Mushrooms are awesome (P<0.05)

“Without leaves, without buds, without flowers;
Yet they form fruit.
As a Food, as a tonic, as a medicine;
The entire creation is precious.”

-weird mushroom poem of sketchy origin

Mushrooms: They have B12! When exposed to UV light, they make vitamin D2.  Protein, fibre, and selenium.  Shall I go on?

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Vitamin D, Fiat Lux, and Circadian Rhythms

Vitamin D synthesis is TEAMWORK!

Skin: 7-dehydrocholesterol + UVB = previtamin D3.
Liver: Previtamin D3 –> 25(OH)-Vitamin D3.
Kidney: 25(OH)-Vitamin D3 –> 1,25(OH)2-Vitamin D3 if you need it or 24,25(OH)2-Vitamin D3 if you don’t.

N.B. one of the major regulatory pathways occurs in skin: if you’re getting a lot of sunlight, then skin darkens to block this step.  Supplemental and dietary Vitamin D3 bypass this… but the dietary Vitamin D supply rarely produces toxicity because it’s not very abundant.  In other words, sunlight Vitamin D never reaches toxic levels.  Supps could (rare, but possible).

Disclaimer: I’m not against Vit D supps, but prefer sunlight whenever possible.

The other major regulatory step is in the kidney.  Production of 1,25(OH)2-Vitamin D3 is tightly regulated — so blood levels don’t decline until your very deficient… so 25(OH)-Vitamin D3 is a better indicator of skin production and dietary intake.

Disclaimer #2: this post is not about any of the pleiotropic effects of Vitamin D or D supps, which range in value from worthless to helpful to possibly harmful.

 

 

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CICO and rant

“Wait… what?  nutrient partitioning?”

Calories In, Calories Out should not be interpreted as “eat less, move more,” but rather kept in its more meaningless form of: “if you eat less than you expend, you’ll lose weight.”  At least then, it’s correct… meaningless, but correct.  Eating less and moving more is no guarantee of fat loss, in part, because total energy expenditure isn’t constant and there’s that whole thing with nutrient partitioning.

For obese insulin resistant folks, this is Low Carb’s strong suit: it causes “eat less, move more”spontaneously.

For some obese insulin sensitive patients, for whatever reason, their adherence and success is greater with Low Fat.  You might say, “yeah, but those suckers had to count calories.”  To that, I’d counter with: “it doesn’t matter, THEY WERE MORE SUCCESSFUL COUNTING CALORIES ON LOW FAT THAN NOT COUNTING ON LOW CARB.”  The spontaneous reduction in appetite obviously didn’t cut it.  Do not be in denial of these cases.

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Ketone bodies as signaling metabolites

*non sequiter*

One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.”  It responds to a glucose metabolite and activates transcription of lipogenic genes.  Insulin helps.  Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:

 

ChREBP

 

More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation.  Benefits of fasting sans fasting?  Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.

Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate.  Anti-aging (mostly worm studies, but still).

 

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Because chocolate

To improve a memory, consider chocolate –NYT

Dark chocolate could improve memory by 25%, but you’d have to eat 7 bars a day –PBS

Dietary flavanols reverse age-related memory decline –Columbia University Medical Centre

dark chocolate

The actual study: Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults (Brickman et al., 2014)

High flavanol group: 900 mg cocoa flavanols and 138 mg epicatechin (that’d be a LOT of dark chocolate).

Control: 10 mg cocoa flavanols and 2 mg epicatechin

Study duration: 3 months

Funding: NIH & Mars lol

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Sweet’n Low

I didn’t want to blog about the artificial sweetener study; to be honest, I didn’t even want to read it.  I just wanted to report: 1) how many Diet Cokes are we talking about; and 2) when are you going to die.

Artificial sweeteners induce glucose intolerance by altering the gut microbiota (Suez et al., 2014)

Non-caloric artificial sweeteners (NAS) = saccharin, sucralose, and aspartame. Saccharin worked the best (worst) in the mouse study, so they tested it in humans.  This was the part I found most relevant: seven healthy volunteers (5 men & 2 women, aged 28-36) who did not typically consume a lot of sweeteners were recruited and given 120 mg saccharin three times per day.  360 mg saccharin is ~10 packets of Sweet’n Low.

