Tag Archives: circadian rhythm

Fasting, circadian biology, and epigenetics

From the best I can gather, one of the more immediate players in circadian biology is the coenzyme nicotinamide adenine dinucleotide (NAD), which participates in a variety of redox reactions.  Fasting increases the intracellular NAD/NADH ratio, setting off a cascade of events involving epigenetics and the regulation of metabolism.

NAD activates sirtuins, a family of deacetylase enzymes.  This is epigenetics.

SIRT1

 

SIRT1 regulates the activity of BMAL1 and CLOCK, two circadian transcription factors, which target NAMPT, an enzyme that synthesizes NAD.  And in a curious feed-forward mechanism, CLOCK and BMAL1 enhance SIRT1 expression… genetic deletion of any of these players induces insulin resistance (Zhou et al., 2014), and this can be recapitulated with constant darkness: reduced BMAL1 and SIRT1, hepatic insulin resistance; the latter can be reversed with resveratrol (which may or may not be acting through SIRT1; this is controversial).  While alcohol does no great favors for circadian biology, if you’re going to imbibe, perhaps a resveratrol-rich Argentinian malbec served, and this might be the important part, at night, when all of this stuff is going on… coincidentally [fortunately], that’s precisely when most choose to imbibe.

Continue reading

Angiotensin: more than just blood pressure.

Pathologically low blood pressure can lead to shock & death.  Angiotensin II is there to prevent that, but it does much more.  A bit non-sequiter, perhaps.

This is what I call teamwork: low blood pressure detected by kidneys –> secretes renin.  Angiotensinogen (liver) is cleaved by renin to Angiotensin I.  Angiotensin Converting Enzyme (lungs [among other tissues]) cleaves angiotensin I into angiotensin II.

RAAS

Angiotensin II increases blood volume and restores blood pressure.  Good if you’ve lost a ton of blood fighting a wild beast; not good if you’re an overweight pen pusher on potato chips.  ACE inhibitors reduce angiotensin II, lowering blood pressure.  ACE is present in lungs probably because it deactivates bradykinin.  ACE inhibitors prevent this which might contribute to one of their side effects, a persistent dry cough which makes these drugs intolerable for many.  One alternative is angiotensin II receptor 1 blockers, or “ARBs.”


If anyone in pharma reads my blog (doubtful, unless they are monitoring for people to polonium-laced blow-dart), this will be their favorite post because I think ARBs are an interesting class of drugs.

If diet and weight loss are inadequate, telmisartan might be the next best thing to manage hypertension in diabetics:  Telmisartan for the reduction of cardiovascular morbidity and mortality (Verdecchia et al., 2011) –> effective at reducing mortality in patients with diabetes.

Efficacy of RAS blockers on cardiovascular and renal outcomes in NIDDM (Cae & Cooper 2012)  –> reduces morbidity and slows progression of renal disease (both hypertension and diabetes contribute to [irreversible] kidney damage, and frequently occur together, which makes this endpoint particularly relevant).  Hyperglycemia should be managed via diet, of course, and ARBs would need to be tested in people following something other than a Western diet (although said people may not even need treatment in the first place) (just thinking out loud here.  Or typing/whatever.)

But enough about blood pressure (<– boring); on to the more interesting stuff:

It started here: Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice (Duchemin et al., 2013)

Then: Candesartan prevents impairment of recall caused by repeated stress in rats (Braszko et al., 2012)

And: Anti-stress and anxiolytic effects of [candesartan] (Saavedra et al., 2005)

[Candesartan] prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding (Saavedra et al., 2006)

[Candesartan] ameliorates brain inflammation (Benicky et al., 2011)   brain inflammation induced by chronic exposure to artificial lights causes depression-like symptoms (in mice) (probably humans, too)

Finally, a human study: Candesartan and cognitive decline in older patients with hypertension (Saxby et al., 2008)

And then there’s this: Angiotensin receptor blockers for bipolar disorder (de Gois et al., 2013)


No mechanistic stuff because, well, I have no idea how it works.  On one hand, it might seem obvious that stress & anxiety can raise blood pressure, so something that lowers stress & anxiety could lower blood pressure.  Candesartan appears to do both (cause <–> effect?).  There are two unique properties of candesartan to note: 1) it gets into the brain; and 2) it leads to increased levels of angiotensin II (which presumably can’t do much because candesartan blocks the receptor for angiotensin II).  Perhaps angiotensin II targets a different receptor?  ARBs might blunt angiotensin II-induced CRH secretion, leading to anxiolysis, stress-tolerance, and pro-cognitive effects (that speculation was made possible by a thread on Avant Labs’ Forum and a few posts by Jane Plain on CRH [eg, here & here]).

Oh yeah, ARBs also prevent cafeteria diet-induced weight gain, insulin resistance, and ovulatory dysfunction [in rats] (Sagae et al., 2013).  And are sympatholytic like bromocriptine (Kishi & Hirooka 2013).

“The Angiotensin-melatonin axis” (Campos et al., 2013).

just sayin’

calories proper

Melatonin is the chemical expression of darkness.

