Thursday, December 24, 2015

Can Melatonin Reverse Prevent Neurogenerative Disease?

The pineal production of melatonin (and gonadotropins) is under photoperiod feedback via nerve circuits with weak or strong synapticity. 

Therefore, the early changes of Alzheimer's pathology is reduced BDNF, reduced neuroplasticity, reduced synapticity.  Melatonin is protective of apoptosis or loss of synapses that have weak activity or signaling frequency.  The result is less output for the retinal sensing cells of photoperiod which are separate from the rods and cones.  Melatonin as an antioxidant becomes weakly produced and therefore weakly protective to the the damage to synapses first, cell function second and neurons third. 

In the Alzheimer's animal model Oxys rodents the damage occurs before beta amyloid deposition or at the soluble beta amyloid state which triggers the inflamasome to damage mitochondria and produce pyroptosis that precedes apoptosis or cell death.  This results in lowered glucose metabolism in early affected areas of brain as seen on glucose based PET scans.  Described as impaired insulin signaling, it might also be a weakened ability to respond to the given insulin effect.  Melatonin the antioxidant reduces inflamasome triggering restoring and reducing damage to synapses, (insulin) cell function second and neuron survival lastly.

Reducing inflammation and improving synapticity, nerve (and somatic cells) function and preventing their escalation to the point of cell death is the heart of my conjecture to prevent neurodegenerative diseases.

To wit.  Health + BDNF (a structural and metabolic turbocharger) - inflamasome.

Healthy diet, exercise, stress reduction plus inflamasome blocking with MELATONIN.

Disordered sleep, depression and stress or learned helplessness are strongly associated with Dementia.  These are symptoms of low BDNF AND low Melatonin.  Here Exogenous Melatonin reversed the early changes of Alzheimer's in this rodent model of the disease.

Conjecture:  Early use of Melatonin will reverse early neurodegeneration changes that lead to dementia.  An early casualty in the disease process is pineal gland circuits loss of synapses, then cell function and then neuron loss.  

In Diabetes the goal is preserve and restore the insulin producing beta cells, their function and their signaling.
In Dementia the goal is preserve and restore the melatonin and gonadotropin producing pineal cells, their function and their signalling.

This may require exogenous insulin (and inappropriate glucagon insulin antagonism) AND Melatonin.  Diabetics have higher prevalence of low testosterone and dementia.  I believe the equality above reveals the preserve and restore potential of BDNF and Melatonin.

Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease 


Saturday, December 19, 2015

Can Melatonin Prevent and Ameliorate Bipolar Disease in at Risk and Affected?

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder


This article is supplementary to the adolescent monocyte macrophage inflammatory findings in progeny of a bipolar parent in advance of expressed disease.  Complex 1 is one of 5 complexes in the mitochondrial electron transport chain that produces ATP or cellular energy.

To wit, in this article older bipolar patients are inflamed and specifically show dysfunction in Complex 1, the downstream target of inflammatory damage to mitochondrial energy production.

Ubiquinol the reduced form of CoQ10, specifically is involved in complex 1 and is an antioxidant  in the cytosol that reduces reactive oxygen species that trigger the inflamasome.  Melatonin is a cytosol AND mitochondrial ( a transcellular) antioxidant that might prevent the activation of adolescent immune macrophage cells that are at risk of neuroinflammatory changes.

Conjecture:  Macrophage cells in the brain otherwise named microglial cells become inflamed and activate the systemic and innate immune system of neurons and their energy producing mitochondria.

Conjecture:  Manifest bipolar disease treatment should target Complex 1 with Ubiquinol in addition to Melatonin supplementation to reduce neuroinflammation.

Conjecture:  Adolescents with a bipolar parent should reduce monocyte macrophage and microglial inflammation by nightly Melatonin supplementation.  They should also follow a Mediterranean diet which is inherently higher with dietary sources of Melatonin.

Melatonin is a safe and harmless supplement which may or may not prevent the "downstream targets of complex 1 dysfunction in bipolar disorder."  

The Downstream Targets of Complex I Dysfunction in Bipolar Disorder

Tuesday, December 8, 2015

Neurogenesis and BDNF and VEGF

Dad,

The TED talk on the factors that improved neurogenesis (production of new nerve in adult brains) resulting in improved memory and improved mood was informative.  It is perfectly consistent with what I have previously pointed out in my DrLiverman.blogspot.com.  It begs the question and evidentiary exegesis below.

How does intermittent fasting, Exercise, Reservatrol, antidepressants and  brain training increases neurogenesis in the hippocampus (the memory learning center of the brain) thereby improving memory and improving mood?  And the corollary question, how does alcohol, opiates and other depressant drugs, high fat diet, chemotherapy, sedentary lifestyle and non-stimulating non-learning environment decrease neurogenesis in the hippocampus thereby degrading memory and degrading mood?

