Protect Your Brain with Real Food

Energy consumption raises GIP and GLP1 in the proximal and distal intestine respectfully. 

Processed foods  that are nearly completely absorbed in proximal intestine raise GIP and reduce GLP1.

Unprocessed foods and low glycemic foods raise both GIP and GLP1.

Fruit juice (processed) raises GIP but fruit with peel and fiber raises first GIP and later raises GLP1.

 GLP1 is neuroprotective. GIP added to GLP1 is even more protective.

They have developed dual agonist for disease state protection.

A smart strategy is to eat real food that has low glycemic index and fiber to feed gut bacteria primarily and secondarily  via fermentation products to raise GLP1 in the distal ileum.

https://www.sciencedirect.com/science/article/pii/S0028390818300406

abstract

In animal models of neurodegenerative disorders, they show superior neuroprotective effects.

Type 2 diabetes is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or Parkinson's disease. The link appears to be insulin de-sensitisation in the brain. Insulin is an important neuroprotective growth factor. GLP-1 and GIP are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson’ disease. Novel dual GLP-1/GIP receptor agonists have been developed to treat diabetes, and they also show good neuroprotective effects that are superior to single GLP-1 analogues. Several newer dual analogues have been tested that have been engineered to cross the blood –brain barrier. They show clear neuroprotective effects by reducing inflammation and oxidative stress and apoptotic signalling and protecting memory formation, synaptic numbers and synaptic activity, motor activity, dopaminergic neurons, cortical activity and energy utilisation in the brain. These results demonstrate the potential of developing disease-modifying treatments for Alzheimer's and Parkinson's disease that are superior to current single GLP-1 mimetics.

This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’

Hormones Make Us Lean or Stout- You Can Manage Your Hormonal Portfolio

Everyday  physicians treat metabolic syndrome and their resulting diseases. 2 of every 3 patients are insulin resistant.

This blog post by Amy Berger  in the link below states an uncommon truth.  I highly recommend her blog, books and YouTube talks and especially appreciate her ease of expression and simplicity of approach to better metabolic health.  Hyperinsulinemia or insulin resistance syndrome can only be reversed by lowering chronic insulin levels (and modifying other hormones.) How?

Low carb diet.

12 hours or more of daily fasting.

Tabata  daily exercise to improve insulin resistance by 39%.

Mediterranean diet.

1. Wheat germ.

2. Nuts and olives.

3. Fruit (skins) and broccoli family vegetables.

(The above are young seeds and sprouts that have chemicals that increase Nrf2 activation that raise antioxidant enzymes.  Antioxidant enzymes are directly proportional to mitochondria mass and basal metabolic rate.)

Amendment to Mediterranean diet.

4. Eggs.  (Animal seeds or sprouts) See above remark about young cells effect on older cells metabolism.

Reduce leaky bowel, bacterial translocation, inflammation that increases CORTISOL with homemade yogurt loaded with probiotics, omega 3 fatty acids, butyrate and lactate.

Reduce stress increased CORTISOL with vagal nerve stimulation to stimulate the CAP cholinergic anti inflammatory pathway.  Two minutes of biofeedback cardiopulmonary resonant breathing at rate of 0.1 cps or one breath every six seconds.  One could also use a transcutaneous vagal nerve stimulator 4 minutes daily.

Restorative sleep and optimized circadian rhythm increases intermittent MELATONIN the restorative and neuroprotective hormone. (Also a great supplement)

Adequate sunlight during the day increases intermittent production of VITAMIN D, the sunshine hormone.  (Also Vitamin D3 is a great supplement especially during the winter months without sunshine)

Magnesium rich foods or magnesium chloride. (Magnesium is required by every ATP energy molecule in addition to other enzymes.)

Avoid processed foods which raise GIP/GLP1 ratios and drive appetite hormone.  GIP is in the proximal small intestine and GLP1 is in the stomach and distal small intestine.  Over processing allows absorption and GIP stimulation and decreased distal carbohydrates for GLP1 stimulation.

I speculate that controlling "chronic" elevation of both CORTISOL and INSULIN is required for optimum health.  Bacterial translocation increases with aging  or inflamaging of gut and may be responsible for insulin resistance syndrome and chronic cortisol elevation because of LPS or endotoxin stimulation of neuroimmune system sensors.  

