MAMMALIAN HIBERNATION FAT STORAGE SURVIVAL SIGNALS

 VERSUS SPRINGTIME ANABOLIC LEAN MUSCLE SIGNALS

 A hibernating animal greatly reduces normal body activities that expend energy.  It survives on energy reserves, classically fat, stored in the body. Hibernation occurs in many animals found from the Arctic to the tropics.  Animals that save energy by hibernation or lethargy, for instance bats and hedgehogs, live much longer than those who are always active.  This is especially obvious in closely related animals. 

 A stressful environment sends signals to the organism to become inanimate until conditions are ripe for growth, repair and vigorous activity.  Perhaps it is not the soporific quiescent time that is the key to enhanced longevity, but the energetic messages of springtime growth that activate rebirth, repair and reawakening.

 During hibernation, an animal lowers its metabolic rate, uses less energy and stops generating the heat necessary to keep its body temperature above that of the environment.  As body activities slow, the animal becomes less and less capable of coordinated movement, gradually slipping into a state of dormancy, or torpor.

 Hibernation typically occurs in bouts, or episodes, lasting from a few days to a few weeks depending upon the animal, body size, outside temperature and time of year.  These bouts of inactivity are interspersed with brief periods of amplified activity, when the animals increase their body temperature to a normal level.

 In the earliest stages of hibernation, metabolic rate slows considerably.  Many animals begin hibernation with a series of short bouts of torpor where their body temperature stays relatively high.  A deeply hibernating animal’s heart rate drops substantially, often to just five to ten beats per minute.

 Breathing rate also decreases.  Many mammals do not breathe continuously during hibernation, often with periods of apnea (absence of breathing) that can last an hour or more. Sleep apnea is a life-threatening problem increasingly seen in humans.

 Hibernation is controlled by a set of complex cues that vary greatly from one group of animals to another and are not well understood. In many animals, seasonal changes in day length, or photoperiod, trigger hibernation.  Shortening days in the late summer and autumn signal many animals to prepare for hibernation.  Extreme heat or drought (communicated by consuming dried grains, seeds and nuts or dehydration induced by diuretics) can trigger estivation, another form of torpor, dormancy and inactivity.

 An organism that hibernates is made up of many cooperative cells.  The genetic programming of each cell responds to thousands of competing environmental molecular messages so that it can properly participate in the shared supportive venture of survival.  Depending on cellular RNA’s interpretation of the symphonic messaging its shared sentient membranes receives and transmits, the nuclear DNA is selected to cause the cell to cooperatively and altruistically commit apoptosis (programmed cell death or cell suicide), involute, become quiescent, grow and function vigorously or reproduce.

 Perhaps the most active compound acting as hibernation-induction trigger (HIT) is an endorphin (an endogenous opiate with some properties similar to morphine).  The effects of HIT are mimicked by drugs that target delta opioid receptors (one of several receptor subtypes matched to morphine and opiate compounds like it).  Activation of the opioid receptor suppresses activation of NFkB and avoids inflammation.

 The compromise of tissue inflammation in response to cryptic bacteria is similar to the physiology of rodent hibernation.  In both cases, systemic inflammation is suppressed.  At the cellular level, this means that other signaling pathways silence the inflammatory NFkB expression pattern.  One of the major nuclear receptors activated in hibernation is PPAR.  PPAR is activated by opiods and sulfides (H2S), which also induce hibernation in rodents. 

 Omega-3 fatty acids reduce inflammation via COX-2 prostaglandins, but also by binding to PPARs.

  Another group of opiate-like compounds called deltorphins, derived from the skin of South American frogs, also bind to delta opioid receptors.  These deltorphins help rats survive severe bleeding and diminish potential damage from strokes induced in mice.  Deltorphins also reduce the injury caused by experimental heart attacks in pigs.

 Epibatidine is the toxic chemical which a tropical frog arms itself against its predators.  Not only is epibatidine very toxic, and the reason it is used by native Indians to make poison darts, but it also turns out to be a superb painkiller.  Two hundred times stronger than morphine, it may well end in a pill that smokers can take if they want to stop smoking, or a drug that might enhance learning or improve our enjoyment of intellectual pursuits. 

 Epibatidine is an organochlorine compound, which confounds somewhat environmental activists’ belief that organochlorines are entirely manufactured chemicals that cause disease and damage the environment.  Epibatidine is highly dangerous, but it is perfectly natural.