Herein is an article comparing studies in rodents and humans verifying exercise and virtual or real environmental enrichment via 1. BDNF (and its pathway) and 2. VEGF (blood vessel growth factor) were fundamental to spatial neurons (bookmarks), neurogenesis, learning, positive mood and neuron survival.

I want to draw your attention to the relation between memory and navigation of actual(or virtual space.)  Prodigious memory feats use memory palaces or a well known location tag for ordered memory objects.  This is akin to a database written on new cells and dendrites (physical connections with other nerves like a clasped handshake) on flash memory in the hippocampus.  Consolidation is the process of transferring those flash memories to cerebral (thinking part of the brain) and  subcortical ( primitive reptile brain) neurons under stress and over time.  This is best accomplished with quality sleep both REM (rapid eye movement dreaming sleep ) and NonREM sleep.

The metabolic health and energy efficiency of those brain cells preserve memory and make them available for use in making new memories or understanding the present in relation to the past and perhaps predicting a possible or likely future.  With exercise, diet and thinking able to increase neurogenesis/ via BDNF, a bio marker of a metabolic turbocharger, and in conjunction with adequate blood flow for energy support from VEGF, it is clear that the exercise, diet and cognitive activity improves and preserves the entire body of cells.

Consider disabled ALS astrophysicist Stephen Hawkins, his body survives decade from a short term terminal disease disconnected from direct brain wiring but enriched from brain activity in a theoretic and virtual realm of physics by the production and sharing of brain produced BDNF.  The BDNF produced is released to peripheral blood and can become a metabolic turbocharger of any cell type.  This is repeatedly demonstrated when exogenous BDNF is injected into organisms and cell cultures.

Lifestyles that promote BDNF improve cellular structure and function and thereby improves life, central executive function (frontal lobe where non-impulsive judgement takes place), mood, social function and the real and virtual environments in which one lives.

One can choose BDNF increasing lifestyle or BDNF decreasing lifestyle with opposite results.
Most do not choose but live a blended lifestyle.  These choices are more impactful at the beginning and end of life before 25 and after 40.

Environmental enrichment and neurogenesis: from mice to humans

The brain is a dynamic structure that constantly undergoes cellular and molecular changes in response to the environment. Ultimately, these experience-dependent changes modify and shape behavior. One example of this neuroplasticity is the robust and continuous generation of new neurons that occurs in the dentate gyrus (DG) of the hippocampus. These new neurons are thought to play a fundamental role in hippocampus-dependent behavior and are modulated by experience and changes in the environment. In this review, we will focus on the cognitive and molecular relationship between environmental enrichment and adult neurogenesis. In addition, we discuss some of the similarities between the human and animal literature in regards to neurogenesis, hippocampus-dependent behavior, and environmental enrichment.
Current Opinion in Behavioral Sciences 2015, 4:56–62
This review comes from a themed issue on Cognitive enhancement
Edited by Barbara J Sahakian and Arthur F Kramer
For a complete overview see the Issue and the Editorial
Available online 2nd March 2015
2352-1546/© 2015 Elsevier Ltd. All rights reserved.

Monday, November 16, 2015

Overview on Importance of Metabolic Cellular Health

Overview of Metabolic Cellular Health

Machines require energy.  Biological entities require energy. Cells require energy.

Organisms degrade because organs degrade because cells degrade because their metabolic energy and substrate needs are not met because their mitochondria are degraded by inflamaging or injury.

Can this be avoided or reversed?  Consider "immortal" cell cultures of human cells and the variable length of life of various mammals as evidence that cellular life and organism life can be enhanced.

All energy comes from the sun and its energy dividends for the "circle of life" on earth.

Spiritual wisdom summarizes the known why, how and what of life  in human thought.  By this I mean to use common frames of Christian scripture to reframe the above biology!

Consider the following scriptures:

Jesus stated in John 10:10, " My purpose is to give them a rich and satisfying life...I came that they may have life, and may have it abundantly."

Proverbs 10:16 states "the wages of the righteous is life..."

Paul states that the "wages of sin is death..."

Consider the following equalities:

Wealth + Wages - Expenses

This formula for secondary property that is important but also can be taken away like silver and gold.

Health + BDNF (brain derived neurotrophic factor) -  Inflamaging (activated cellular innate immune activity)

This formula for primary property is more essential for life and cannot be taken away for the gain of others.

Here I see the energy and health of the cell as essential for a rich, satisfying and lengthy life for you.  More BDNF and less Inflamaging.  In the word of Mr. Miyagi, "wax on, wax off" meaning more life is the balance of more wax/life building action.