A single exception disproves a rule.  1 of 3 adults (and most children) are metabolically healthy despite the western diet which makes them resilient.  I speculate that strong exterior barrier function of  healthy gut, skin and respiratory linings, and healthy internal barrier linings including the blood brain barrier accounts for their resilience to simulators of inflammation.

In other words, leaky gut allows bacterial translocation and  causes chronic inflammation that manifest as chronic hormonal drivers of insulin resistance syndrome.  I suspect this is the core  or root cause of dysbiosis, a driver of leaky bowel, chronic hormonal dysregulation and insulin resistance syndrome.  Therefore vagal nerve simulation and homemade yogurt and other fermented foods are essential to climb out of the metabolic insulin resistance hole to become whole and resilient.

http://www.tuitnutrition.com/2016/11/obesity-is-hormonal.html#more

Obesity is (mostly) a Hormonal Issue: Let's Stop Pretending it's Solely About Calories

Cortical Nerve Network Plasticity; Build Out then Maintain.

Developing children have basal nerve stem cell formation and therefore basal neurogenesis and repair.  In short, basal cortical plasticity.

Not so the mature adult.  Once the brain is well formed or built, neurogenesis becomes a function of autophagy and stemness maintenance.  

Daily twelve hour or more fasting promotes autophagy and stemness.

Other stemness maintenance agents are spermidine for proteostasis and autophagy, melatonin, hydrogen rich water and Nrf2 activators such as sulforaphane which also increases autophagy.

Separately, both spermidine (wheat germ) and Sulforaphane (broccoli sprout extract) have increased healthspan and lifespan 30% in yeast, c. Elegans worms, fruit flies, mice and human cell cultures.

Except from: On the Role of Basal Autophagy in Adult Neural Stem Cells and Neurogenesis

Adult neurogenesis persists in the adult mammalian brain due to the existence of neural stem cell (NSC) reservoirs in defined niches, where they give rise to new neurons throughout life. Recent research has begun to address the implication of constitutive (basal) autophagy in the regulation of neurogenesis in the mature brain. This review summarizes the current knowledge on the role of autophagy-related genes in modulating adult NSCs, progenitor cells and their differentiation into neurons. The general function of autophagy in neurogenesis in several areas of the embryonic forebrain is also revisited. During development, basal autophagy regulates Wnt and Notch signaling and is mainly required for adequate neuronal differentiation.

The available data in the adult indicate that the autophagy-lysosomal pathway regulates adult NSC maintenance, the activation of quiescent NSCs, the survival of the newly born neurons and the timing of their maturation. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187079/

Vagal cardiorespiratory breathing improves fluid intelligence and other organ function

This article is interesting relative to cardiorespiratory resonant breathing.

Buteyko breathing improves asthma because of breathing retaining?

Prayama yoga breathing also improves asthma similarly.

In India diabetes is mitigated by this breathing technique.

In the case below asthma measurably improves.

Stress symptoms are lowered.

Why?

Cardiorespiratory resonant breathing activates a vagal reflex that improves the brain by lowering cortisol and increasing BDNF; it improves organ function by activating the CAP cholinergic anti-inflammatory pathway by releasing acetylcholine into circulation to phenotypicaly shift angry M1 macrophages into M2 status macrophages.  That shift reduces immune stress that degrades cells, tissues and organs.

Vagal nerve stimulation also tunes the ensemble of 5 unique human abilities.

I infer that this "tunes"or connects the human "hive" mind in every individual to improve their fluid intelligence which allows novel problem solving.

https://www.tandfonline.com/doi/abs/10.1080/09593985.2017.1400139

Breathing pattern recordings using respiratory inductive plethysmography, before and after a physiotherapy breathing retraining program for asthma: A case report

