THE YEAR IN CIRCADIAN REVIEW...........2023 key papers

A day in your life on Earth is just a collection of hours, but a life to a person is a collection of memories that build a coherent wisdom.  It requires you to be awake during the day and asleep when the sun is absent.  This rule is axiomatic for diurnal mammals.  The final blog of 2023 brings you the best papers to illuminate the ideas in this opening paragraph.

Why is melanopsin/retinol key to understanding all human disease? In physics, time in itself, absolutely, does not exist; it is always relative to some observer or some object because of how light builds it. Without a clock I say 'I do not know the time’. You do not. This is why evolution built one in the SCN and uses melanopsin and retinol to control the peripheral clock genes to drive renovation. The SCN clock must run fast than the melanopsin mechanism to make sense of the chaos around us.

The implications of this statement are far reaching. Without matter time itself is unknowable. Time is a function of matter; and matter therefore is the clock that makes infinity real. This is why the time crystals in you are coded for DNA. If you ask me, the brain, in fact all neuroectoderm was innovated by evolution to tell time. I think it is the single most important function of the nervous system.

Time is a function of how entropy flows and entropy flows according to how heat flows in a system. Mitochondria create heat when they are irradiated by light. Clocks become more accurate the higher periodicity they have. Daily & seasonal light alters the circadian periodicity of clock genes. The diurnal changes of sunlight from sunrise to sunset change the amount of water made in your mitochondria. Sunlight creates water.

Biology is so difficult to explain without understanding what light is doing at the subcellular level. What an impressive cycling process like a multifunction relay signaling flow switch multiplied to reduce. Wouldn’t it be so much easier to just use numbers. Then everyone would get it crystal clear even the fifth grader.

1. Sato and Sato said in their July 2023 paper that "the circadian regulation of metabolism for health and disease, “dominates” metabolic homeostasis =  light trumps food.  Imagine that.

https://academic.oup.com/endo/article-abstract/164/7/bqad086/7186648

2. Light disrupts clock gene BMAL1.  CLOCK and BMAL1 are positive regulators of circadian gene expression, and PER and CRY are the negative regulators that operate under day and night cycles.

And in a curious feed-forward mechanism, CLOCK and BMAL1 enhance SIRT1 expression… genetic deletion of any of these players induces insulin resistance.  Indoor life under manufactured light decrease SIRT 1 causing insulin resistance.  No food needed.  Do you hear that?  

Did you know in in 2023 we found out that the very same core clock gene, Bmal1,that impaired glucose absorption in the intestine in mice also happens in humans?  No food needed.  Just bad light can do it.  This goes on to affect systemic glucose homeostasis.  Imagine that.  https://academic.oup.com/endo/article/163/9/bqac119/6651710

3.  SIRT 1 lowers with INDOOR living.

Why is this a big deal?

NAD+ is one of the more immediate players in cytochrome 1 that is a huge driver of circadian biology in humans.  It is the coenzyme called nicotinamide adenine dinucleotide (NAD+). It participates in a variety of redox reactions in the matrix that help generate DDW.  Solar exposure and fasting work with light frequencies to slow ECT flow and this can increase the intracellular NAD/NADH ratio if the light environment is dominated by sunlight.  It won't do this with artificial light.  It lowers NAD+.  This is what sets off a cascade of circadian events that can destroy tissues because they involve epigenetics and the regulation of growth and metabolism of man.  LIGHT DOES THIS.  NOT FOOD OR FUELS.

SUN + fasting -> NAD+ -> SIRT1 -> BMAL1/CLOCK -> NAMPT -> NAD+

NAD+ major effect is to activate the sirtuins as the reaction above shows.  This is a family of deacetylase enzymes.  When you understand what UV and IR light are doing to a matrix, you can see why fasting could potentially be seen as a circadian reset biohack.  It won't work in fake light when ALAN is present.

SIRT1 also activates PGC1a in liver (Rehan et al., 2014), which enhances fatty acid oxidation, at a time when HUMANS require it during sleep in the absence of ALL light at night.   https://www.frontiersin.org/articles/10.3389/fnmol.2018.00496/full

4. Centralized scientism relies on mice studies to create beliefs they hold to be truthful as part of the dogma.  Did you know despite the importance of the mouse in centralized research, the levels of circulating gonadal steroids across the estrous cycle are not established with any temporal precision?  True.  The observations made in the study once again prove the decentralized axiom that you can never learn the truth from lab mice without light controls.  Why?  The paper provided the first detailed assessment of fluctuating gonadal steroid and reproductive hormone levels across the mouse estrous cycle and it indicated that species differences exist between mice and other spontaneously ovulating mammalian species.  Imagine that.  https://academic.oup.com/endo/article/164/6/bqad070/7159815

5. Many textbooks on biochemistry and endocrinology will tell you growth hormone is released during slow wave sleep.  It is simply not true.  POMC controls it in the medial basal hypothalamus.  