Perform activities that promote BDNF levels.
Avoid activities and substances that reduce BDNF or that yield more inflamaging than BDNF, more wax off than wax on.

Consider as adjuncts to more BDNF, anti-inflamaging strategies to avoid activation of the cellular inflamasome and its components NLRP3, Pro-interleukin 1beta and Caspase which together lead to apoptosis or programmed cell death.

Agents that inhibit the inflamasome components include Melatonin, DHA and Beta hydroxybutyrate (coconut oil or MCT oil derivative), red near infrared light.  See prior blogs for details.  Also know that medications including centrally acting ACE and ARB drugs inhibit the inflammasome and prolong life in heart failure, renal failure and cognitive decline secondary to neurodegenerative diseases.

Monday, October 26, 2015

Melatonin plus exercise yields neuroregeneration


Here using a middle cerebral rodent infarct model the following conclusions can be drawn:

1.  Melatonin protects injured but recoverable stunned brain cells. (Antioxidant effect)
2.  Exercise increases connectivity of neurons that survive. (BDNF effect)

3.  Both together protect via Melatonin inhibiting Reactive oxygen species directly, inhibiting inflammasome indirectly; and, Exercise increasing BDNF directly and thereby increasing nerve connectivity via dendrites, synaptic message amplification, cellular energy metabolism, hippocampal neurogenesis allowing reintegration of the command and control of these cells for future recovery and conscious use.

The brain of the brain is the hippocampus.  It learns, predicts and motivates the rest of the brain.
Adult neurogenesis is what makes BDNF the memory chemical.
Adult neurogenesis is what makes BDNF the positive mood chemical.

BDNF promotes distal command and control systems primarily as a hormone effect with neuron  connections as target organ.
BDNF promotes cellular energy efficiency as a paracrine effect with energy sensing and promotion as targets.

Pivotal role of melatonin plus exercise as a neuroregenerator following focal cerebral ischemic injury

  1. Yonggeun Hong2,3,4
+ Author Affiliations
Among the numerous studies related to therapeutic mechanism following stroke, neurogenesis plays a critical role. Therefore, we hypothesized that combination therapy with melatonin and exercise might exert on the neurogenesis after focal cerebral ischemia. Sprague-Dawley rats were randomly divided into control (Con) and middle cerebral artery occlusion (MCAo) groups treated vehicle (Veh), melatonin (MT), exercise (EX), and melatonin with treadmill exercise (MT+Ex). MCAo-induced neurological deficits were improved by melatonin with and without exercise. Furthermore, we confirmed the expression of NeuN and Doublecortin were significantly reduced in MCAo+Veh, while melatonin with without exercise attenuated these alterations. The expression of BDNF, in particular mature-BDNF was increased, but not pro-BDNF after MCAo. These changes were reduced at chronic phase of MCAo. GFAP expression was increased in lesion area of MCAo+Veh, then melatonin with and without exercise decreased these changes. By histological examination, MCAo-induced infarction volumes were reduced by melatonin with and without exercise. We found that neurite length from perikaryon was markedly diminished than control rat. However, melatonin plus exercise promotes neurite outgrowth from penumbra to infarct core lesion. Thus, these results demonstrate that melatonin plus exercise could contribute to neuroregeneration and support the potential use for stroke. Funding: 2014R1A1A3051724, 2013 Post-Doctoral Research Program of Inje University, 2012R1A1A2005089, 2013R1A2A2A01067169, KGM4611512

Adolescents with bipolar lineage have decreased BDNF and increased inflammasome activity.

Adolescents with bipolar lineage have decreased BDNF and increased inflammasome activity.  

Can one prevent and or improve bipolar onset or symptoms in susceptible or diagnosed individuals?  

BDNF is normal in bipolar individuals without symptoms but decreased in both depressed and manic states.

Bipolar has 1% lifetime prevalence.  Depression has 6% prevalence.

How to treat follows:

DHA and Melatonin reduces brain Inflammasome activity.  Slow paced breathing reduces brain TNF alpha and cortisol.
1.  DHA. 1000 mgs daily.
2.  Melatonin 3 mgs at evening.
3.  Shoulders level throughout belly breathing 5 seconds in 5 seconds out for 2 minutes twice daily.

Intermittent fasting, high intensity interval exercise, slow paced breathing and brain.hq.com increases neuroprotective BDNF.
1.  See beginning of blog.


I believe from this evidence below that Bipolar and other mood disorders can be prevented or countered by the same treatments for prevention of Alzheimer's and Parkinson's; 1. increasing BDNF and 2. inhibiting the inflammasome especially of glial and macrophage cells which are the bridge between cellular innate immunity and the systemic immune system.

