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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Also, I’m open to suggestions, so please don’t hesitate to leave a comment or contact me directly at drlagakos@gmail.com.

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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Breaking: Melanopsin Discovered in Human Adipose Tissue

PRELIMINARY FINDINGS. PRELIMINARY.

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“It is clear that centrally mediated circadian rhythms play an important role in human health and our results provide initial information about how appropriate sunlight exposure to subcutaneous white adipose tissue (scWAT) might act as a peripheral circadian sensor that contributes to metabolic health. In contrast, a lack of sufficient bodily exposure to sunlight may contribute to long-term scWAT dysfunction and the current epidemics of obesity, diabetes and cardiovascular disease.”

WUUUUUT

Melanopsin is the blue light photon receptor in our eyes responsible for relaying sunlight to the SCN to entrain the central pacemaker. Well, a group of scientists accidentally discovered it fat cells:

Subcutaneous white adipose tissue express a light sensitive signaling pathway mediated via a melanopsin/TRPC channel axis (Ondrusova et al., 2017)

Figure “C” takes the cake. Electrophysiology studies show this receptor is highly sensitive to 465 nm blue/green, meaning it’s probably definitely melanopsin.

and guess what it does?

LIPOLYSIS — see Figure “E” above. Activation of melanopsin reduces the size of lipid droplets and lowers leptin. Interestingly, it also reduces adiponectin.

 

 

They also discovered this in mice, who are covered with fur and most of their melanopsin-containing scWAT is on their bellies which would never be exposed to the sun anyway. So….

Join my Patreon! It’s fun and I’ll tell you what to do with these findings. Five bucks a month gets you full access to all articles and there are many other options. It’s ad-free and you can quit if it sucks 🙂

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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HAMMER TIME

Breakfast

Sunlight

The power of a good walk

Circadian rhythms: blocking the blues. AND THE GREENS

 

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Need vs. Optimization: Omnivores & Carnivores.

Humans are omnivores but does that mean we need to eat plants AND animals?

To address this, we first need to ask 2 questions:
1) need for what?
2) need vs. optimization?

STORY TIME

Scientists were determining the amino acid requirements of cats by feeding them semi-synthetic diets with various levels of each amino acid, one at a time. Tedious. A lot of cats x a lot of amino acids x a lot of levels of each amino acid = a lot of work. What made it even more difficult (and equally more interesting) was that they didn’t know what they were looking for — this was long before we knew what we know now about biology.

Tyrosine

Funny thing, when they got to tyrosine: below a certain level and their black cats started turning red! At an even lower level, certain neuroloogical abnormalities set in. So, how much tyrosine do cats need? Enough to maintain their beautiful black coats? I think we can all agree that the level which induced neurological abnormalities was too low. What about fur color?

 

What if female cats prefer males with beautiful black coats? So the males have a better chance at reproducing if their diet is at the higher level of tyrosine. I’d say fur color is pretty important in this #context! [how ya like ‘dem apples]

Need vs. Optimization

Note: this occurred over the course of weeks-to-months, not hours-to-days.

Note (2): unlike humans, cats are obligate carnivores. Real, actual, carnivores.

 

 

Arginine

Below a certain level of arginine and the cats looked dizzy, wobbled around, and some of them died.

Not weeks-to-months. Hours-to-days. This is what it’s like to be a carnivore. They NEED to eat meat or die rapidly (this is one of the few examples of an acute nutritional deficiency causing severe toxicity in the entire animal kingdom).

Cats have an inability to downregulate protein degradation and need arginine to dispose of the nitrogens via urea cycle. Humans just reduce burning proteins when protein intake is low.

 

 

Part 2Lobsters are omnivores and arginine is weird.

Lobster tail is rich in arginine (this might be what gives it a bit of a sweet-like flavor). If lobsters are fed an arginine-deficient diet, they go cannibal and eat other lobsters’ tails!

What does this say about lobster arginine requirements?

Need vs. optimization: they’re perfectly healthy, but is preventing cannibalism a “need?”

. .  .   .     .        .             .                     .

 

 

So, I ask again: Humans are omnivores but does that mean we need to eat plants and animals?

One retrospective study showed stroke victims who had consumed blueberries the day before showed significantly less cognitive decline post-stroke than those who hadn’t. Blueberries. Not green tea, blackberries, or dark chocolate. Blueberries. Do humans need to eat blueberries?

What if this was confirmed in a double-blind RCT? Is preventing post-stroke cognitive decline a need or an optimization?

Which is more important to you?

I didn’t have it in me to put this behind a paywall because while I think the answer is getting simpler & simpler (eg, SunlightHunger-Free Diet[s] and DietFitshot Blue-Blockers, etc.), fad diets are getting weirder & weirder. Just eat like an adult.

