Category Archives: Vitamin D

Circadian rhythms and cancer: potential mechanisms

Humans are incredible omnivorous beasts that can thrive on a great variety of diets, but crumble if you mess with their sleep.

Circadian arrhythmia is thought to be a driving force behind a few types of cancer.  But how, exactly, does seemingly harmless things like artificial light, skipping breakfast, or jet lag actually promote tumorigenesis?  There are many potential mechanisms, and I’d bet different circadian disruptions promote different cancers in different #contexts.

In some cell types, circadian disruptions which dampen amplitude increase proliferation.  This has led to some researchers to believe a robust circadian rhythm per se is tumor-suppressive.  In agreement with this, many tumor suppressors are direct targets of circadian transcription factors.  As was observed in some skin cancers, you may want suppressed proliferation at some times of the day but not others, so the tissue can renew properly.  But you don’t want, for example, skin cells to be proliferating while they’re being exposed to UV light, so this process happens at night (in circadian fashion).

Circadian transcription factors also directly interact with endogenous antioxidant systems.




Cancer clocks out for lunch: disruption of circadian rhythm and metabolic oscillation in cancer (Altman, 2016)


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Circadian timing with REV-ERB and PERIOD

The circadian proteins Bmal and casein kinase (CK) enhance and degrade Period (PER), respectively, by completely different mechanisms.  Both are necessary, but at different times of day… #context

Gross oversimplification: the Bmal party is kicked off in the morning by LIGHT, and acts to increase PER by night (among many, many other things).  As the day progresses, REV-ERB the Repressor slowly shuts down Bmal, so that peak PER occurs in the evening and doesn’t carry over until the next morning.  GSK3b activates REV-ERB the Repressor.  Lithium puts the system in fast forward, leading to phase advance* and ZZZ’s when timed right, at night… I think


Lithium GSK3b image


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LIGHT timing for circadian entrainment

Basically, this much is pretty obvious now: LIGHT and food in the morning + darkness after sunset = proper circadian entrainment.  But the how is pretty cool; LIGHT affects different biochemical pathways at different times of the day, which is how it can either advance or delay your circadian phase.

LIGHT entering the eyes is perceived by ipRGCs which then dish out glutamate and PACAP.  These mediators go on to activate receptors in the SCN (the “Master Clock”).

Depending on the time of day, glutamate and PACAP affect different pathways.


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Dopamine and breakfast

T.S. Wiley wrote a lot about the protein-rich breakfast; here’s my understanding of her take on it.

N.B. I highly recommend her book, Lights out: sleep, sugar, and survival.

Quotes are mainly taken from the text. I’ve tracked down some of the cites; the rest are in the back of the book, albeit somewhat unorganized :/

Part 1. We naturally have a cortisol spike first thing in the morning, known as the Cortisol Awakening Response (CAR).  This peak, which can be screwed up by artificial light at night or a big evening dinner, helps support morning light-induced dopamine.


Dopamine is great, but may induce impulsivity if it’s unfettered.

Enter: the protein-rich breakfast. It provides tryptophan and a bit of insulin to promote serotonin synthesis (eg, Manjarrez-Gutierrez et al., 1999).

Not enough serotonin to make you crazy, just enough to balance the dopamine = impulse control.

~ circadian balance achieved ~

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Sunlight and the circadian rhythms in your skin

SUNLIGHT entrains circadian rhythms.  It gives us vitamin D and melanin; it can give us a sunburn, but some evidence suggests that it does NOT cause skin cancer.

“lifetime sun exposure appeared to be associated with a lower risk of malignant melanoma” (Kennedy et al., 2003)

Anecdotally (or so I’ve heard), skin cancer frequently develops in places not regularly exposed to sunlight.  If true, this flies in the face of the dogma which goes something like this (Tl;dr): ultraviolet light from the sun penetrates into the nuclei of skin cells and damages DNA; if the right [wrong] genes are altered/mutated and the mutated cells proliferate, it can develop into a tumor (gross oversimplification).

So, what might explain the discord?

LIGHT entrains the circadian clock; this includes regulating cell cycle genes.  Aberrant cell cycling may lead to out-of-control proliferation in the wrong context, aka cancer.  Interestingly, some evidence suggests that part of the circadian regulation of cell cycle genes includes turning down proliferation when exposure to UV light is expected to be high (daytime); so DNA repair machinery has more time to fix any cell cycle genes that are mutated by UV light before the cell proliferates (Geyfman and Andersen, 2009) = lower chance of creating and propagating a potentially cancerous skin cell.

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Dark Skies and Light Pollution

The mission of the International Dark-Sky Association is “to preserve and protect the night time environment and our heritage of dark skies through quality outdoor lighting.”  They’re all about stressing the importance of lighting on health, light pollution, and some really interesting stuff.

For more on the topic, check out their website,, and Paul Bogard’s book, The End of Night: Searching for Natural Darkness in an Age of Artificial Light.

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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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