This bipolar disease prevention strategy is analogous to diabetes prevention strategy via exercise and diet.  

The link below has abstract and full text.

http://onlinelibrary.wiley.com/doi/10.1111/bdi.12231/full


Joseph Thomas (Tony) Liverman, Jr.

Saturday, August 15, 2015

BDNF Levels and Addiction are Inversely Proportional

Corticostriatal BDNF and alcohol addiction — ScienceDirect

Alcohol, like opiates, reduce BDNF gene expression which moderates substance use.
Low BDNF = high substance use...uncontrolled substance use.
My DrLiverman.blogspot.com is based on lifestyle that promotes higher BDNF, improved metabolic health and reduced inflamaging.
Intermittent fasting, low glycemic diet, 4 minutes of high intensity interval exercise daily, weekly resistance training, 2 minutes of slow paced diaphragmatic breathing and brain speed training all increase brain and peripheral BDNF.

Addicts and alcoholics could apply this science in their recovery plans.
This includes gambling from prior studies.
Brain speed training alone reduced relapse of gambling or opiate use from 68% to 44% in separate published studies.
If combined lifestyle changes raises BDNF gene expression and levels, one could reasonably expect increased reduction of relapse.
In another study comparing high intensity interval training with and without brain speed training combined allowed men to pedal 115% farther in an exercise to exhaustion test compared to 42% without a second proved BDNF elevator.


Corticostriatal BDNF and alcohol addiction


Joseph Thomas (Tony) Liverman, Jr. MD

Melatonin as Antioxidant Blocks Inflamasome Caused Fibrosis

This article was sent to me stating that melatonin prevented or cured an animal model of pulmonary artery hypertension.

Melatonin as preventative and curative therapy in pulmonary hypertension.


This is a provocative abstract.  I had also previously reviewed other various animal models of inducing pulmonary artery hypertension and cardiomyopathy. (Resulting in thickened, fibrosed blood vessels, heart and lung interstiums with decreased compliance or elasticity.). Incidentally this also describes changes occurring with skin aging.

To wit.  The fibrosis, inflammation and pulmonary artery hypertension is due to pressure and degenerative changes via the inflamasome mechanism.  Melatonin blocks the increase in oxygen radicals that activate the inflamasome cascade of caspase and Il-1B.
Melatonin can be given ahead or at the time of ischemia-reperfusion and acts via blocking the inflamasome.

This same inflamasome causes pyroptosis or cellular degradation leading to disruption of cellular calcium potassium channels and mitochondrial integrity with further activation of the inflamasome.  Without energy or capital, cells degrade, fibrose or die.

This is the fate of pancreatic beta cells and alpha cells.  Inflamasome activation and mitochondrial pyroptosis leading to energy poor cells and little or no production of glucagon or insulin.

Broadly speaking, there are studies supporting four methods to block the inflamasome.

1. DHA 1000 mgs daily.
2. Melatonin 3-6 mgs in evening.
3.  MCT oil or coconut oil 30 mls daily blended in food or liquid.
4.  Red Near Infrared light absorbed by cytochrome c in mitochondria yielding additional infusion of ATP for cell energy and cell capital.  More on this in my next blog post.

The core defect of metabolic syndrome is decreased fatty acid oxidation leading to greater reliance on glucose metabolism and net loss of peak cellular energy.  A cell or business bleeding energy, cash or capital will become weak.
BDNF is a bio marker for efficient fatty acid oxidation and metabolic health.
When BDNF is elevated by lifestyle, diet and brain fitness, cells have abundant energy with strong reserves in stored body fat for the body and glucose and ketones for the brain.

Experiment:  treat metabolic syndrome patients with Mediterranean diet, intermittent weekly fasting, HIIE 4 minutes daily, Weekly resistance training, Brain speed training to restore BDNF levels and fatty acid oxidation.  With and without the 4 blocking the inflamasome measures above.  Return to normal? Reversed metabolic syndrome?

An inverse study variation of the above would be to inversely treat metabolic healthy persons and give a high carb diet, little or no exercise, no computer access no socialization.  
Prisoners? Trauma victims? Open heart surgery patients? Stroke patients?  BDNF should go down, energy down, apathy up, cognitive slowing ( all symptoms of depression) and increased inflammatory markers up as the inflamasome is not inhibited.  Expect increase numbers of Metabolic syndrome markers with inflammation markers up.



Joseph Thomas (Tony) Liverman, Jr. MD









Light Energy Increases Cell Energy; and Cell Production Efficiency

Light Energy Increases Cell Energy; and Cell Energy Production Efficiency.