GH-releasing hormone (GHRH) and somatotropin release-inhibiting factor (SRIF; somatostatin). GHRH stimulates GH release whereas SRIF inhibits GH. Human males exhibit life long ‘pulsatile’ secretion versus female's who exhibit a ‘continuous’ secretion from their somatotrophs.  One sex continuously makes endogenous UV light biophontons in the hypothalamus and one does not.   UV light stimulates POMC translation and cleavage.   

• Slow waves (SWs) are thought essential for sleep-dependent recovery processes.
• Their amplitude, incidence, frequency and slope reflect synaptic strength.
• Their regulation has been postulated to be independent of circadian phase by centralized dogma.
• We now have data below that all characteristics of SWs depend on circadian phase control of the SCN

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503801/

When melanin is degraded by hypoxia it becomes norepinephrine and dopamine.   Norepinephrine decreases GH secretion by increasing the release of somatostatin. This central effect, due to the activation of α1-adrenergic receptors, has been demonstrated in mammals.  

Dopaminergic agonists have been shown to increase GH release, as well as to decrease hypoglycemia-, levodopa-, and arginine-induced increases in GH release. Because dopamine can increase both GHRH and somatostatin release, it appears that this balance can change under different physiological conditions.  Light stress is critical here.  

The dorsal longitudinal fasciculus (QE #47) is found within the dorsal brainstem tegmentum. It passes through the periaqueductal gray matter and contains both ascending and descending fibers.

The ascending fibers pass from the reticular formation (sleep center) passing to the hypothalamus thus transmitting information related to the viscera. In turn, the descending portion arises also from the hypothalamus and passes to a variety of brain areas responsible for processing pain, cardiorespiratory functions and the autonomic system. Finally, the efferent fibers will also terminate on the preganglionic fibers of the autonomic nervous system.

https://academic.oup.com/jes/article/6/11/bvac146/6702162

6.  Kids with high risk type 2 diabetes should have their urine assessed for circadian dysruption.  When melanin degrades internally more catecholamines are made and this will be filtered through the kidneys.  Urinary catecholamines are a great marker endogenous melanin destruction.  

https://academic.oup.com/jes/article/7/2/bvac190/6889558

7. Why is shift work always associated with metabolic issues in humans?  Experimental circadian misalignment data have shown minimal effects on steroidogenesis at the adrenal gland level.    The same was not true of the sex steroids.  This is why gonadal cancers occur so often in shift workers. This dichotomy also predisposes night-shift workers to metabolic ill health. The decentralized clinician should always look at  the adrenal steroid cascade, including cortisol and the main adrenal androgen 11-ketostosterone.  Why?  It should always be evaluated during the biological morning in the case of shift workers because testosterone and estrogen, are highly dependent on the shift-work schedule.  https://academic.oup.com/jes/article/6/12/bvac153/6731224

PCOS is characterized by a constellation of interrelated reproductive abnormalities, including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It is frequently associated with insulin resistance and obesity. These reproductive and metabolic derangements cause major morbidities across the lifespan, including anovulatory infertility and type 2 diabetes (T2D).  Most centralized textbooks report PCOS has no known cause.  Shift work and light and night are the main offender.  The paper above explains why it happens.  No more mystery for PCOS ladies.  Turn the lights off after sunset and avoid all nnEMFs.  In Endocrine Reviews this year, authors Dapas and Dunaif discussed these insights

8.  Type 1 diabetic women teach us a lot about how light controls female oocyte behavior.  

Often modern women living with type 1 diabetes complain of changes in glucose values according to the different phases of menstruation. This has been confirmed in several studies showing that the glycemic pattern varies according to the different phases of menstrual cycle in most women with T1D.  Why?  Did you know that menstuation links to NO and blood glucose variations in the capillary bed? 

