http://cassiopaea.org/forum/index.php/topic,26988.msg332183.html#msg332183
Epigenetics major signal transducer is found in the cellular signaling found in our cell membranes that interact with the environment and our inner hormones that signal our epigenetic switches that sit on our genes inside the nucleus. Since it is clear that
our cold adapted pathways use sensory afferents to signal to open the Ancient Pathway, I think it is time we just have a blog in the CT series that discusses what a normal 24 hour day is like in a human circadian biology.
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WHAT HAPPENS WHEN STEP 20 [the surge of prolactin] IS BROKEN IN MODERN HUMANS?
This commonly happens in diabetics, but it is now becoming a very common finding in modern humans because of the excessive use of technology after sunset. These artificial lights also tend to be quite bright and completely un-yoke the normal circadian signals from the hormone response.
Light after sunset reduces the prolactin surge we normally see in humans. When we see chronic lowered prolactin surges we also see lower growth hormone secretion during the anabolic phases of sleep. Lowered chronic GH secretion directly affects cardiac and skeletal muscle function because the process of
autophagy is made less efficient as our life continues. Lowered GH and the sex steroid hormones at sleep lead to loss of cardiac function. This is why heart failure is strongly associated with low IGF-1 and sex steroid hormone levels. When growth hormone is not released in normal amounts, it also decreases our lean muscle mass and increases our fat percentage in all our organs and in our body. This leads to slowly declining organ dysfunction and poor body composition. We can measure this process clinically by looking for falling DHEA and GH levels levels as we age.
WHAT HAPPENS IN NORMAL AGING IN STEP 21 [the large circadian prolactin surge]?
Aging is among the most common features found in studies on modern humans when DHEA and GH craters on hormone panels. The loss of the prolactin surge is especially prominent in post menopausal women. Most women begin to suffer from falling DHEA and GH levels around age 35-40 while they are still in peri-menopause. The higher their HS-CRP levels, the faster they enter peri-menopause and the quicker they enter menopause. They also age faster on a cellular level because thei circadian chemical clocks are sped up. As a consequence, their telomeres shorten faster as well. Women have higher levels of leptin for child bearing, so they are more prone to leptin resistant issues then men. Leptin is sexually dimorphic hormone. This helps explain why older women struggle with cognitive haze, loss of body composition, poor sleep, and increased levels of heart disease after menopause.
Many physicians think the losses they suffer are due to the loss of estrogen from ovarian failure, but the loss of growth hormone and progesterone production are far more significant on their physiology. Progesterone is the off switch to anything that is pro growth. Modern women are usually estrogen dominant even after menopause because of mismatches in circadian biology. Cognitive loss is especially common in post menopausal women. They also lose on average 1% of their bone mineral density per year from menopause in large part due to the loss of progesterone, not estrogen. Loss of progesterone also corresponds to poor sleep in these women too. Replacing progesterone in women has a major affect on their sleep and bone stock. It also dramatically improves their memories and cognitive function as well.
SNACKING AFTER DINNER: EFFECT ON CIRCADIAN CYCLES:
If you choose to eat within 4 hours of sleep you will never see the prolactin surge you need, because any spike in insulin turns off this critical sleep time release that corresponds to the cellular maximums of the autophagic process for humans. Something also happens.
Agouti, the incretin gut hormone also rises in the blood to higher than normal levels to block leptin from entering the brain. Diurnal cycles for agouti are coupled to
NPY and have major affects on leptin. Agouti is a gene product that normally increases the release of leptin from fat cells at night to signal the brain of what the energy status is of the body. This is great when it is working well.
When it is elevated due to heavy carbohydrate use in our diet it creates a massive problem. This is why late night carbohydrate snacking is a real bad thing to do.
It appears
12-3 AM are the critical hours at night are where the remnants of mammalian hibernation lies for our species.
These are the anabolic times for sleep when we are re building our proteins and recycling our cellular contents. They are three of the most important hours in all human biology.
If you miss them, you can bet you have several neolithic diseases for sure. Why you ask?
If these three hours are not reached enough during our sleep cycle, autophagy is never optimized and cellular repair does not occur for our cells. This means we are using old broken down parts in our cells as the next day arrives at 6AM and cortisol rises again to wake us up.
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PROLACTIN, DOC?
You must be asking, why is this prolactin hormone so important in a warm adapted human? Prolactin is not just a hormone that secretes human milk. That is the best known action of prolactin, but not the most important.