Breathing retraining (BR) improves symptoms, psychological well-being and quality of life in adults with asthma; but there remains uncertainty as to mechanism of effect. One of the intuitively logical theories is that BR works through altering breathing pattern. There is currently no evidence, however, that BR does result in measurable changes in breathing pattern. In this case report we describe the effects of physiotherapy BR on a 57-year-old female with a 10-year history of asthma. Data were collected before and after a physiotherapy BR program comprising three sessions over 18 weeks: breathing pattern (respiratory inductive plethysmography (RIP); physiology (end tidal carbon dioxide (ETCO₂), heart rate, oxygen saturations, spirometric lung function); questionnaires (Asthma Control Questionnaire (ACQ), Hospital Anxiety and Depression Score, Nijmegen Questionnaire); and medication usage. After BR, the patient’s symptoms improved. Her physiology was largely unchanged, although her FEV₁ increased by 0.12L, peak flow by 21L/min. The patient reported using less Salbutamol, yet her asthma control improved (ACQ down 1.5). Her Nijmegen score dropped from positive to negative for hyperventilation (from 39 to 7). Her anxiety-depression levels both reduced into ‘normal’ ranges. The patient’s expiratory time increased, with longer respiratory cycles and slower respiratory rate. No changes were seen in relative contributions of ribcage and abdomen. Controlled trials are now needed to determine the generalizability of these findings.

Joseph Thomas (Tony) Liverman, Jr.

Health and Disease is a NONLINEAR FUNCTION

TG/HDL ratio is the strongest predictor of insulin resistance syndrome which is the root cause or strongest cause of atherosclerotic morbidity and mortality.  Not LDL!

Endothelial dysfunction increases as arteries become stiff and microvascular vessels become less able to normally promote flow mediated dilation to increase metabolism and function of cells, tissues and organs, like the heart, brain and kidneys.

Study table 1.  As ratio increases every parameter of metabolic syndrome increases.

Blood pressure, fatty liver,  diabetes, etc correlates.

I suspect sleep apnea also correlates and the ratio improves with cpap.

Mediterranean diet, exercise, vagal nerve stimulation, 12 hours of fasting REDUCE RISK EXPONENTIALLY.  This means that small changes  in ratio produces greater rewards for atherosclerosis prevention.

Compare ACE/ARB to metoprolol.  The former reduces diabetes (insulin resistance syndrome) 9% and the latter increases diabetes risk 9%.  It follows that endothelial dysfunction, arterial stiffness, heart failure, stroke, dementia and acute coronary syndrome mean occurrence is therefore shifted toward or away from disease.  

The Mediterranean diet studies show an 8 fold reduction in coronary artery disease 

( 2% vs 16%.)  Does a 9% downward shift in diabetes risk (18% from metoprolol) result in. fold or 800% reduction in coronary artery disease, a non linear result that costs the same.  Lifestyle changes cost next to nothing and therefore is priceless.

This study also informs about the non linear relationship or exponential increase (or decrease) in risk.  Small changes and small costs are exponentially beneficial.  TG/HDL ratio is a useful biomarker of right track wrong track.

401 K is exponentially increased at retirement from strongest to weakest by time (start early), interest rate (aggressive but safe asset allocation model) and capital ( invest all lose money up to maximum.)

Knowing where the leverage in any system allows minimum effort to achieve Herculean outcomes.

https://lipidworld.biomedcentral.com/articles/10.1186/s12944-018-0776-7

Triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio and arterial stiffness in Japanese population: a secondary analysis based on a cross-sectional study

Jia-Lin Dai

Lipids in Health and Disease201817:130

https://doi.org/10.1186/s12944-018-0776-7

©  The Author(s). 2018

• Received: 20 November 2017
• Accepted: 14 May 2018
• Published: 29 May 2018

Background

Previous studies have revealed that triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio (henceforth TG/HDL-C) is one of major risk factors of cardiovascular diseases, insulin resistance and metabolism syndrome. However, there are fewer scientific dissertations about the correlation between TG/HDL-C and bapWV. This study was undertaken to investigate the relationship between Triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio and brachial-ankle pulse wave velocity (baPWV) in Japanese.

Methods

The present study was a cross-sectional study. 912 Japanese men and women, aging 24−84 years old, received a health medical a health check-up program including the results from baPWV inspection and various standardized questionnaire in a health examination Center in Japan. Main outcome measures included TG/HDL-C ratio, baPWV, fatty liver, postmenopausal status. Abdominal ultrasonography was used to diagnose fatty liver. Postmenopausal state was defined as beginning 1 year after the cessation of menses. It was noted that the entire study was completed by Fukuda et al., and uploaded the data to the DATADRYAD website. The author only used this data for secondary analysis.

