Tag Archives: mortality

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.

 

circadian-image

 

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

 

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Circadian rhythms and prostate cancer

Observations:

Incidence of prostate cancer is higher among pilots, flight attendants, and rotating shift workers than the general population (RR as high as 3.0 in some cases!).

Circadian rhythms of androgens is absent & clock genes are disrupted in prostate cancer; the latter of which is reversible with melatonin which also suppresses prostate cancer progression.

Interestingly, radiation treatment is significantly more effective before 5pm than after.  I don’t know why this is; could be a spurious correlation.  Or not.

 

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Circadian disruption impairs survival in the wild. Again.

We evolved on Earth, with regular 24-hour “circadian” cycles; abandoning them is incompatible with survival.  Natural Selection does not look upon this favorably.

Natural selection against a circadian clock gene mutation in mice (Spoelstra et al., 2016)

 

The first time this was discussed, HERE, they ablated the master circadian clock, the SCN, which made the animals arrhythmic with a bollixed circadian period:

 

scn-lesion-activity-image

 

scn-lesion-period-image

resulting in significantly increased predation in the wild:

 

scn-lesion-activity-survival

 




 

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Circadian Disruption Impairs Survival in the Wild

…just read that huge disasters, ranging from Exxon Valdez to Chernobyl, may have been due, in part, to ignorance of basic principles of circadian rhythms.  Gravitas.

 

circadian rhythms

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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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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’

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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.

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Look AHEAD – Nutrition Disinformation 2.0

The day you’ve all been waiting for has finally arrived.  Results from the Look AHEAD study have been published.  When I first wrote about this study (HERE), it had been prematurely halted because the intervention was providing no benefits.  Everybody was in a state of shock and awe because Low Fat didn’t save lives.  But that was before we even had the data.  

Reminder: the “intensive lifestyle intervention” consisted of a Low Fat Diet & exercise.  The results?  Yes, they lost more weight than control, but they also took more Orlistat (of which I’m not a fan, see HERE for why):

orlistat

Orlistat = pharmaceutically enhanced low fat diet. 

Their normal diets were not healthy, but neither was low fat –>

med use

Medication use increased drastically in both groups.  The pundits have gone wild because medication use was lower in the intensive Low Fat group at the end of the study, but this is Nutrition Disinformation 2.0.  Eerily reminiscent of the recent Mediterranean Diet study, the conclusions are the same: keep eating poorly and the need for medications will increase.  You can call it a lot of things, but not “healthy.”  The alternative –>  How to define a “healthy” diet.  Period.


Significant adverse events:SAE

The only thing to reach statistical significance was more fractures in the intensive Low Fat group, but you didn’t read any headlines that said “Low Fat breaks bones.”  Imagine if that happened on low carb [sigh]  The next closest thing to statistical significance was increased amputations in the intensive Low Fat group :/

gem:History of CVD

Translation: if you were healthy at baseline, then you could tolerate a low fat diet.  Otherwise, not so much.  This is exactly what happened in the Women’s Health Initiative.

Ha

needless to say, none of the “possible explanations” they considered were Low fat diet Fail.

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How to define a “healthy” diet. Period.

Whether you’re strictly adhering to a diet or just doing your own thing, if year after year your GP is prescribing more and more medications to stave off morbidity and keep you intact, then the diet you’re following is most likely Fail.  The same is true if your body weight is creeping upward or your quality of life is creeping downward.lunchables

The glaring Fail of all 3 diets in the recent Mediterranean Diet Study for the medications criteria threw up a huge red flag.  As a brief refresher, at baseline and 5 years later, prescription medication usage was as follows:

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Mediterranean Diet Fail – Nutrition Disinformation, Part I.

Do not get your hopes up, do not pass GO!  do not collect $200.  The Mediterranean Diet.  Fail.

Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (Estruch et al., 2013)

This is one of the biggest diet studies we’ve seen in a while, and no doubt it was a very good one.  It very effectively put the Mediterranean Diet to the test.

I felt compelled to write about this study out of fear for the nutrition disinformation that it would likely inspire.  The Mediterranean Diet is associated with all good things, happiness, red wine and olive oil; whereas the Atkins Diet is associated with artery clogging bacon-wrapped hot dogs and a fat guy who died of a heart attack.  Nutrition disinformation.

If you ran a diet study with 3 intervention groups for 5 years, and by the end of the study everybody (in all 3 groups) was on more prescription medications, would you conclude any of the diets were “healthy?”  If so, then we should work on your definition of “healthy.”

Study details: big study, lasted roughly 5 years, and the diet intervention was pristine.  Mediterranean diet plus extra virgin olive oil (EVOO) vs. Mediterranean diet plus nuts vs. low fat control.  They even used biomarkers to confirm olive oil and nut intake (hydroxytyrosol and linoleate, respectively).  Compliance was good.

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