  Animals that have a fairly constant food supply generally have a hormetically extended life span if subjected to the mild stress of calorie restriction.  Hibernation is a natural form of calorie restriction as well as a stress response and likely participates as part of the gene expression that lengthens lifespan.

 To prepare for hibernation, many animals eat large quantities of food, which, as a survival mechanism, is stored in the body as energy-providing fat.  In hibernation and estivation, metabolism slows as a survival response to harsh conditions.

Hibernating bears have what would seem to be dangerously high cholesterol levels.  Because they live off their own fat, bears winter cholesterol levels are more than twice what they are in summer and more than two times higher than those of most people (except for those humans also responding to their own hibernation signals).

 Surprisingly, black bears do not develop disuse osteoporosis during long periods of quiet because they still maintain osteoblastic bone formation during hibernation.  Because of this, bone volume, mineral content, porosity and strength are not adversely affected by annual periods of disuse. Actually, cortical bone bending strength increases with age in hibernating black bears without a significant change in porosity.  

 Other animals require remobilization periods 2-3 times longer than the immobilization period to recover bone lost during disuse.  Black bears, which hibernate for as long as 5-7 months annually, have evolved biological mechanisms to modify the adverse effects of disuse on bone porosity and strength as well as muscle mass.

 While bone and muscle mass is preserved, weight loss is extreme among bears leaving the nest.  Between early fall and late spring, male black bears will typically drop between 15-30% of their body weight, while lactating mothers can lose up to 40%.

 Hibernation greatly increases the health, happiness and longevity of many species of turtles and tortoises.  Hibernation offers many benefits besides synchronizing reproductive cycles and stimulating hormone development.

  The hibernation period provides time for turtles to replenish their immune systems.  While skipping hibernation for a year or two may not result in an observable decline in health, over a period of years turtles tend to become immune-compromised.  Also, hibernation is necessary to maintain normal hormone activity in the body, especially in the thyroid gland. 

 The thymus is a tiny organ located under the human breastbone that is present in all mammals.  It is the major site for T lymphocyte differentiation and immune response.  In humans, the thymus is most active during puberty, but under stress and as we age, it shrinks and loses functionality, leading to immune system decline and increased susceptibility to colds, flu and other ailments.

 But the thymus does not degenerate in all mammals.  Hibernating animals such as the Alaskan ground squirrel are able to renew the lymphoid tissue of their thymus as they sleep every winter.  Oral supplementation with thymus glandulars shows promise for boosting and re-regulating human immune systems.

 Human hibernation may not be as improbable as it sounds. Two genes have been discovered in humans that may trigger hibernation by directing enzymes to burn fat instead of carbohydrates.  Fat polar bears (the ones that are ready to fast) do not become diabetic even though they have insulin resistance.  Polar bears rarely use sugar as an energy source and instead rely almost entirely on fat (their own or that in their diet).

 When humans have to resort to using their own fat stores as an energy source, for example during low-carbohydrate diets, alcoholism, starvation or uncontrolled diabetes, ketoacidosis can result.  With too few carbohydrates, people become overloaded with acidic ketone bodies, the byproducts of fatty acid breakdown as well as deamination of proteins.

 This acid state diminishes alkaline reserve, eventually leading to loss of buffering capacity and enhances one’s possibility of slipping into coma.  Ketoacidosis can be smelled on a person's breath, due to the lungs excreting aromatic acetone, a direct byproduct of the spontaneous decomposition of acetoacetic acid.  Acetone is often described as smelling fruity or like nail polish remover.

 Monkeys who get injections of a hibernation-induction trigger lose interest in food.  Some primates hibernate in the wild and Russian peasants did over a hundred years ago to cope with difficult winters.

 Urea (a product of nitrogen metabolism), can build up in human blood and become toxic.  Bears, on the other hand, go for months with no urinating and never develop this problem. They have microbes in their gut that can convert urea into a form of nitrogen they can use to make new amino acids (the basic building blocks of protein).  Humans have urea-chomping microbes, too, but are not as efficient as bears at recycling urea.

 As body temperature drops during hibernation, brain waves normally present during sleep gradually diminish.  Some theorize that animals become sleep deprived during hibernation and that they arouse periodically in order to catch up on their sleep. 