Melatonin is secreted from the pineal gland, the seat of the soul, the third eye.   Pinealectomy induces circadian arrhythmia and has interesting effects on adipose tissue biology.

Exhibit A.  In 2004, Alonso-Vale and colleagues showed that 6 weeks after pinealectomy, [melatonin-deficient] rats subjected to fasting exhibited an impaired energy conservation response.  That is, they lost more weight and significantly depleted their adipocytes:

pinealectomy

Continue reading

Pharmaceutical-grade circadian manipulation.

BMAL1 and CLOCK, ‘positive’ regulators of circadian gene expression, activate transcription of the negative regulators Per, Cry, and Rev-erb.  PER and CRY inhibit BMAL1 and CLOCK, whereas Rev-erb inhibits Bmal1.  It is said that Rev-erb is “an important link between the positive and negative loops of the circadian clock.”  You don’t really need to know any of that to follow this blog post.

circadian genes

Continue reading

Circadian disruptions impact behavior and metabolism in a tissue-specific manner.

The control of circadian gene expression is complex, with layer upon layer of suppressors and enhancers, numerous transcription factors, and a lot of interactions.  A gross oversimplification: Clock and Bmal1 are positive regulators of circadian gene expression; Per and Cry are negative (you don’t really need to know any of this).

 

Some pretty cool progress has been made in examining the effects of global and tissue-specific deletion of circadian rhythm-related transcription factors.  Bear with me 🙂

For example, global Bmal1 knockout mice (ie, mice that don’t express Bmal1 anywhere in their whole body.  Zero Bmal1.  Nil.) (Lamia et al., 2008).  These mice are obese, and exhibit impaired glucose tolerance yet improved insulin sensitivity.

Continue reading

Implications of the circadian nature of ketones.

Ketosis.  Happens during starvation and also by restricting carbohydrates (and protein, to a lesser degree)… might be important for epilepsy and bipolar disorder, too.

ketogenesis

Ketostix measure urinary acetoacetate (AcAc) and reflect the degree of ketosis in the blood probably about 2-4 hours ago.  Blood ketone meters measure beta-hydroxybutyrate (bHB) right now.  bHB fluctuates to a greater degree, eg, it plummets after a meal whereas AcAc takes longer to decline.  AcAc/bHB is usually around 1, but increases after a meal (Mori et al., 1990):Ketone body ratio

Conversely, when glucose levels decline and fatty acid oxidation increases, liver redox potential drops which reduces AcAc/bHB.

Continue reading

Circadian biology: jet lag, mood, & potential role of BP regulatory peptides

There are enough connections here to suggest it’s an interesting rabbit hole.  Besides the effects of ARBs & desmopressin on mood and cognition, blood pressure regulation is not interesting <– fact.  But if it ties into fertility, circadian biology, and seasonal changes in how we should be doing things…

Way back in 1998 when I was graduating high school, Murphy and colleagues were screwing with “light-entrainable” and “food-entrainable” oscillators of circadian rhythmicity (1998).  They did this in two lines of rats, one with intact vasopressin signaling and one without.  With little mechanistic work, they showed vasopressin mediates circadian effects driven by light; and rats without vasopressin were more entrainable by meal timing.  N.B. in addition to the posterior pituitary, vasopressin is also found in the famous circadian light-regulated SCN neurons (Rosving 2010).

While it is speculated to play a role in social behaviors and sexual motivation, vasopressin is primarily known for its anti-hypotensive effects.  When plasma volume drops, vasopressin is secreted to decrease urinary water loss and increase blood pressure.  This is antagonized by alcohol, which is thought to be one reason why alcohol can dehydrate you.

Continue reading

Fiat lux

Humans have a peculiar relationship with light: differences in brightness, wavelength, and even circadian timing all have biologically meaningful effects.

The right combination of timed light exposure and hot Blue Blockers is probably not only the solution to jet lag, but also to a whole host of other health problems.  Maybe you can’t completely escape the bane of the modern condition, but there are some tools, widely available, accessible, and even free in some cases (eg, sun), that may be of benefit.  

The frequency of light impacts circadian rhythms. 

Wright showed this in 2004.  The subjects wore special glasses with LEDs that emitted light of varying frequency for 2 hours, from 6 to 8 in the morning (65 uW/cm2).  Salivary melatonin measurements commenced at 7 pm.  As seen in the figure below, blue but not red light induced a significant phase advance in melatonin onset:

AM blue light phase advance

And for the whole group:all colors

Continue reading

The hot Blue Blocker Experiment

The eyes are the window through which light must pass, regardless of sightedness.

FACT: we don’t realize the importance of circadian biology.  Or at least we don’t act like it.  And we’re certainly not going to turn off our iPhones & laptops when we’re supposed to.  Potential intervention: hot Blue Blockers.  They’re a band-aid, no doubt, but they might help.  Jane Plain raised a potential concern with this here.  In brief, we can block blue light from molesting circadian biology with hot Blue Blockers, but extraocular light exposure could betray such feeble attempts.  

