxidants

There isn’t a strong case to make for antioxidant supplements. They’ve been shown to do nothing more often than not, and even harm in a few cases when dose & #context were mismatched (eg, ATBC and CARET). This is part of what led to the conclusion that we want an appropriate “reactive oxidative species *tone*” or “antioxidant balance.” Or “landscape.” Or some other catchphrase of the week.

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In line with this, animal models that genetically up- or down-regulate antioxidant pathways are predicted to show negative or no effects because they are, practically by definition, generating a mismatch.

In humans under normal conditions, I believe pro- and anti-oxidants are balanced by our own endogenous processes. If we ingest something that produces a bit too much ROS, they’ll be neutralized. If we ingest something that induces antioxidant processes, they’ll be used if necessary and degraded if not. In other words, as long as you’re not mega-dosing beta-carotene or smoking 2 packs a day, etc., then none of this should matter.

 

 

NRF2

Which brings me to NRF2. I like the concept of periodically inducing our own endogenous detox processes because it seems like they’ll either help or do nothing. Not harm. It’s like, stacking the deck in your favor.

Nrf2: ket target for the treatment of neurodegenerative diseases

 

Bioactive Neutraceuticals and Dietary Supplements in Neurological and Brain Disease: Prevention and Therapy

If you ingest something that induces NRF2 and something needs detoxifying (for example, some manifestation of improper ROS tone or inflammation or something), then NRF2 will get it done. Otherwise, NRF2 goes away in about 20 minutes (Kobayashi et al., 2004).

 

Reminders: still looking for a pair of hot blue blockers? Carbonshade and Spectra479 are offering 15% off with the coupon code LAGAKOS. And Kettle & Fire is offering 20% off of their delish broths/stocks HERE.

 

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Light & melatonin: timing is everything

This is kinda like circadian rhythms’ second Nobel Prize. Technically it was LED lights back in 2014, but if you don’t see the connection, I have failed.

Suggest pre-readings: Melatonin sensitizes the system and LIGHT timing for circadian entrainment

Melatonin plays a pivitol role in circadian entrainment. Literally thousands of papers published about it every year.

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THIS IS WHY YOU NEED BLUE BLOCKERS: A single night light exposure acutely alters hormonal and metabolic responses in healthy participants (Albreiki et al., 2017)

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Pregnancy dieting and #moderation: just don’t be extreme

“If you can’t absorb B12, no amount of steak will help you” (more on this below)

Just like practically everyone in the field, I’m uncomfortable with the word moderation, in part because one person’s moderation can be wildly different from another’s.

Remember the Motherwell studies? In brief, they asked a group of expecting women to ditch carbs and eat a ton of meat instead (about a pound per day), and compared them with a group not given diet advice. It was designed to compare an extreme diet to an average diet (note: they didn’t assess the opposite extreme, ie, high carb vegan).

Tl;dr: babies were healthy at birth but developed a variety of health problems later in life. Perfect study design? No. Better than ALSPAC? Kinda, yeah.

 

 

In the context of today’s topic, I’ll define moderation as “not extreme” (bear with me here) (unless ALSPAC is retracted or something… which is possible given the study design.)

 

Meat consumption during pregnancy and substance misuse among adolescent offspring (Hibbeln et al., 2017) (aka ALSPAC)

 

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The *other* spicy things

Wasabi, horseradish, mustard, radish, etc., etc.

 

The Isothiocyanates (ITCs) (for example, allyl isothiocyanate [AITC])

 

It’s basically cancer’s second worst enemy (just after ‘shrooms). Also an enemy of anything that tries to eat AITC-containing plants (it’s even harmful to the plant itself!). Actually, AITC is stored in a harmless form, as a glucosinolate. The enzyme myrosinase is stored separately. When the cell walls are broken (something bites into it), and myrosinase comes in contact with glucosinolate, AITC is formed. In the animal kingdom, it’s kinda like tear gas. It’s even harmful to the plant, but better a little chemical burn than eaten alive.

 

 

Side note: store-bought wasabi is usually horseradish and maybe some mustard, but for the #context of this article, it doesn’t really matter because they all contain isothiocyanates. If you want to get the right thing, try and find the actual plants; they’re not easy to confuse:

Wasabi:

 

 

 

Remember NRF2?

Wasabi does that, too!

 

Horseradish:

 

 

 

 

Isothiocyanates

For us, it’s what drives the mouth-burning, sinus-clearing, and eye-watering sensations.

Unlike capsaicin (the *other* spicy things; eg, from hot peppers), the burn is much shorter in duration because AITC is water soluble. Try eating a habanero and putting out the fire with ice water.

YOU’RE MAKING IT WORSE

Capsaicin is fat-soluble; it doesn’t dissolve in water (especially cold water) – so you’re basically just spreading it all around your mouth. Try something with a little fat instead.

 

Mechanisms of action of isothiocyanates in cancer chemoprevention (Navarro et al., 2011)

chemoprevention > chemotherapeutic

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.