Immediately after prolactin is released during sleep, another signal is sent to the anterior pituitary to release the largest amount of Growth Hormone as we sleep (GH). GH is stimulated only during autophagic sleep cycles in stage 3 and 4…..to increase protein synthesis for muscle growth……all while you’re dissipating heat via the uncoupling proteins. This is where the major release of GH occurs in humans post puberty when they are warm adapted. 99.9% reading this blog are warm adapted.
If you chose to become cold adapted the GH story radically changes, as laid out in CT-6 [his last blog post]
The implications here are huge for the warm adapted human, if this prolactin surge is not adequate to allow us to enter the anabolic stages of sleep.
Prolactin surge is diminished by both artificial light at night and by foods that stimulate NPY, (namely carbs and protein) when they are eaten in fall and winter when biology says they should not be available.
If you are leptin resistant for any reason, have sleep apnea, you will always have an altered body composition because of a low GH level and an altered sex steroid profiles on testing. The reason is because
DHEA is the immediate precursor for those hormones and is always low in people with bad sleep efficiency. Most VLCers who are warm adapted face this very problem today.
VLC diet is best used in the cold adapted mammal and not the modern warm adapted lifestyle. In essence, this diet is a mismatch for our modern lifestyle. This is why so many bloggers think ketosis is a dirty word for performance and body composition.
This all implies as you age you will have higher body fat %, lower muscle mass %, if autophagy is not optimized by great sleep. This is precisely what we see today in most modern humans as they age. Invariably, their sleep cycles and sleep durations are poor and decreased from their childhood levels. As they age, there is a chronic insidious erosion of circadian biology by decisions made by modern humans over and over again.
WHAT ABOUT TEMPERATURE VARIATIONS IN WARM ADAPTED HUMANS?
Where does temperature enter the picture? In warm-blooded animals, homeotherms such as humans, can change their metabolism in order to keep their heat production equal to the heat loss. Such animals have a temperature control system and thereby maintain a rather constant core temperature. Warm-blooded animals live with the advantage of an unchanged cell activity and temperature in their core. However, the human core temperature falls during the estrogen phase of the menstrual cycle (pro-growth) and during sleep (circadian rhythm by melatonin).
The lowest temperature of the day for modern humans is usually between 2 AM and 6 AM. The temperature cycle is part of the normal circadian periodicity. Our biological clock seems to be synchronized with the rotation of the globe daily.
Meal composition and timing, light cycles and temperature plays a role in altering normal cycles and autophagic optimization.
Ovulation releases a sharp rise in morning temperature with its estrogen surge. Progesterone effects seem to explain the higher temperature in the last phase of the menstrual cycle where it calms the the pro growth effects of estrogen. In post menopausal women, this balance is usually not ideal, and it leads to many menopausal complaints these women face today.
The reduced temperature induced by melatonin in sleep is needed for Central Nervous System autophagic repair, for another, less well known reason. The lowered temperature sets the stage for the biologic quantum effects to be optimal on our neurons microtubules that facilitate learning and neuronal spouting that occur brain wide.
This is why if you don’t sleep well you feel badly the next AM, and your mental performance suffers the next few days on cognitive tasks. Research also shows your learning is severely impaired because of lowered BDNF and changes in diurnal cortisol due to the sleep deficit. This is why we monitor truck drivers and airline pilots sleep and wake cycles by law!
Moreover, in hospitalized ICU patients or the elderly when this occurs, it sets the stage for the appearance of acute onset delirium. This is exacerbated when they also have a simultaneous cytokine storm from sepsis or obesity. We see this often in hospitalized patients who can not sleep well in ICU’s. Acute delirium states very much look the same as chronic sleep deprivation patients we see clinically as well. Inducing cold, using progesterone and using hypnotics helps manage these conditions. I mentioned this in my hour long Paleo fx talk last week.
Read this link in 3/11/2012 NYT: http://well.blogs.nytimes.com/2012/02/27/really-the-claim-your-body-clock-can-determine-when-you-get-sick/
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VIP regulates the circadian rhythm in humans and most mammals. VIP is a gut hormone and is found in our taste receptors too! So if we taste sweetness from carbs in our diet when its warm and they are growing in the environment, our brain is expecting us to be in a warm season…….not a cold one.
So sweet means warm not cold to the brain. If you mismatch that and eat carbs at the wrong seasonal time you create inflammation in the brain and it throws off our chemical clocks in our cells and ages us faster. That means our telomeres get shorter. This is not good.