The moon used to control the reproductuve cycle in humans.  Artificial light from fire onward effectively extinguished this link in modern women.  Can we still experience the real effect in a disease model?  Yes.  Type 1 diabetic women show the effect because they have no light controls.  Normal non diabetic women experience a transient pregnenolone steal syndrome to stimulate ovulation.  This is how a light stress event every month was used by biology to control fertility timing.  

Lunar cycles modulate the estrus cycle of many mammals because the moon can and does reflect blue light from the sun at night to the Earth as it goes through its revolutions monthly around Earth.  That is why they influence woman's hormone cycles assuming she is properly connected to Earth, sun and the lunar cycles. MOST ladies aren't properly coupled, therefore, their hormone effects are muted and lowered in modern females. This is why estrus has vanished in modern humans and proof it still has influence can be seen when women get together and live together their cycle will all become coupled oscillator again, just like molecular resonance theory predicts. When the negative and positive feedback loop in the circadian mechanism is uncoupled from one another the result is the extinction of both sides of the coupled system. This extinction effect manifests in the pregnenolone steal syndrome.  Look at the link of T1D to latitude below.  

In high latitudes cold stimulates increasing blood glucose over time.  

In T1D women glucose levels rise linearly throughout the menstrual cycle, reaching a maximum in the late luteal phase. Then a sharp decrease was seen for most participants at the beginning of menstrual bleeding.  This links light blood glucose to the lunar cycle because of how light varies.  

T1D human females and corals teach us how important light is to fecundity.  Remember fecundity in humans is controlled by the leptin melanocortin pathways.  

Among all, probably the most spectacular and documented event orchestrated by animals according to the lunar cycle is certainly the mass spawning of corals. Like inside a shaken snow globe, once every year, the barrier reef explodes of eggs and sperms, few days after Full Moon, during late spring/summer nights, a phenomenon even visible from space. Unfortunately, reef corals are losing this critical reproductive synchrony, due to the anthropogenic impact of artificial light at night. This phenomenon threatens several species, not only corals but entire reef communities.  This is why modern infertility in humans is increasing as well.  

Starting with the beginning of the last century, a multitude of scientific studies have documented that the lunar cycle times behaviors and physiology in many organisms. It is plausible that even the first life forms adapted to the different rhythms controlled by the moon. Consistently, many marine species exhibit lunar rhythms, and also the number of documented “lunar-rhythmic” terrestrial species is increasing. 

Organisms follow diverse lunar geophysical/astronomical rhythms, which differ significantly in terms of period length: from hours (circalunidian and circatidal rhythms) to days (circasemilunar and circalunar cycles). Evidence for internal circatital and circalunar oscillators exists for a range of species based on past behavioral studies, but those species with well-documented behaviorally free-running lunar rhythms are not typically used for molecular studies. 

Thus, the underlying molecular mechanisms are largely obscure: light reflection from of the moon varies with every day to increase blood glucose.

Lunar rhythms of light, dark, and gravitation changes cause alteration in the human transcriptome, proteome, and physiology. The proxy for these effects is seen in the hormonal variation of humans.

Most women who have circadian control experience a menstrual cycle that is connected to every new moon. And the 4 phases of the menstrual cycle seem to correspond to the 4 phases of the moon (new moon: menstruations, first quarter: follicular, full moon: ovulation and last quarter: lutheal).  https://academic.oup.com/jcem/article/107/10/2793/6648857

9.  Papers are now out showing how POMC cleavage and light cause type 2 diabetes and lead to sleep apnea.  It turns out that the steeper your diurnal cortisol slope is, it will be associated with a smaller and higher midnight cortisol levels.  As this POMC effect occurs you will see a greater risk of developing type 2 diabetes in people.  As this occurs the clinician should expect comorbid rise of hypertension and obstructive sleep apnea.  This is all due to light effects on POMC translation.  It shows you why type diabetics are created by modern light choices.  https://academic.oup.com/jcem/article/108/9/e679/7109980

10.  Neurosurgeons deal with patients with Cushing disease due to pituitary tumors.  In my 30 year career one thing I always saw in every case I dealt with was a loss of the pulsatile effects of cortisol secretion in those with a tumor.  Because of this I knew light was behind the growth of the tumor.  Now we have a paper showing you my instincts were correct.  ACTH variability is suppressed in patient with Cushing disease, and that remission of the pulsatile release of cortisol is associated with restoration of this variability.  Seeing AM and PM light helps these people recover this ability tremendously and this is why seeing the sunrise and sunset matter in POMC biology.  https://academic.oup.com/jcem/article/108/11/2812/7187942