For the rest of this article and to support the show, head over to Patreon!

Three bucks a month for access to all articles and there are many other options. And it’s ad-free.

If you’re on the fence considering it, try it out, you can cancel at any time! Also, there is a limited number of positions remaining at the $3 level.

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

 

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Circadian Rhythms. Nobel Prize.

18th Century: French astronomer Jean-Jacques d’Ortous de Mairan observed the mimosa plant opened it’s leaves during the day and closed them at night. It would continue to do this even in complete darkness. Thus, a bona fide circadian phenomenon. He didn’t know about circadian rhythms and thought the plants could “sense” when the sun came up, but he was still a genius. He also speculated temperature may have been a factor. Not bad!

 

 

Some of the seminal Nobel Prize-related papers are listed below, but the discovery in brief:

The protein PERIOD (Per) increases over night and decreases during the day. That’s because when another protein, TIMELESS (Tim), reaches a critical threshold, it binds to Per, they enter the nucleus and halt further production of Per. This is the foundation of circadian rhythms. Since these discoveries, made DECADEs ago, we’ve learned it’s WAY more complicated.

 

 

. . .   .     .        .              .

 

 

 

Most of their research was done in fruit flies. You might be thinking, “Yeah, but fruit fly? That’s worse than mouse!”

Polymorphisms in PERIOD cause circadian-related sleeping disorders.

In humans. (eg, Viola et al., 2007, Drake et al., 2015, and Lee et al., 2015.)

 

 

Polymorphisms in many circadian genes mimic certain aspects of self-induced circadian arrhythmia (ie,  skipping breakfast & eating late at night, not getting enough light in the morning & too much in the evening, etc.)… it kills me when I hear about kids playing on their iPads & smart phones late at night. At least get some blue-blockers! (coupon code LAGAKOS is still good for 15% off Carbonshade and Spectra479.)

 

For the rest of this article, head over to Patreon!

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

 

also, reminder, can still get 20% off Kettle & Fire’s awesome broths HERE.

 

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Project FermenTRP

People have been fermenting food for a long time, all over the world. Different cultures have different traditional fermenting techniques for various foods and beverages (eg, Bell et al., 2017). Many things, ranging from grapes, milk, and cabbages, even meat and fish. For all intents and purposes, it’s practically universally viewed as a beneficial and healthful practice …

for the ‘biome and beyond

#psychobiotics

 

Maybe it’s just because a robust ‘biome lowers the sugar content of your diet! LOL jk I’m sure it’s far more complex than that.

 

Also, the shelf-life of most ferments is forever, so when the zombie apocalypse happens, it’s a good skill to have.

 

Part 2. Project FermenTRP

I started down this rabbit hole because the TRP theory of muscle cramps is interesting. And, well, I got carried away LOL .

 

The idea of a “superfood” is kinda silly, but virtually all TRP agonists are found in so-called superfoods. Fermenting is cool, too, so I decided to combine the two because why not

 

[I know, I know, photography isn’t my specialty]

 

#torched

 

 

Torching habanero peppers does not lessen the burn. To be honest, I’d go with a WAY less hot pepper. And combine with other TRP activators. For synergy. Or something.

 

 

The TRP-theory, in brief:

An interesting theory on the treatment of muscle cramps

Herbs, spices, TRP receptors, and pain

TRP channels in the treatment of muscle pain & cramps

 

Here are some of the more common sources of TRP agonists in the literature:

Hot Peppers (capsaicin) (doesn’t have to be habanero) (DO NOT USE HABANERO)

Involvement of thermosensitive TRP channels in energy metabolism (Uchida et al., 2017)

Targeting nociceptive TRP channels to treat chronic pain: current state of the field (Moran and Szallasi, 2017)

 

Peppercorns (piperine)

Activation of TRPV1 and TRPA1 by black pepper components (Okumura et al., 2010)

 

Ginger (gingerols)

Effects of ginger and its pungent constituents on transient receptor potential channels (Kim et al., 2016)

 

Garlic (allicins & sulfides)

The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin (Macpherson et al., 2005)

Diallyl sulfides in garlic activate both TRPA1 and TRPV1 (Koizumi et al., 2009)

Intragastric administration of allyl isothiocyanaate increases carbohydrate oxidation via TRPV1 but not TRPA1 in mice (Mori et al., 2011)

 

Cinnamon (cinnamonaldehyde)

Effects of TRP channel agonist ingestion on metabolism and autonomic nervous system in a randomized clinical trial of healthy subjects (Michlig et al., 2016)

 

Mustard & Wasabi (isothiocyanates, I think)

The capsaicin receptor TRPV1 is a crucial mediator of the noxious effects of mustard oil (Everaerts et al., 2011)

Thermosensitive TRP channels and brain function (Tominaga, 2016)

 

Cloves (eugenol)

Oregano, thyme, and clove-derived flavors and skin sensitizers activate specific TRP channels (Xu et al., 2006)

 

There are many more, but those are just some of the ones that made it to part 3.

 

In brassica, speramus.