Results

After adjusting potential confounders (age, sex, BMI, SBP, DBP, AST, ALT, GGT, uric acid, fasting glucose, TC, LDL, eGFR, smoking and exercise status, fatty liver, alcohol consumption and ABI), non-linear relationship was detected between TG/HDL-C and baPWV, whose point was 5.6. The effect sizes and the confidence intervals on the left and right sides of inflection point were 12.7 (1.9 to 23.5) and − 16.7 (− 36.8 to 3.3), respectively. Subgroup analysis showed, in participants with excessive alcohol consumption (more than 280 g/week), that TG/HDL-C had a negative correlation with BAPWV (β = − 30.7, 95%CI (− 53.1, − 8.4)), and the P for interaction was less than 0.05,

Conclusion

The relationship between TG/HDL-C and baPWV is non-linear. TG/HDL-C was positively related with baPWV when TG/HDL-C is less than 5.6. In addition, while the trend is opposite in excessive alcoholic subjects.

Brachial-ankle pulse wave velocity (baPWV) is served as an indicator to quantify arterial stiffness []. As an independent risk factor of cardiovascular events, baPWV is used in clinical for early evaluating the functions and structural changes of vascular wall [, ]. Despite of the fact that western countries have not fully accepted baPWV, more and more publications on this research methodology came from these countries since 2009 []. Atherosclerosis Risk in Communities (ARIC) study and the Bogalusa Heart Study, the two large-scale studies in U. S, have used baPWV as indicator to assess arterial stiffness [, ].

Previous studies have revealed that triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio (henceforth TG/HDL-C) is one of major risk factors of cardiovascular diseases, insulin resistance and metabolism syndrome [, , , , , ]. Some scholars consider that TG/HDL-C can better predict vascular risk than either does []. However, there are fewer scientific dissertations about the correlation between TG/HDL-C and bapWV. In only a few dissertations [, , ], as authors used the TG/HDL for analyzing categorical variables. In addition, they used GLM as a sole method of data analysis, in which the independent variables and dependent variables must be linear. But in biomedical research, connection between exposures and outcomes may be non-linear. In that case, researchers need a more effective method to deal with non-linear relationship.

Increase Mitochondrial Mass for a Hotter, Healthier Metabolic Rate

Walking is a vagal tone relaxing endeavor that does not increase mitochondrial mass.

Mitochondrial mass is higher in professional athletes than moderately activated amateurs.

Why this is important?

Lower mitochondrial mass persons with activity reach their lactate threshold earlier in exercise.  

Lactate inhibits fat burning relative to carbohydrate metabolism.

The goal is to burn more fat per day or fat per time whether one is resting (basal metabolic rate) or exercising (activity metabolic rate maximum.)

In effect, more mitochondria raises both metabolic rates and eliminates STORED ENERGY FAT and a high fat western diet fat content.

Higher metabolism, higher fat burning, lower BMI AT THE SAME LIFESTYLE.

One makes more antioxidant enzymes or bullets whenever one is burning fat.

Mitochondrial biogenesis is increased relatively by the following.

Exercise where high intensity interval exercise is better than steady state exercise.

Diet where Mediterranean diet food supplements INCREASE ANTIOXIDANT ENZYMES, because they are like "young cells" which make more antioxidant enzymes because they contain more chemical signals that produce them.

(Antioxidant enzymes are directly related to mitochondrial biogenesis.)

Heat as in sauna, climate, hot tubs and exercise which activate heat shock proteins which are directly related to mitochondria and is an exercise mimetic.

Thinner persons have higher mitochondrial mass and or better lower lactate producing diets (Carbohydrate).

HIIE increases mitochondrial mass 14% and jogging 60 minutes aerobically 9% and walking 0 to less.

Are women "hotter" before or after sauna, Mediterranean diet and high intensity exercise?

I know they are "healthier" and with intermittent fasting able to maintain high metabolic rate and burn faster excessive fat stores.

The above discussion is also relevant to the single cell and cell biology.

Exercise related lactate threshold, like aerobic exercise testing, indicates ability to burn fats and not produce lactate from carbohydrates.

Metabolic rates directly correlate to aerobic fitness and mitochondrial mass.