If you like my style and would like to see my paywalled stuff (or if you just want to show some support) head over to Patreon! Full access for a five bucks a month and there are many other options. It’s ad-free and you can cancel if it sucks 🙂

Also, I’m open to suggestions, so please don’t hesitate to leave a comment or contact me directly at drlagakos@gmail.com.

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 HERETrueDark is running a pretty big sale HERE.  BLUblox just upped their game with their 550‘s.
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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Is gluconeogenesis demand-driven? answer: it depends (#context strikes again!)

Context #1. The easiest way to explain gluconeogenesis (GNG) is how it relates to starvation. If you’re not eating food, your brain still needs a steady supply of fuel. Mostly glucose at first (ketones come later), but since you’re not eating anything, glucose comes from hepatic GNG (huge potential supply*) or glycogenolysis (limited supply). *One of the precursors for GNG, glycerol, comes from stored fat (which you’ll die of something else before you run out of stored fat bc GNG).

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In this case, it is mostly true that GNG is demand-driven.

 

If you’re interested in this, more HERE.

 

Context #2. Protein (which also contains GNG precursors) doesn’t acutely increase glucose. But you might think protein does convert to glucose via GNG but protein also induces a splash of insulin which is why blood glucose doesn’t rise. Read this blog post at least up to the awesome Fromentin study: “8% of the blood glucose produced under optimal gluconeogenic conditions came from dietary protein.” But also check out the Conn & Newburgh studies. And Gannon.

 

 

This is usually the reason recreational keto dieters say they can be high protein, which either ends up looking like PSMF or it’s probably not very ketogenic (which doesn’t really matter in this #context; protein is restricted in therapeutic ketogenic diets).

#BenignDietaryKetosis #BDK

 

 

For the rest of this article (or if you just like what I do and want to support it) head over to Patreon! Full access for a measly five bucks a month and there are many other options. It’s ad-free and you can cancel if it sucks 🙂

Also, I’m open to suggestions, so please don’t hesitate to leave a comment or contact me directly at drlagakos@gmail.com.

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 HERETrueDark is running a pretty big sale HERE.  BLUblox just upped their game with their 550‘s.
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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Context #3. the mouse doctor is in 🙂

Context #3b. Chronic high protein.

Context #4. Random thoughts on animal foods.

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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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Brain Health: Intermittent Fasting or Caloric Restriction

Brief note: the definitions of IF and CR vary widely. For the sake of simplicity, in this article, if IF results in weight loss, then it’s also CR. CR, by definition, results in weight loss and typically includes ~3 meals a day. Neither diet specifies macros. Weight loss is a confounder to keep in mind.

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For example, in this 3 month-long study, 30% CR was compared to an increased unsaturated fatty acid group and a control group (Witte et al., 2009). CR group lost weight whereas the other two groups actually gained weight (unintended). In this study, 30% CR resulted in an apparently pretty impressive improvement in memory:

 

 

HOWEVER: The actual dietary changes in each group were… interesting (see Table S1) — the control group ended up doing dietarily almost exactly what the CR group did… so why didn’t their memory score improve? Why didn’t they lose weight? I don’t know, but something seems fishy.

CR garners zero points for this.

 

 

Next on the docket is a systematic review (Benau et al., 2014), which concluded: “The combined results are equivocal: several studies report no observable differences as a result of fasting and others show specific deficits on tasks designed to test psychomotor speed, executive function, and mental rotation.” That was based on 10 studies. Given the nature of human biology, “no effects of IF” would not have been unexpected. Kinda surprised at all of those negatives.

The ice age fairy tales go something like this: no food for a day or two improves your cognitive capacity, makes you sharper so you can get your next meal (be it via hunting, gathering, or whatever).

I’m not anti-IF; in fact, I think everyone in weight maintenance should be able to go through the night without the need to wake-up to eat. I’m just commenting on the available studies by people who aren’t selling books on the topic.

For the rest of this article or if you just like what I do and want to support it, head over to Patreon! Five bucks a month for full access. It’s ad-free and you can cancel if it sucks 🙂

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 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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Intermittent fasting is nothingsauce

So Twitter got supermad when I said the human studies on intermittent fasting are not compelling. Not the anecdotes or n=1’s. The actual human studies.
And instead of “not compelling,”
I may have said “nothingsauce.”

Hilarity ensued. I was bombarded with
ALL.
THE.
ANECDOTES.

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Someone was kind enough to send me all the proof that I was wrong. Here are the 5 non-Varady studies, reviewed.

Tl;dr: as long as you’re not eating like a child, “Eating > not eating. QED.”