 

For the rest of this article and much more, head over to Patreon!

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Circadian rhythms & the blues. AND THE GREENS

Approximate wavelengths, in nanometers (nm):

680         red
595         amber
525        green
497         blue/green
470         blue

 

 

[Strongly] suggested pre-reading: Artificial light and circadian rhythms: blocking the blues and The Hot Blue-Blocker Experiment

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Study 1 tested the effects of different wavelengths of light exposure (compared to total darkness) from midnight til 2 AM on melatonin suppression on night 1 and melatonin onset on night 2 (Wright and Lack, 2001). Note: there was no light on night 2.

On night 1, they found that 470 (blue), 497 (blue/green), and even 525 (green) suppressed melatonin, ranging from 65 to 81%.

 

 

However, remarkably, on night 2 those same wavelengths had a carry-over effect, delaying melatonin onset by 27 to 36 minutes!

 

 

This is why lens color of your blue blockers matters. Orange lenses block blue, although blue/green and even green can still have a detrimental impact. Redder lenses more effectively block in the green range.

If you get up to pee or whatever in the middle of the night, it might be prudent to rock your blue-blockers and/or have a lamp with a red bulb.

The following graphs show you how much light is blocked by different lenses – remember, we want as little transmission up to around 525 nm (according to study 1 [above] and study 2 [below]).

However, for a quick and dirty test you can do at home, the people at Spectra479 put this together:

 

 

 

 

Carbonshade and Spectra479 are offering 15% off if you enter the coupon code LAGAKOS at checkout.

 

Normal gray-lensed Ray-Bans block about 85% of all light. Cool for blocking UV, but you’re still getting about ~15% of blue and green light. That’s too much.

 

 

 

 

 

Spectra479s block 99.8% of 450-510nm, which fully encompasses blue to blue-green.

 

 

 

 

 

Carbonshades block 99.8% of 400-570 nm, which fully encompasses blue to green, so the largest range of protection according to study 1 (above) and study 2 (below).

 

 

 

 

I haven’t seen the spectral transmission data on Carbonshades, although they performed the best on Spectra479’s at-home test.

 

The popular orange-lensed Skypers block 98% of blue light and probably not too much green (as per the transmission data below and Spectra479’s at-home test).

 

 

 

 

Remember that coupon code LAGAKOS for 15% off Carbonshade and Spectra479.

 

For more steps on how to strengthen your circadian rhythms, the potential importance (and relevance) of blocking BLUE/GREEN, and a discussion of the science… head over to Patreon!

Also many more interesting tidbits and some advice, like who might need to upgrade their blue-blockers.

Three bucks a month for access to all articles and there are many other options. And it’s ad-free.

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The importance of entraining skeletal muscle’s circadian clock (and how)

“Literally, every single model of skeletal muscle circadian arrhythmia mimics aging sedentary people who skip breakfast, stay up late, and get sick.”

But first, the human studies that confirm these newer findings aren’t restricted to preclinical models: 1) a randomized CROSSOVER study; two weeks of modest caloric restriction. Same diet; either 5.5 or 8.5 hours of sleep.

In other words, circadian rhythms broke or woke (Nedeltcheva et al., 2010):

 

 

Same diet & energy expenditure + circadian arrhythmia = lose less fat and more muscle. This is basically the opposite of optimal. Large error bars because it was a CROSSOVER study, although it still managed to reach statistical significance.

And this happened despite lower 24-hour insulin AUC (Nedeltcheva et al., 2012). GRAVITAS.

 

 

And in an ad lib setting, “Laboratory studies in healthy young volunteers have shown that experimental sleep restriction is associated with a dysregulation of the neuroendocrine control of appetite consistent with increased hunger and with alterations in parameters of glucose tolerance suggestive of an increased risk of diabetes” (Van Cauter et al., 2007).

 

 

Part 2. THE BETTER PART: The muscle clock, how it works, and how to fix it.

 

 

 

Similar to other peripheral circadian clocks (eg, liver, adipose, lung, etc.), the muscle clock is entrained by LIGHT via the central pacemaker located in the SCN and feeding (via an as of yet unclear mechanism), but also scheduled exercise.

Interestingly, mice who had been subjected to a 6-hour phase advance adapted faster if they exercised early in the active phase (would be morning for humans).

 

 

Much of these data are summarized in a review in Frontiers in Neuroscience (Aoyama and Shibata, 2017).

The muscle clock is entrained by timed exercise but also feeding. This was demonstrated by showing the circadian rhythms in a subset of muscle-specific genes in fed mice were absent in fasted mice.

It is thought that the muscle clock’s function is to prepare us for the transition from the resting/fasting phase (night) to the active/fed phase (day)… and although I like that phrasing, this seems somewhat subjective (and really hard  to test/prove even on a hypothetical level).

 

 

Part 3. The BEST part: impact of various muscle clock disruptions.

Hint: THEY’RE ALL BAD.

 

For the rest of this article (including my interpretation and advice), head over to Patreon!

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