ATP is the currency of cellular energy in man and animals.  Death of microbes (single celled organisms) can be confirmed by the absence of ATP which is transiently made to power the cell.  It is like the "manna from heaven" in that it provides energy sustenance transiently because it so readily discharges the energy to make heat or heat and  cellular activity.  90% of the oxygen used by the body is consumed by mitochondria, the cellular energy factory, in making and storing energy in the phosphate bonds of ATP and ADP.  The predominant source of that energy is the sun transferred to our planet as light energy.  It warms the earth with heat and provides the source of energy for plant photosynthesis.  All animals consume plants on earth or plankton in the ocean.  Energy from the sun directly from plants or indirectly from animals that eat only plants.  For warm blooded man, sunlight = warm environment + ATP.

Does light energize the cell directly?  Yes, but only in small amounts.
The red and near infrared frequency are absorbed by cytochrome c in the mitochondria and absorb the energy as an electron and send the power to make ATP through the electron chain transport system that makes power or ATP for the cell.

How is this useful?  It is useful in the same way that heater strips are useful in heat pumps.  When the mitochondria becomes degraded and inefficient, light energy is the most efficient way to make ATP, just as heater strips make energy more efficient because the available temperature gradient is narrow.

In effect, aging inefficient mitochondria cannot make enough energy to refurbish and improve cellular functions to fight aging, senescence and cell death.  Light therapy empowers the cell to heal and regenerate!

What evidence is there for light regeneration of cell, organs and organisms?

Rabbits underwent posterior knee deconstructive surgery damaging ligaments and  cartilage.  The post-op knees were treated with sham light and red near infrared light separately.  The sham light treated knees were damaged after healing.  The red near infrared light knees were not damaged after healing.

Knees treated with red near infrared light checked before and after treatment have reductions in synovial fluid inflammatory markers including COX2, TNF alpha and IL-6 levels.  These are the targets for inflammatory treatments NSAID such as ibuprofen and TNF blockers such as Humira used in rheumatoid arthritis.

In rodents who have their bilateral sciatic nerves interrupted by removing a short length of the nerve but connecting the two ends by placing them in a sheath treated with and without red near infrared light; greater healing and less oxidation radicals occurred within the sheath of light treated side.

In cell culture, red near infrared treated cells have shifted ADP/ATP ratios indicating greater production of ATP.

The Willow Curve is a commercially available red near infrared laser treatment of knees, hips and shoulders with endorsements of pain relief and improved function that resulted in delay of scheduled surgical joint replacement.

Red LED light has successfully treated acne with and without blue wavelength light to disrupt the bacteria responsible for acne.

There are an abundance of LED devices.  Examples include the LED devices sold by Elixa.com.  These have single or double arrays.  I use the dual array of red near infrared 120 array device that delivers 1J/CM2/Min.  Published treatments of joints used 10-22 joules of energy daily.  Published treatments of cells in culture used 2-10 joules of energy.  Therefore I would use red only 2-10 Joules for skin or superficial structures (protecting or shielding the eyes and thyroid) and use red near infrared 10-22 Joules in two divided doses for joints or deeper structures.

One could use adjunctive light treatments for joint pain, wound healing, inflammatory acne and neuropathy.

Moreover, there is research on local light treatment and distal effects, a so called abscompal effect.  In traumatic brain injury animal subjects treating the normal side of the brain improved the opposite untreated sided.  In two genetic rodent models of Alzheimer's disease, treatment of the lower leg with 22 joules of red near infrared light resulted in prevention and delayed onset of dementia.  In another animal model of drug induced Parkinson's disease leg treatment with 22 joules of red near infrared light prevented Parkinson's disease.

Could one prevent or delay neurodegenerative disease with light treatment of the tibia the lower leg bone?  The distant tissue improvement was the result of activating adult mesenchymal stem cells in bone marrow.  When activated or energized, the stem cells migrate to tissue secreting inflammatory cytokines ie. brain tissue.  They remain stem cells and do not make new brain cells.  They message or increase local  healing growth factors to do the protecting or healing.

Thursday, July 9, 2015

Intermittent Fasting Reduces Aging; and Systemic Sclerosis?

Intermittent fasting reduces aging;  and systemic sclerosis!  See commentary and article below.

If systemic sclerosis is both autoimmune and innate immunity related and the macrophage is the bridge between the two systems, INCREASING the macrophage's ability to phagocytosis or eat and destroy superfluous inflammatory inciters in their cytoplasm would regulate or re-regulate the inflammation of both systems!

Aging also degrades macrophage through reduced AUTOPHAGY leading to reduced protective function and increased degenerative function. 