 An element that can contribute to seasonal affective disorder (SAD) is disruption in one’s natural circadian rhythm.  This internal rhythm is dictated by a tiny nerve cluster in the brain (the suprachiasmatic nucleus) that runs our biological clock and is directly influenced by light.  It entrains similar little genetic clocks found in all cells from fruit flies to humans.   

 Because the winter months provide less light than the summer months, sleep cycles can get disrupted.  Lack of sustaining breakfast to start the day is also a circadian rhythm buster, as is eating substantial quantities of food 2-3 hours before bedtime.  Coffee in the morning (besides the obvious coffee in the evening) disrupts sleep cycles at night as does more than one or two drinks of alcohol in the evening.

 The primary feature of seasonal affective disorder is a pattern of depressive or manic episodes that occurs with the onset of the winter months.  As the days become shorter, and the weather colder, there is an increase in vegetative depressive symptoms.  Symptoms include tiredness, fatigue, depression, crying spells, irritability, difficulty concentrating, body aches, diminished sex drive, poor sleep, decreased activity levels as well as overeating, especially of carbohydrates, with associated weight gain.  In pronounced versions, significant social withdrawal occurs too.  Some understand the pattern as expression of human hibernation during the winter months.

 The second phase of the disorder is the tendency for these symptoms to abate once the days become longer and warmer in the spring.  SAD people are most responsive to light therapy early in the morning, just when melatonin secretion begins to wane, about 8-9 hours after the nighttime surge began.  Again, the hibernation analogy works well. 

 The psychological response is disinterest in social activities, the narcissistic signal-stimulus-hibernation mini-cycle.  The narcissistic signal is preceded by a depressive phase.  The narcissist invariably goes into self-absorbed hibernation before the emission of a selfish signal, doing so in order to gather the energies that will be needed for extended torpor.

 Is the depression caused by dehydration, a decrease in sunlight, by colder weather, or by the increased isolation and stress of coping with the winter months? Stress, in general, causes depression. Sunlight, entering through the retina, stimulates the production of brain chemicals as well as vitamin D that have an antidepressant effect.

 

 People have experienced SAD following the development of cataracts or after wearing sunglasses for an extended period of time and during overcast, rainy periods.  People in the southern USA experience SAD in the summer from staying indoors where air conditioning allows them to escape the unbearable summer heat.  People have also experienced SAD moving into a basement suite or an office on the north side of a building or after painting the interior of their home a darker shade of color.

 Depression is likely an evolutionary adaptation useful in analyzing complex problems, enhancing survival.  Studies of depression in rats show that the 5HT1A receptor is involved in supplying neurons with the fuel they need to fire continuously, as well as preventing them from breaking down. 

 These important processes allow depressive rumination to carry on uninterrupted with minimal neuronal damage, which may explain why the 5HT1A receptor is so evolutionarily essential.  The 5HT1A receptor binds to serotonin, lack of which is linked to depression.  Boosting serotonin is the aim of most current antidepressant medications.

 Many other symptoms of depression make sense in light of the idea that analysis must be uninterrupted.  The desire for social isolation, for instance, helps the depressed person avoid situations that would require thinking about other things.  Similarly, the inability to derive pleasure from sex or other activities prevents the depressed person from engaging in activities that could distract him or her from the problem.  Even the loss of appetite often seen in depression could be viewed as promoting analysis because chewing and other oral activity interferes with the brain’s ability to process information.

 Depression may not be a malfunction, but a mental adaptation that brings certain cognitive advantages.  People in depressed mood states are better at solving social dilemmas. Expressive writing promotes quicker resolution of depression, perhaps because it helps depressed people gain insight into their problems.

 Hibernation messaging is created when we as human mammals get too little natural light, too little water, eliminate dietary fat and eat dried seeds, nuts and grains and even worse, crisp, caramelize and cook our foods to a golden brown (mimicking stressful heat shock proteins which are primitive alarm molecules signifying stresses of forest fire or infection).

 

At the cell level

 

 A critical role exists for cell membrane ‘lipid rafts’ in regulating the cell cycle, the survival, and the entry into apoptosis of hematopoietic stem cells (HSCs).  Lipid raft micro-domains are cholesterol-enriched and glycosphingolipid-enriched patches in the plasma membrane into which various functional molecules are distributed.