Paradoxically lactate also signals the muscles to increase mitochondrial mass.  This occurs because 30% of lactate produced by type 2 muscle fibers engaged in high intensity exercise is converted into pyruvate and acetylCoA which signals mitochondrial biogenesis.

https://link.springer.com/article/10.1007/s40279-017-0751-x

Assessment of Metabolic Flexibility by Means of Measuring Blood Lactate, Fat, and Carbohydrate Oxidation Responses to Exercise in Professional Endurance Athletes and Less-Fit Individuals

February 2018

Abstract

Background

Increased muscle mitochondrial mass is characteristic of elite professional endurance athletes (PAs), whereas increased blood lactate levels (lactatemia) at the same absolute submaximal exercise intensities and decreased mitochondrial oxidative capacity are characteristics of individuals with low aerobic power. In contrast to PAs, patients with metabolic syndrome (MtS) are characterized by a decreased capacity to oxidize lipids and by early transition from fat to carbohydrate oxidation (FATox/CHOox), as well as elevated blood lactate concentration [La⁻] as exercise power output (PO) increases, a condition termed ‘metabolic inflexibility’.

Objective

The aim of this study was to assess metabolic flexibility across populations with different metabolic characteristics.

Methods

We used indirect calorimetry and [La⁻] measurements to study the metabolic responses to exercise in PAs, moderately active individuals (MAs), and MtS individuals.

Results

FATox was significantly higher in PAs than MAs and patients with MtS (p < 0.01), while [La⁻] was significantly lower in PAs compared with MAs and patients with MtS. FATox and [La⁻] were inversely correlated in all three groups (PA: r = −0.97, p < 0.01; MA: r = −0.98, p < 0.01; MtS: r = −0.92, p < 0.01). The correlation between FATox and [La⁻] for all data points corresponding to all populations studied was r = −0.76 (p < 0.01).

Conclusions

Blood lactate accumulation is negatively correlated with FATox and positively correlated with CHOox during exercise across populations with widely ranging metabolic capabilities. Because both lactate and fatty acids are mitochondrial substrates, we believe that measurements of [La⁻] and FATox rate during exercise provide an indirect method to assess metabolic flexibility and oxidative capacity across individuals of widely different metabolic capabilities

Preventing and Reversing Aging 1,2,3

Is anything more quintessential of aging as sensory loss of hearing (and vision?)

Here age related decline in Nrf2 expression (lack of bullets) leads to cortical auditory degeneration.

Step 1.  More  antioxidant enzyme bullets.  Step 2.  Increase Vagal tone, calm down microglia.  Step 3.  BrainHQ.com to increase BDNF  and rebuild a parallel processing auditory cortex.

This is something I literally did in a study N of 1.

This statistically valid research of step 3 alone produces a 135% increase in auditory processing speed and 230% increase in visual processing speed.  

Why is the processing speed so important?. The sharp  area of central focal vision is small, like a flashlight beam, that uses scanning and processing to see the bigger picture.  PROCESSING, important for seeing, hearing, comprehending and remembering.  Auditory sampling speed determines processing speed and accuracy.

Bullets, Vagal tone and BDNF build.   Age related Epigenetic switching off of Nrf2, alpha 7 Nicotinic acetylcholine receptors and BDNF CpG gene promoter sites is directly correlated to aging and disease in cells, tissues, organs and people.

https://europepmc.org/abstract/med/30272261

Age-associated decline in Nrf2 signaling and associated mtDNA damage may be involved in the degeneration of the auditory cortex: Implications for central presbycusis.