One activity known to increase phagocytosis is INTERMITTENT FASTING or fasting once a week for 23-24 hours.  Restricting  carbohydrate and protein, but not fat, is required because the action of gene switching follows lowering of insulin and insulin growth factor 1.  I have performed weekly fasting for over 2 years.  On fasting days I substitute modified bulletproof coffee (containing coconut oil) i.e. coffee without glucose or protein, (stevia, heavy cream and 30 mls of MCT or coconut oil) for the 2 missed meals and snacks.  This provides beta hydroxybutyrate for brain energy needs that supplements stored glucose release from the liver.  This brief fasting turns on genes of longevity and regeneration, increases helper proteins called chaperones to correct misfolded proteins such as enzymes and lastly takes any superfluous trash or misfolded proteins and loose mRNA and recycles them through PHAGOCYTOSIS into usable elements that are harmless and not able to incite the inflamasome and degrade the macrophage cell purpose.

Increased PHAGOCYTOSIS is the opposite of reduced AUTOPHAGY ; improvement preserves the function of macrophages despite age, disease or disorder.  See abstract below.


Innate immune system involves toll like receptors and the inflamasome and is generally considered a form of individual cell immunity.  Adaptive immunity is the immune system to protect the organism such as antibodies and cellular immunity of macrophages and T lymphocytes.

Tony Liverman

Abstract

Macrophages provide a bridge linking innate and adaptive immunity. An increased frequency of macrophages and other myeloid cells paired with excessive cytokine production is commonly seen in the aging immune system, known as ‘inflamm-aging'. It is presently unclear how healthy macrophages are maintained throughout life and what connects inflammation with myeloid dysfunction during aging. Autophagy, an intracellular degradation mechanism, has known links with aging and lifespan extension. Here, we show for the first time that autophagy regulates the acquisition of major aging features in macrophages. In the absence of the essential autophagy gene Atg7, macrophage populations are increased and key functions such as phagocytosis and nitrite burst are reduced, while the inflammatory cytokine response is significantly increased - a phenotype also observed in aged macrophages. Furthermore, reduced autophagy decreases surface antigen expression and skews macrophage metabolism toward glycolysis. We show that macrophages from aged mice exhibit significantly reduced autophagic flux compared to young mice. These data demonstrate that autophagy plays a critical role in the maintenance of macrophage homeostasis and function, regulating inflammation and metabolism and thereby preventing immunosenescence. Thus, autophagy modulation may prevent excess inflammation and preserve macrophage function during aging, improving immune responses and reducing the morbidity and mortality associated with inflamm-aging.
© 2015 S. Karger AG, Basel


Article / Publication Details

Received: 6/13/2014 8:13:00 PM
Accepted: 11/25/2014
Published online: 3/10/2015
Issue release date: June 2015
Number of Print Pages: 17
Number of Figures: 6
Number of Tables: 2
ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)
For additional information: http://www.karger.com/JIN


Open Access License / Drug Dosage / Disclaimer

Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution 3.0 Unported license (CC BY 3.0) (www.karger.com/OA-license-WT), applicable to the online version of the article only.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


Mind Body Age = Cellular Energy + Regenerative Gene Expression6 - Degenerative Inflammation Activation

Energy + Regenerative Gene Expression - Degenerative Inflammation Activation = Metabolic Resilience OR Organism/Organ/Cell Age

Read first the conclusion of the paper linked below.

http://onlinelibrary.wiley.com/doi/10.1111/imr.12295/pdf

The conclusion wrongly implicates obesity and not macrophage and micro glia (brain macrophage) activation or cellular innate immunity activation as the culprit in degeneration even though they showed evidence that calorie restriction and intermittent fasting blocked the activation of inflammatory macrophages ( whether fat or not, young or old.)  They also showed that NLRP3 knock out mice did not get age related inflamaging.

The evidence herein shows how BHB beta hydroxybutyrate from calorie restriction and/or coconut oil inhibits activation of damaging macrophages and microglia which prevents organ damage in the body and brain respectfully. 

Moreover, intermittent weekly fasting reduced many of the age related inciters of the innate immune system or inflamasome, through auto phagocytosis of waste in lysozymes rendering the molecules unable in their reduced elements to incite NLRP3, thereby prolonging quality of life and length of life.  This occurs at the beginning of a prolonged fast which has three actions, make essential proteins, activate cellular chaperones or folding helper proteins to correctly fold misfolded proteins and recycling of persistently misfolded proteins in lysosomes or chemical bags that convert molecules into elements for recycling.

The article more than hints that both "disease and conditions" are improved by blocking the inflamasome  of which NLRP3 is the initiator.  Moreover it also implicated crystals and clearing of crystals as important whether they be cholesterol, Uric acid or beta amyloid crystals in preserving cell, organ and organism integrity.  