 

 The physiological role of lipid rafts is well defined in Thymus-cell receptor (TCR) signaling at the 'immunological synapse' induced by TCR antigen recognition at the T-cell: antigen-presenting-cell junction.  T-cell receptor engagement induces clustering of lipid rafts and concentrates activated TCR and downstream signal transducers within lipid rafts.  As larger rafts have greater potential for concentration of transducers and for exclusion of negative regulators, lipid raft size controls T-cell receptor signaling and functional outcomes.

 

 There is also a striking similarity in our blood forming stem cell hibernation and the nematode Caenorhabditis elegans dauer formation.  As with mammalian hibernation and C. elegans dauer formation (an enduring larva goes into a type of stasis to survive harsh conditions), the PI3K–Akt–FOXO pathway seems tightly linked with stem cell dormancy.

 

 Lipid raft clustering induced by cytokine stimulation activates this pathway and is essential in promoting division by both hematopoietic stem cells and progenitor cells.  Inhibition of lipid raft clustering suppressed the PI3K–Akt–FOXO pathway and induced hibernation in HSCs ex vivo.  It also caused apoptotic death of progenitor cells even in the presence of cytokines.

 The PI3K–Akt–FOXO pathway controls cell cycle, apoptosis, metabolism and longevity.  This pathway is crucial in cell cycle and death control in C. elegans and is now being researched in mammalian systems.   Akt-regulated FOXO family members block cell-cycle progression at phase G1and protect human dormant cells from oxidative stress, while antagonizing apoptosis.

 It is interesting that the PI3K–Akt–FOXO pathway involved in C. elegans dauer formation also operates in mammalian hibernation and in dormant stem cells in the bone marrow niche.  The tight correlation between membrane lipid raft status and the PI3K–Akt–FOXO pathway indicates that lipid raft reorganization holds the key to precise regulation of the Akt–FOXO pathway in hematopoietic stem cells.

 C. elegans worms that had their pha-4 genes removed showed no enhanced longevity while on restricted diet.  Over-expressed levels of pha-4 in worms increased longevity when on the restricted diet.  These genes play a key role in development, and then in later life in regulating glucagon, insulin’s balancing hormone (with a major role in maintaining glucose levels in blood, especially during fasting).  Pha-4 is likely the primordial gene that helps an animal overcome stressful conditions to live a long time through dietary restriction conditions.

 Dauer pheromones signal C. elegans worms to enter a hibernation phase when food supply is low.  At high concentrations, dauer pheromones also act as mating pheromones.  If pheromone level is too low, dauer does not work.  If you add more, you get mating response.  If dauer gets very high, the mating response stops and worms go into hibernation.  This is a classic curved parabolic response to a  messenger molecule. 

 Unfortunately, anti-leukemic therapy likely activates in leukemic stem cells the same mechanisms that induce quiescence and maintain hibernation in bone marrow-niche HSCs, so they can re-emerge after therapy is halted.  Antibacterial therapies do the same for the surviving micro-organisms within biofilm.

 Melatonin, the hormone that makes us sleepy, is intimately related to light and darkness.  When the eyes no longer receive UV light, the brain notices that it’s getting dark, and signals from the suprachiasmatic nucleus prompt the release of melatonin from the pineal gland.  Levels peak during the darkest hours of the night.  As light levels slowly increase with the approach of dawn, melatonin levels go down and the body prepares to awaken.

 The best vitamin D is what is made from cholesterol by exposing skin to natural sunlight.  But this mechanism doesn’t work equally well for everyone, and given the limitations of modern lifestyle and dietary sources, replenishing body stores with a high-quality vitamin D supplement can be helpful in minimizing symptoms of SAD.

 The berries of spring are rich in resveratrol and similar phytochemicals called salvestrols.  These pigments that help plants cope with stress communicate this mild stress to our genes.  The hormetic genetic response maintains cell health and supports normal cell cycle activity while it promotes apoptosis (programmed cell death) in unhealthy cells. 

 These phytochemicals reduce inflammation by encouraging normal inflammatory nuclear factor kappa beta (NF-kb) and cyclooxygenase-2 (COX-2) enzyme activity, boosting cardiovascular health (by promoting normal platelet activity, maintaining normal vessel relaxation and providing antioxidant protection of LDL particles).

 Resveratrol promotes normal activity of the SIRT-1 gene (involved in calorie restriction, fat mobilization and efficient mitochondrial function) and is a superior antioxidant with high ORAC value.