Europe PMC

Central presbycusis is the most common sensory disorder in the elderly population, however, the underlying molecular mechanism remains unclear. NF‑E2‑related factor 2 (Nrf2) is a key transcription factor in the cellular response to oxidative stress, however, the role of Nrf2 in central presbycusis remains to be elucidated. The aim of the present study was to investigate the pathogenesis of central presbycusis using a mimetic aging model induced by D‑galactose (D‑gal) in vivo and in vitro. The degeneration of the cell was determined with transmission electron microscopy, terminal deoxynucleotidyl transferase‑mediated deoxyuridine 5'‑triphosphate nick‑end labeling staining, and senescence‑associated β‑galactosidase staining. The expression of protein was detected by western blotting and immunofluorescence. The quantification of the mitochondrial DNA (mtDNA) 4,834‑base pair (bp) deletion and mRNA was detected by TaqMan quantitative polymerase chain reaction (qPCR) and reverse transcription‑qPCR respectively. Cell apoptosis and intracellular ROS in vitro were determined with flow cytometry. The levels of nuclear Nrf2, and the mRNA levels of Nrf2‑regulated antioxidant genes, were downregulated in the auditory cortex of aging rats, which was accompanied by an increase in 8‑hydroxy‑2'‑deoxyguanosine formation, an accumulation of mtDNA 4,834‑bp deletion, and neuron degeneration. In addition, oltipraz, a typical Nrf2 activator, was found to protect cells against D‑gal‑induced mtDNA damage and mitochondrial dysfunction by activating Nrf2 target genes in vitro. It was also observed that activating Nrf2 with oltipraz inhibited cell apoptosis and delayed senescence. Taken together, the data of the present study suggested that the age‑associated decline in Nrf2 signaling activity and the associated mtDNA damage in the auditory cortex may be implicated in the degeneration of the auditory cortex. Therefore, the restoration of Nrf2 signaling activity may represent a potential therapeutic strategy for central presbycusis.

Joseph Thomas (Tony) Liverma

Chronic Disease and Network Theory Paradigm for RESILIENCE

Theses concepts,  in abstract below, are relevant to disease prevention and management.

Globally they imply RESILIENCE of each of three  barrier defenses or compartments; outer, intermediate and inner.

A breach or increased permeability of successive compartments promotes inflammation and weakening of each successive layer. (Increased CRP)

One can extend the organism, organ compartment fractal further into tissue, cell, cellular organelle and then to sub-sub compartments like the MAM or mitochondrial associated membrane with the endoplasmic reticulum or the nuclear membrane pore.

The integrity of each compartment depends on the integrity and bioenergetics of each "barrier membrane."

Disease management requires  cell, tissue and organ survival first, then membrane leak repair, then recovery of bioenergetics.  

A strategy of increased antioxidant enzyme capacity, immune response moderation and increased and improved mitochondrial energy production reverses and prevents disease and death while promoting RESILIENCE.

Oxidative stress is reduced by Nrf2 activators.

Immune stress is reduced by vagal activation and bicarbonate (Win Hof hyperventilating breathing technique) inactivation of  the acetylcholine antagonist (acetylcholinesterase) via mesothelial cell stimulation.

One of the most potent transcriptional Nrf2 activators is butyrate and beta hydroxybutyrate, (a ketone produced by fasting and exercise.)

One of the most potent  cellular (including brain) energy substrates under stress is lactate.

Both butyrate and lactate therefore potentially restore the"outer barrier" meaning the skin, mucous membrane and intestinal endothelial lining.

Both butyrate and lactate are produced in lactobacillus ruggeri homemade yogurt which leads to the following:

Thickening of barrier cells. Restoration of cell tight junctions and barrier function.

Reduced barrier cell layer inflammatory cells.

Increased collagen and reduced MMP the enzyme that destroys collagen and the tight junction proteins that function like mortar in a brick wall.

Increased oxytocin and stronger larger muscles.

Therefore, the  supplements in that yogurt, restores the outer barrier compartment.

Butyrate is also absorbed and effects all other barrier and tissue cells to promote RESILIENCE.

https://www.sciencedirect.com/science/article/pii/S0306987717304255

A new model for chronic diseases

Chronic diseases are defined diseases whose symptoms last for at least six months and tend to worsen over time. In Europe, they cause at least 86% of deaths.

In this speculative unifying model I set a new hypothesis for the etiology of the majority of chronic diseases. The main aim is to put order and observe our organism in a systemic way, connecting pathologies we now see as disconnected phenomena, with the conceptual frameworks of complex systems and network medicine.

Chronic diseases could be caused by a first unsolved acute infection. In case the pathogen cannot be completely eliminated, it becomes a persistent infectious. After the acute episode, some mild symptoms will occur and probably disappear; the chronic disease will remain latent over time. It will manifest even after years or decades, in the presence of another acute infection, a particular stress, trauma, or another event. The presence of the persistent infectious elicits changes in the immune and systemic regulation, and these processes degenerate over time. They will assume their rules and patterns, being independent from the initial stimulus. The key to understand the dynamics and individuality of chronic diseases is the immune system and its networks. The immune mechanisms that can lead to the persistent response are mainly the switch from the Th1 to the Th2 immunity and the molecular mimicry.