The section on Vitamin D was also revealing as an agent to modify inflammatory response in all tissues and not just in bone osteoclasts.  The combination of vitamin D3 and K2 removes calcium crystals from atheromatous plaques thereby blocking the NLRP3 activation leading to atherosclerosis, ruptured plaques and/or aneurysmal rupture.


Saturday, June 13, 2015

Alzheimer's Review Article Prescription for Action.

Brain metabolic health and Body metabolic health are linked through shared metabolism, inflammation and repair pathways.  

Therefore improving the metabolism of the body or brain helps both.  
Inhibiting the inflamasome cascade helps both brain and body.  
Promoting the repair and longevity gene expression in brain and body cells builds resilience for both.  

What would supply evidence of increased physical resilience?

A body with increased aerobic capacity for exercise?
A body with increased lean body mass?
A body that metabolizes fat into ketones after an overnight 10 hour fast?
Increased beat to beat heart rate variability?
More good HDL cholesterol?
Less bad LDL cholesterol?
LDL cholesterol particles that are larger, with lower particle count and hence are less atherogenic?
Increased BDNF, GDNF and NGF?
Increased insulin sensitivity?
Increased sympathetic, parasympathetic tone?
Increased subcortical and cortical brain speed for auditory and visual processing speed?

ALL the above RESULT FROM THE FOLLOWING PRESCRIPTION that increases BDNF.

1. Mediterranean diet with supplemental MCT and coconut oil. 30 ml once daily for low dose and up to 4 doses daily for high dose.

2.  HIIE 4 minutes daily 5 or more days per week.  Resistance training once per week (low dose) or 3-5 times per week (high dose)

3.  Brain training up to 40 hours or 90 percentile.  Note that subcortical sensory processing is the most improved part of the brain, the automatic non thinking part of responding to brain exercises. Alzheimer's is believed to begin in the brain stem and degrade noradrenergic neurons antegrade to the higher cortex.

4.  2 minutes of slow paced breathing 5 secs in and 5 secs out for two minutes twice daily.

5.  VLS#3 a commercial probiotic has recently been shown in mice to reduce inflammation in the brain by its effect on modulating the gut-brain axis and increasing BDNF either directly or indirectly by inhibiting micro glia action in the brain.  These bacteria may increase short chained fatty acids in the gut from unrestricted starch such as the fiber of nuts.

Alzheimer's Review Article Summarized

Alzheimer's has a decade long phase of Glucose hypo-metabolism (reduced metabolism) in the brain. Ketone body (a special derivative of fat) metabolism remains unaffected and intact. 

Sub cortical (the root level, reactive non-thinking base of the brain) damage precedes  Alzheimer's. 
Beta-amyloid protein (an abnormal cell waste product) is toxic.
Micro glia (immune function cells in the brain) inflame and degrade neurons (nerve cells) and astrocytes (nerve support cells.)
Impaired astrocyte function degrades cognitive function from damaged energy metabolism for the neuron (nerve cell) and decreased inhibition of micro glia action to destroy nerve cells and their connections. 

Mitochondrial DNA is inherited from the mother in humans. 
Glucose hypometabolism (inability to use glucose for energy) is more severe with 2 demented parents, intermediate with only demented mother and least with only demented father. 

Glucose hypometabolism leads to less hexokinasei (an enzyme used in glucose metabolism) binding of mitochondrial anion channels (energy requiring revolving door of the mitochondrial wall) which prevents escape of untreated and damaging ROS (reactive oxygen species analogous to rust particles). More cellular ROS activates oxidative stress (rust) and inflamasomes (chemical committee or molecule that degrades cells). Beta-amyloid in the mitochondria increases ROS production that can escape from the mitochondria into the cell and cause inflammation. 

APP or amyloid precursor protein is produced by neurons, astrocytes and microglia. The latter 2 can rapidly produce APP when stimulated by neuronal injury. 
When cleaved (separated into 2 parts) to an active form by alpha secretase (enzyme= protein that alters another protein), it is soluble and neuroprotective (useful during development)
When alternatively cleaved by beta secretase (an enzyme) it is soluble but not neuroprotective. Further action by gamma secretase (enzyme) makes soluble beta amyloid and a generator of ROS and inflamasone activation. With increasing and concentrated amounts, beta amyloid precipitates in cells and forms non-soluble aggregates. 
Dementia correlates best with soluble Beta amyloid which is the toxic form. The precipitates and plaques of beta amyloid are only non-soluble residues of the invisible soluble toxins that have already damaged the cell and brain. (Analogous to radioactive precipitates or aggregates after a nuclear blast, the damage is done and only the contamination remains)

This leads to oxidative stress, release of stimulating glutamate (a brain chemical that 
activates, energizes or over energizes) which causes extra synaptic NMDA receptor 
activation and synaptic loss. (Analogous to a power surge that damages the function)

The  damage by soluble beta amyloid (which blocks glucose uptake, oxygen uptake and astrocytes mitochondrial depolarization producing a dead battery/mitochondria) is blocked or prevented by addition of pyruvate, the end product of glucose metabolism in the cell outside of the mitochondria which next becomes fuel for the mitochondria. 