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The circadian clock not only can generate its own rhythms but can also be entrained by the environmental light-dark (LD) cycle. Multiple single cell circadian oscillators that are present in the clock can, when synchronized, generate coordinated circadian outputs which ultimately regulate the overt rhythms.
VIP is a gut polypeptide, has been identified as one of the main neurotransmitters of SCN [suprachiasmatic nucleus, the nervous system responsible for most circadian behavior can be localized to the suprachiasmatic nucleus (SCN)] neurons and participates in SCN function. These SCN neurons are retino-recipient and are found in the core of the SCN. They are activated by light, and exogenous application of
VIP can reset the circadian clock in a manner similar to that of light application, both in vitro and in vivo. It is estimated that 9%–24 % of SCN neurons express VIP.
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One of the main chemical constituents of SCN neurons is vasoactive intestinal polypeptide (VIP). Such neurons are retino-recipient and activated by light. Exogenous application of VIP resets the SCN circadian clock in a light-like manner both in vivo and in vitro. These resetting actions appear to be mediated through the VPAC2 receptor (a type of receptor for VIP). Unexpectedly, genetically ablating expression of the VPAC2 receptor renders the circadian clock arrhythmic at the molecular, neurophysiological and behavioral levels.
These findings indicate that this intrinsic neuropeptide acting through the VPAC2 receptor
participates in both resetting to light and maintenance of ongoing rhythmicity of the SCN.
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VIP (along with GRP and AVP) show circadian variations in the level of mRNA in constant contact with environmental conditions from our tongue and our gut. When light becomes long lasting in summer, NPY dominates the SCN in mammals……
when light becomes low and temperature falls to 50-55 degrees constantly at our surface cold receptors, and eNOS rises and blocks all photic [penetrated by or receiving ligh] input to SCN and circadian rhythms are maintained by a new program. Alpha MSH [melanocyte-stimulating hormone] induces and potentiates that seasonal change within the hypothalamus as laid out in CT-6 blog.
{More info here: http://cassiopaea.org/forum/index.php/topic,26988.msg330007.html#msg330007 and http://cassiopaea.org/forum/index.php/topic,27112.msg329806.html#msg329806}
THE MORAL: So the brain is wired for foods when they grow naturally, not when we “feel or think†we can/should eat them regardless of their availability in modern times.
Leptin sensitivity directly regulates VIP production. VIP regulates the circadian rhythm and entrains the SCN to light.
When it is cold, leptin is released from fat cells in large amounts, and we begin to use eNOS to entrain our SCN to cold cycles and we should avoid carbs like the plague then. Remember from CT-6,
cold empties fat cells like a screaming fire would empties a crowded cinema.
In cold, the pituitary-hypothalamic portal is involved in the production of lots of alpha MSH and ACTH. When MSH rises, you are allowing the brain to control everything to get you to optimal. This should make it abundantly clear that
cold and warm adapted mammals are not sharing the same circadian biology.
Cold selects for supreme LS and superior hormone optimization as laid out in the CT 6 blog.
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THE COLD LINK: WHY CT SIMPLY ROCKS
Cold temperatures sensitize us to leptin by causing it to be released from fat cells over time leading to a lower level in the blood chronically. Low temperatures also cause us to increase our RER, while eating a low calorie diet and still maintaining our lean skeletal muscle mass. These findings show that during very low-calorie diets, and low temperatures , are a stimulant of a FAS [fatty acid synthetase] inhibitor, like leptin, and would raise malonyl-CoA levels, while decreasing the expression of NPY and AgRP.
Clinically this results in sustained satiation for longer periods of time with less food. Remember that
NPY is also the neuropeptide that is high in the SCN during high light levels when carbohydrates are highest. This peptide is directly regulated by leptin function. S
o if one is leptin resistant it appears to the SCN that winter has become summer. This is a circadian mismatch and a source of inflammation in the brain. When cold comes and light drops eNOS is induced and shuts the SCN off to photic entrainment of the circadian clock.
The reason for this is not only annual seasonality, but for periodic ice ages mammals have faced on earth, and appears to be our primordial situation for life.
This is clearly a survival mechanism that
is hardwired into all mammals by evolution, but the ancient pathway has another more important role that we have failed to uncover yet. (FACTOR X)
The environment required for the cold pathway expression is under cold, low light, and low calorie conditions. All must all be met at once. This is precisely what all cold adapted eutherian mammals are ideally adapted to. These are modern human ancestors, and their biochemistry is foundational to our current paleolithic Ferrari engines. Many believe this pathway represents a starvation response (not), but its real biologic value is of even more interesting. We will talk about this later this year.