It seems to be based, in part, on an experiment by Campbell & Murphy (1998).  They tried to experimentally screw circadia by exposing an isolated spot of skin on the back of the knee to 3 hours of bright light.  Melatonin data weren’t shown, but the authors said they mirrored body temperature:

Campbell Murphy

It worked (for body temperature, at least).

But FAR more interestingly, Czeisler showed bright light-induced melatonin suppression in blind people was reversed if they covered their eyes!!!Czeisler

This is wild.  Unless there is something CircadianlyMagical about the skin on the back of the knees, then these findings refute those of Campbell.  Czeisler’s findings were confirmed by Hatonen (1999) in sighted people: black circles = no light exposure; open squares = full-face light exposure with eyes closed (partially blunted melatonin secretion); and open circles = full-face light exposure with eyes open (fully blunted melatonin):Hatonen

Of note, blind eyes and closed eyes aren’t the same as covered eyes.  There were, however, 2 people who exhibited no melatonin inhibition with closed eyes.  Perhaps some are intrinsically more light-resistant, or have robust eyelids or something.


It seems as though we needn’t worry about Campbell’s findings after all because they were directly refuted by Hebert (1999):Hebert

The light exposure protocol in both of the studies was identical: 13000 lux to the back of the knees for 3 hours.

Print

Perhaps we should’ve demanded to see Campbell’s melatonin data?  Or not.  Lushington confirmed Hebert’s findings (albeit with only 11000 lux):Lushington

In 2000, Lindblom blasted 10000 lux at a much larger surface area – chest & abdomen – and found no effect on melatonin:Lindblom

The eyes are the window through which light must pass, regardless of sightedness.


Was all of this blog post irrelevant until now?  Maybe. (sorry)

Sasseville compared bright light-induced melatonin suppression in people wearing boring shades (top graph) or hot Blue Blockers (SolarShield Orange Lenses) (bottom graph):

Sasseville

The orange lenses transmit slightly less light than the boring ones (32 vs. 52%), so they accounted for this by hitting the hot Blue Blockers with more lux (4000 vs. 2200… this is directly in their faces, so it couldn’t be >10000 lux like in the previous studies)… this still resulted in more irradiance hitting the hot Blue Blockers, so the odds were stacked against them (I think, #physics).

Lux: luminous flux per unit area
Irradiance: electromagnetic radiation per unit area

Melatonin suppression is important, but what we’re really talking about here is SLEEP.  And in 2009, Burkhart showed just that.  When assigned to hot Blue Blockers (NoIR Polycarbonate Lasershields), sleep quality markedly improved:

Burkhart

(granted, randomization was horribly bollixed, but it is what it is).


Sasseville came through again in 2009, this time for shift workers.  Their subjects had to wear hot Blue Blockers (Uvex Skypers) when they were leaving work [in the morning].   It worked.

Sasseville II

In sum, don’t sweat extraocular light exposure, and anyone with a metabolic disturbance who lives a remotely modernized existance, paleo or otherwise, might benefit from these.

Flash forward to 2017… Circadian rhythms: blocking the blues. AND THE GREENS

calories proper

Become a Patron!

hot Blue Blocker experiment: expectations = none.  I’m a “non-responder.”  This might not be the best time of year to conduct such an experiment, but the combination of high motivation and low patience prevailed.  And I still use my computer a lot at night.

This is a diary of sorts.
day 1: initial observations.
Started wearing them about 2 hours before sunset.  Outside sky prior to dusk looks like insane alien invasion.  But creepy red bathroom light looks exactly the same.  #physics.

Morning of day 2: Usually wake once or twice in the middle of the night, but didn’t…

Evening of day 2: Started rocking the shades 2 hrs prior to bedtime.  Same awesome yellow-ness and crisp resolution of the sunset.  It really looks like another planet.  I also could’ve probably stared directly at the sun with impunity (but didn’t).

Morning of day 3:  new conclusion: I think I usually wake up a few hours prior to dawn, but hot Blue Blockers prior has shifted this to a few hours earlier.

Morning of day 4:  same!  Hot Blue Blockers make me need to pee 4 hours sooner after falling asleep <– I’m a “responder!”
Mood, sleep quality, & energy levels stable <– “non-responder,” but willing to give it more time.  Burkhart’s study showed a near doubling of sleep quality, but it took 3 weeks.

P.S. FWIW, I’m wearing these, so definitely not going out in public places.

It’s paleo: Hypothyroidism impairs reproductive success in bitches.

Kisspeptin was discovered in Hershey, Pennsylvania, and was named after Hershey’s Kisses.  It has 776 pubmed citations going back to 2001, and may (or may not) play a key part integrating circannual reproduction patterns and seasonal thyroid function.

Kisspeptin was originally identified as a protein that inhibited breast cancer and melanoma.  This might also provide insight into the WHO’s recent declaration of shift work as a “probable” carcinogen.

Exhibit A. TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin (Klosen 2013)

In this study, TSH infusion in short-day adapted hamsters (who are in winter non-breeding mode) induced summer phenotype & kisspeptin.  It also fattened them up a bit.  These TSH secreting neurons express melatonin receptors, but not those for TRH or T3 (Klosen 2002), so it is said to go something like this:Kisspeptin feedback diagram

Continue reading