Beta hydroxybutyrate, a ketone energy chemical derived from medium chain triglycerides such as coconut oil, also blocked soluble beta amyloid damage.  

Energy supplied, in the form of pyruvate, prevented cognitive decline (synaptic signaling or long term potentiation and synaptic loss) without reducing amyloid precipitates and plaques in a mouse model of Alzheimer's. 

Conjecture:  since a small level of supplemental energy 4mM of beta hydroxybutyrate like pyruvate 5mM inhibits soluble beta amyloid damage; and because beta hydroxybutyrate binds NLRP3 to prevent activation of the inflamasone which leads to cell death;  improved metabolic health represented by ketosis after 10 hour fast, high BDNF levels (which amplifies metabolism and promotes neuroplasticity and repair) plus low glycemic Mediterranean diet supplemented with MCT and Coconut oil (which makes beta hydroxybutyrate and improves cell membrane function and integrity) plus DHA 900 mg (the omega 3 fatty acid in the brain that demonstrably 
improves language acquisition in the young, improves short term memory by 50% in mild cognitive impairment, a precursor of dementia in the elderly and also improves measurable synaptic and phospholipid membrane functions) would treat both 1.the hypometabolic glucose energy deficit in the cell (ketone such as beta hydroxybutyrate for mitochondrial fuel) and 2. Beta hydroxybutyrate blocks NLRP3 and damage from increased ROS (activation of NLRP3) that results from reduced glucose use for energy in the cell fluid leading to expulsion of ROS from mitochondria. 

Dementia may begin in the subcortex (the brain stem or root level of brain below the cortex) first, an antegrade degeneration originating in the brainstem (root) and secondarily affecting the brain cortex (tree)

The brain stem sends noradrenergic (a stimulant chemical) projections to the cortex. The same system responsible for heart rate variability, indirectly; is directly responsible for beta adrenergic receptor (the target of noradrenalin and adrenalin) stimulation that suppresses the activity of inflammatory transcription factors (gene switches in the DNA) causes alterations in nuclear localization of proteins (chaperones that help fold proteins into their optimum shape for action), and induces gene expression via cAMP-response element binding protein activation (creb =an active protein made by DNA with help from chaperone proteins) which are neuroprotective and anti-inflammatory.   1. These creb proteins increase expression of neurotrophic substances including BDNF (brain derived neurotrophic protein),GDNF (glia derived neurotrophic protein) and nerve growth factor. The absence of these factors are 
permissive for dementia. 2.Noradrenergic enhances metabolism. It promotes glycogenolysis the release of glucose from liver and muscle stores.  It also enhances the rate that NAD and cytochrome can increase the production of ATP with increased demand or intensity of movement or cellular work.


Sunday, June 7, 2015

Improving BDNF is Improving Metabolic Health

Improving BDNF is Improving Metabolic Health


I recommend a fitness regimen that enhances BDNF, (brain derived neurotrophic factor), which increases brain neuroplasticity and metabolic efficiency peripherally in body cells and centrally in brain cells.
Higher BDNF reduces fatigue. 
Lower BDNF, secondary to aging or insults, increases fatigue. 
BDNF is increased by High intensity exercise, resistance training, deep breathing involving the diaphragm and vagal nerve and brain training.
Therefore I recommend the following:

4 minutes of high-intensity Tabata intervals e.g. Timer app for iPhone performed on exercise bike 5 or more days per week. Other exercises can substitute, sprinting, jumping.

2 minutes twice daily of slow paced breathing, 5 secs in 5 secs out, preferably belly inhalation and slow forceful chest exhalation using a power pose as in video below. Maximum movement out of diaphragm while breathing in and maximal movement of sternum in on breathing out.

Brain training at BrainHQ.com 20 minutes daily up to 40 total hours. 

All 3 training exercises above increase BDNF, heart rate variability and stamina; which increases RESILIENCE of physical, mental and emotional domains. 

Bonus weekly resistance exercise to improve and reduce Sarcopenia or lean muscle loss mentioned previously on this blog.

My conjecture about the difference in power and submissive posing effects on testosterone and cortisol is related to differences in breathing i.e. Slow diaphragmatic versus fast chest breathing. The former stimulates vagal  tone, the latter stimulates sympathetic tone. The former decreases Il-6, a blood marker of inflammation cascade activation; the latter increases Il-6 especially hyperventilation.