This temperature gradient gradually reduces all hunger, pain, thirst, and facilitate sleep in humans and all mammals. These functions were all selected for by evolution via natural selection pressures faced by eutherian mammalian evolution. Moreover,
these effects of leptin cause specific epigenetic modification effects on the other hypothalamic hormones or peptides derived from POMC [pro-opiomelanocortin] protein cleavage. Those changes are linked via the biology of the POMC neurons in the arcuate nucleus.
Leptin and its receptor is especially sensitive to changes in temperature and to the light cycles that humans and all mammals face. Leptin is intimately tied to hunger, it is linked to thyroid function and directly tied to fat metabolism in all mammals. [...]
EVERYONE REUNITE FOR SLEEP AND IMMUNITY: In the warm adapted human
Simultaneously, while sleep is rebuilding our cellular terroir (think levee one), the immune system is also undergoing autophagic repair as well. That is another reason why the temperature has to fall in our bodies. Usually, temperature rises and this causes immune function to rise and more easily activate in response and duration in fever, stress and infections. This activation depletes our immune system of its reserves during high light waking hours.
Dropping our temperature as we sleep allows us to repair it. During sleep this is when the body re-tools our immunity to function optimally the next day. What controls this entire orchestra of hormonal regulation? Its all leptin mediated……..and the brain is the master receptive organ to its function.
Sleep is a time for recycling and rebuilding to get us ready for the next day. It is also a time when our immune system is retooled to fight the battle the next day.
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It has now been shown that sleep increases telomere lengths on leukocytes in humans. Sleep has also been theorized to effectively combat the accumulation of free radicals in the brain, by increasing the efficiency of endogeneous antioxidant mechanisms. These mechanisms are mediated by the hormone DHEA which is the major antioxident in the brain and correlates directly with effective sleep by lowering IL-6 levels. Progesterone is another critical hormone for brain homeostasis and learning as well.
Sleep is vital to mammals, but it is supremely vital to humans, because they have shrunk the benefits of hibernation into 2 short critical hours of their sleep cycle because of the massive growth of their brains extinguished the need to sleep through the winter months.
Since man can directly control his environment, therefore, being awake during winter was naturally selected for in his direct ancestors before the primates species because they have the same adaptations.
The programs that control our fat mass (leptin) however still remain tied to our ability to sleep well.
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SLEEP IMPLICATIONS:
A University of California, San Diego psychiatry study of more than one million adults found that
people who live the longest self-report sleeping for six to seven hours each night. Another study of sleep duration and mortality risk in women showed similar results. Researchers at the University of Warwick and University College London have found that
lack of sleep can more than double the risk of death from cardiovascular disease, but that too much sleep can also be associated with a doubling of the risk of death, though not primarily from cardiovascular disease. Professor Francesco Cappuccio said, “Short sleep has been shown to be a risk factor for weight gain, hypertension, and Type 2 diabetes, sometimes leading to mortality.
These all tie to a failure of autophagy in sleep stages 3 and 4 mentioned above. Here, we see why poor sleep links to sleep apnea and the neolithic diseases that are associated with sleep apnea.
Growth Hormone is released in pulsatile fashion from 12-3 AM during restorative sleep cycles 3 & 4, and this hormone facilitates autophagy and recycling of proteins. In essence GH keeps us younger and in great shape when we sleep like a rockstar. The problem is modern man does not sleep well because of his brain’s creations. (Modern Technology)
The metabolic phase during sleep at this time is anabolic which favors repair; anabolic hormones such as growth hormones (as mentioned above) are secreted preferentially during sleep.
If things are working well things get repaired at night as we sleep, and if sleep is poor repair either absent or sub optimal. When this occurs chronically stem cells are used to replace cells instead of using cellular recycling processes that are normally used. Sleep is vital for all our organs rebuilding and retooling.
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Using the cold adapted pathway described in CT 6, is the best way to protect from all circadian erosions, considering we no longer hibernate and have to rely on the two hours of anabolic sleep we get as a replacement. Cold lowers all inflammatory cytokines across the board.
In warm adapted humans, it becomes clear that inflammation is the single most destructive obstacle to human health. This implies that understanding how to control leptin becomes paramount for the warm adapted human.
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Temperature and light have massive biological effects on our biochemistry. We need to be aware of this.