 

 

Alternate day calorie restriction (ADCR) improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma (Johnson et al., 2006)

Study design: n=10, 8 weeks, NO CONTROL GROUP. Every other day they ate 20% of normal and ad lib the other days. This would’ve been much cooler if they included a 40% caloric restriction and weight maintenance (WM) control groups. The former to see if ADCR was superior to a similar reduction in energy intake and the latter because people behave differently when their being observed (regardless of which group they’re in) (few studies include a WM control group).

Result: body weight declined by 8%. Is that worth having nothing but a snack every other day? How about compared to 40% CR? Nothingsauce?

Oh yeah, uric acid increased and BDNF decreased. So, gout, kidney stones, and cognitive deterioration. Yummy nothingsauce.

 

The effects of modified alternate-day fasting diet on weight loss and CAD risk factors in overweight and obese women (Eshghinia et al., 2013)

Study design: similar to the above, and also lacking a control group.

Result: BW declined by 7%.

Critique: same. No control group. Would this have been better than CR or anything else? They basically just say “it’s relatively safe;” but it’s not, really… and some forms of intermittent fasting can have harmful side effects.

 

For the rest of this article (including some LOLZ & facepalming), head over to Patreon! It gets better (or worse, depending on how you look at it): metabolic mayhem, rebound hyperglycemia, some circadian chicanery #eTRF, and much more.

And stay tuned: since BDNF actually declined in the Johnson study, I’m following up with a review of intermittent fasting vs. various aspects of cognition, memory, mood, sleep, etc.

On Patreon, five bucks a month gets you full access. It’s ad-free and you can cancel if it sucks 🙂

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. TrueDark is running a pretty big sale 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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Isocaloric MCT-supplemented ketogenic diet may improve cognition in Alzheimer’s patients

Two-thirds of the time, it works half of the time 🙂

Yes, we all pretend to know the mechanism how ketones may improve cognition in MCI/Alzheimer’s, but we don’t. Nobody does.

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-Preferred fuel? kinda meaningless

-Niacin receptor? if so, where are the studies on niacins or even nicotinamide riboside (the latter is kind of unrelated, but should yield some niacin in vivo) (P.S. blog post on NR in the works).

-Epigenetics? Idk. Of those, I’d say probably all contribute somehow.

Ketogenic Diet Retention and Feasibility Trial #KDRAFT (Taylor et al., 2017)

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The power of a good walk.

I walk a lot. Usually after meals; sometimes for sunlight & exercise, other times just because it’s a habit and I like doing it. Sometimes even twice a day (eg, after breakfast and lunch).

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But seriously, it’s way healthier than I thought. This has been in-and-out of the news a few times over the years, but I was always like, “duh,” until I finally looked at the numbers. In some cases glucose & insulin excursions are down 20, 30, even 50%! (mostly depending on the distance covered, but also speed) (but mostly distance).

LOL there are like, a million studies titled “breaking up prolonged sitting improves everything” haha

And since the effects are acute, a lot of well-controlled RCTs — the flipside of that is you have to do it every day… my opinion is that total glycemic exposure over the course of your life is an important metric (more on the MOA below); and with the rise of continuous glucose monitoring systems, this will be proven true.

Exhibit A. The biggest intervention (VERY long walks, 5-6 hrs/d), but most profound results (Manohar et al., 2012)

 

 

 

Exhibit B. Prolonged sitting vs. a 30-minute walk vs. 1.5 minutes walking every 30 minutes throughout the day (Peddie et al., 2013). Both of these interventions are very doable, imo.

In this study, the total daily exposure was 49, 47, and 30 mM / 9 h. 90 seconds of walking every 30 minutes cut glucose by almost half. HALF. Insulin also dropped precipitously. If you work a sedentary job, MAKE TIME FOR THIS. EVERY DAY. GO NOW.

For the rest of this article (it’s good, I promise!) and much more (or if you just like what I do and want to support it), head over to Patreon! Five bucks a month for all 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 please don’t hesitate to leave a comment or contact 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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Brain health: more easy steps

When describing the length of one of his students’ fingers, the great classical guitarist Andres Segovia said “she has more long fingers than anyone else” — he meant longer fingers… English wasn’t his strong suit haha

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Maximize sunlight exposure, minimize artificial light (or at least get some hot blue blockers). Get at least some physical activity. Those are the basics. Moving on…

Tl;dr: Beef heart, calf liver, and maybe some supps 🙂

Coenzyme Q10

Coenzyme Q10 isn’t approved for the treatment of anything, but hear me out.

We have about a gram of CoQ10 in our entire body, concentrated in the mitochondria of highly oxidative tissues (Saini, 2011). It is found at around 60-110 ug/g in heart (eg, Ercan and El, 2011Aberg et al., 1992).

 

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