 

 Hormesis is described as ‘preconditioning’ by mild stressors, which alters gene expression of an organism, allowing greater capacity to handle all stresses.  Hormetic pathways activated by pigmented phytochemicals involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors and other protective proteins.

 Specific examples of such pathways include the life-extending sirtuin–FOXO pathway triggered also by calorie restriction or resveratrol, the protective (when tethered) proinflammatory NF-κB pathway and the Nrf-2/ARE pathway, which upregulates expression of phase II detoxifying enzymes and antioxidants, thus enhancing elimination of noxious stimuli.  Hormetic phytochemical actions of the Nrf-2/ARE signaling pathway are a classical expression of a neuroprotective mode of action of many specific dietary phytochemicals.

 Resveratrol causes a 14-fold increase in the action of the antioxidant system MnSOD in cells.  MnSOD reduces superoxide and thereby confers resistance to mitochondrial dysfunction, permeability transition and apoptotic death in various diseases.  It helps in lifespan extension, inhibits pancreatic cancer and provides resistance to reperfusion injury as well as radiation damage.  Resveratrol interferes with all three stages of carcinogenesis: initiation, promotion and progression. 

 

 Resveratrol also significantly increases natural testosterone production by being both a selective estrogen receptor modulator and an aromatase inhibitor.  It increased intracellular glutathione levels via Nrf2-dependent upregulation of gamma-glutamylcysteine ligase in lung epithelial cells, which protected them against cigarette smoke extract induced oxidative stress. 

 

 Curcurmin and resveratrol are able to inhibit TNFalpha-activated NF-kB signaling in adipocytes and therefore significantly reduce cytokine expression.  Curcurmin and resveratrol provide a safe approach to reduce chronic inflammatory properties of fat.

 

 Seanol is a unique patented polyphenol/phlorotannin extract from Ecklonia cava marine red/brown algae grown off the coasts of Korea and Japan.  Polyphenols, which are antioxidants found in many land-based products such as berries, tea leaves, grapes, pomegranates, fruits, and vegetables (and in Seanol), have a molecular structure of two to four connected rings.  These rings “trap” damaging free radicals.

 

 Trans-resveratrol from red grapes has a two-ring molecular structure and, green tea has a four-ring molecular structure.  However, Seanol has similar polyphenols and phlorotannins, which have a more sophisticated molecular structure of eight rings, which allows it to trap many more free radicals.

 Seanol is both water and fat soluble, so it can easily penetrate phospholipid membranes, working inside of cells for maximum protection.  Even better, it easily crosses the blood/brain barrier to give the brain extra antioxidant protection.  Since Seanol is fat soluble, it stays in the body longer, as much as 12 hours, compared to water soluble antioxidants which are excreted in the urine in roughly 30 minutes.

 

 Seanol helps increase brain alpha waves, a good indication of relaxing blood vessels to the central nervous system and increasing blood flow, promoting brain activity as well as increasing energy and endurance.  Seanol also helps stimulate the production of acetylcholine, the brain chemical of learning and memory as well as the neurotransmitter that modulates and reduces immune inflammatory response in the digestive system, joints and arteries via the vagus nerve.

 Astaxanthin is a deep red-colored phytonutrient pigment synthesized by microalgae called Haematococcus and is also found in Krill oil.  Grown in fresh water, the alga produces its own powerful medicines that protect it from oxidation, UV radiation and other environmental stresses. 

 When harvested from algae and concentrated into a liquid, astaxanthin becomes a very powerful antioxidant, demonstrating 550 times the antioxidant power of Vitamin E.  Astaxanthin eases arthritis pain, prevents Alzheimer's disease, speeds recovery from exercise, boosts physical endurance, prevents cancer, stabilizes blood sugar and protects the entire cardiovascular system.

 Typical supplemental doses of astaxanthin are 2-4mg per day.  Mike Adams, the Health Ranger took up to 16mg per day and noted that health benefits kept increasing as the dose increased.  Benefits included outstanding athletic performance, a significant reduction in muscle soreness and joint pain, radical improvements in resistance to UV sun exposure, stabilized blood sugar and better mood.

August 26, 2009

Steven N. Green, DDS

10261 SW 72 St., #106

Miami, FL 33173

305-273-7779

Antiagingdentist.com or sngreen.com

ddsgreen@bellsouth.net