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Circadian Mismatch and Chronopharmacology

Part I: Circadian Mismatch

1. Artificial light at night suppresses melatonin (Lewy et al., 1980); induces “circadian mismatch.”

2. Circadian mismatch is associated with and/or predisposes to breast cancer (eg, He et al., 2014 and Yang et al., 2014).

3. In this epic study, human breast cancer xenografts were exposed to blood taken from healthy, pre-menopausal women during the day (melatonin-depleted), at night (high melatonin), or at night after light exposure (melatonin-depleted) (Blask et al., 2005). They showed that tumors exposed to melatonin-depleted blood exhibited higher proliferative activity than those exposed to melatonin-repleted blood. This has been deemed one of the most “ethical” studies to demonstrate a causal link between circadian mismatch and cancer.

4. And to make matters worse, circadian mismatch also reduces the efficacy of cancer drug therapy (Dauchy et al., 2014).  This study showed that, in a rodent model of breast cancer, exposure to light at night (circadian mismatch) enhanced tumor development and induced tamoxifen-resistance, and this was abolished by melatonin replacement.

melatonin

They also suggested a mechanism: tumors metabolize linoleate into the mitogen 13-HODE.  Melatonin suppresses linoleate uptake.

linoleate 13-HODE

 

 

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Vegetable oil fatty acids are not essential. 

They are conditionally essential at best, only if docosahexaenoic acid (DHA) is lacking.  We can’t synthesize omega 3 fatty acids, and indeed they do prevent/cure certain manifestations of “essential fatty acid (EFA) deficiency” (Weise et al., 1958), but DHA can do all that and more.  Not that I recommend this, but a diet completely devoid of 18-carbon vege oil fatty acids will not produce EFA deficiency in the presence of DHA. (“vege,” rhymes with “wedge”)

Essential fatty acid metabolism

 

The “parent essential oils” are linoleic acid (LA) and alpha-linolenic acid (ALA).  The others, which I think are more important and the truly “essential” ones are eicosapentaenoic acid (EPA), arachidonic acid (AA), but mostly just DHA.

The first manifestation of EFA deficiency is dermatitis (Prottey et al., 1975).  Some people say LA is necessary to prevent this, but it would be better phrased as “LA prevents dermatitis;” not “LA is necessary to prevent dermatitis.”  All of the evidence suggesting LA is essential is in the context of DHA deficiency.

Technically, we can convert a bit of ALA to DHA, estrogen helps, testosterone doesn’t (women have better conversion rates)… and I’d speculate that the reverse is probably easier (DHA –> ALA).

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Pharmaceutical-grade circadian enhancement?

Is it possible to improve the amplitude and resiliency of your circadian rhythms?  Is this desirable?  Yes and yes, I think.

Go the fuck to sleep.png

 

Introducing, the aMUPA mice (Froy et al., 2006).  What you need to know about ’em: they have very robust circadian rhythms.  How is this assessed?  Take some mice acclimated to their normal 12 hour light-dark cycle (LD) and place them in constant darkness (DD).  Then take liver biopsies and measure circadian genes to see how well they still oscillate throughout the dark day; this is also known as the free-running clock, and it craps out differently in different tissues depending on a variety of factors.  Most of the time, however, it’ll run for a few days in the absence of light.  Circadian meal timing also helps to hasten re-entrainment.

 

 

Note in the figure below: 1) there are two distinct lines of aMUPA mice; and 2) both exhibit a greater amplitude in circadian oscillations during free-running, or DD conditions.

strong circadian rhythms

 

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Evolution stole this dude’s circadian rhythm

I got a laugh out of this one; not for the actual content, but because of how the authors worded their findings.  They sure love their fishies.

We have two very closely related fish, both Mexican tetra, Astyanax mexicanus, one with eyes who lives on the surface, and another who’s blind and lives in dark caves (“Pachon”).  It’s thought that they were the same species one day; divergent evolution.

 

note: eyeless

note: eyeless

The blind ones are circadian arrhythmic (Moran et al., 2014).  Surface-dwellers are more active during the day than night (blue line, left figure below), and their free-running circadian clock maintains this in the absence of photic input (blue line, right figure).  The blind ones, on the other hand, exhibit no circadian rhythm in the light or dark (orange lines):

 

Circadian rhythm metabolism

 

Cave-dwellers are circadian arrhythmic.  This is both in their natural photoperiod (ie, darkness) and in light-dark conditions (which is technically an environmental mismatch, but since they’re eyeless, it doesn’t really matter).

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