The first persistent infectious will also modify the susceptibility to other pathogens, facilitating new infections and new consequent persistent infectious.

From the immune point of view, our organism is divided into three compartments: the outer one, which comprehend all the surfaces in contact with the environment, the intermediate one, which comprehend the internal organs and tissues, and the innermost one, comprehending the Central Nervous System and the adluminal compartment of the seminiferous tubule. The immune key-role is played respectively by the mucosa-associated lymphoid tissue, the endothelium, the blood–brain barrier and blood-testis barrier. The chronic diseases follow a progressive scheme, involving the three compartments from the outer to the innermost one.

The primer microorganism at the origin of the majority of diseases could be streptococcus, or staphylococcus. Both cause acute in children, with a great variability of responses and symptoms, and both cause molecular mimicry.

This model can be tested and proved in more ways, I propose here some of them.

It could pave the way to a radical change in our comprehension and therapeutic approaches to chronic diseases.

Joseph Thomas (Tony)

Bioenergetics Nrf2 and Spermidine; Mitochondria and Endoplasmic Reticulum

Hydrogen rich water reduces senescence by reducing ROS directly and indirectly by activating Nrf2.  Nrf2 activation slows cell aging in trisomy 21.

Mitophagy ultimately removes ROS producing mitochondria and replaces them with efficient cleaner mitochondria.

It is oxidative damage by ROS that damages the MAM mitochondrial associated membrane shared with the endoplasmic reticulum. That blocks the local production of melatonin and other antioxidants that protects the marriage of mitochondria and endoplasmic reticulum.  This results in less exchange of "goods and services" needed to safely produce energy.

Consequences?

Metabolic failure triggers SENESCENCE or CANCER. Both are age and and disease related.  Both lead to stem cell failure and decline.

Reversal from Nrf2 activators and spermidine restores metabolic success and REVERSES aging, carcinogenesis and stem cell failure, the ultimate cause of death.

p53 leads either to restoration or senescence and apoptosis depending on energetic capability/ROS ratio signaling.

Highlights

•

Hydrogen alleviates the senescence process of BMSCs in vivo.

•

Hydrogen decreases the intracellular ROS levels.

•

Hydrogen reduces the expression of senescence-related proteins p53 and p21.

•

Hydrogen alleviates senescence of BMSCs via ROS/p53/p21 pathway.

https://www.sciencedirect.com/science/article/abs/pii/S0753332218328403

Hydrogen alleviates cellular senescence via regulation of ROS/p53/p21 pathway in bone marrow-derived mesenchymal stem cells in vivo

Senescence has become a hot point issue in recent decades and requires urgent attention. As a novel and effective antioxidant, hydrogen has been proved to alleviate cellular senescence in endothelial cells in vitro. However, the effects and mechanisms of hydrogen on senescence in vivo are still unclear. In the present study, 12-month-old Sprague Dawley (SD) rats were intraperitoneal administration of hydrogen-rich saline (HRS, 10 ml/kg). Subsequently, bone marrow-derived stem cells (BMSCs) were harvested for the detection of hydrogen antisenescence effects and mechanisms. The results showed that the number of senescence-associated β-galactosidase (SA-β-Gal) positive cells was reduced in BMSCs from rats treated with HRS. BMSCs in rats treated with HRS possessed a better proliferation ability, showed more effectively tri-lineage differentiation potential, and had less percentage of cells in G1 cell cycle arrest than the control cells. Additionally, HRS administration inhibited the production of intracellular reactive oxygen species (ROS) and decreased the expression of senescence-related proteins p53 and p21. Our results revealed that hydrogen could alleviate cellular senescence in vivo. And the underlying mechanism of antisenescence effects of hydrogen in BMSCs was via the ROS/p53/p21 signaling pathway. Thus, hydrogen could be a new and convenient strategy for alleviating senescence and for therapy of age-related diseases.

RESILIENCE is Two Sides of a Reciprocal COIN

There are two models of premature aging; progeria and trisomy 21.

What protects rapidly aging cells protects our  shower aging cells.

Nrf2 slows aging and cell senescence in trisomy 21.

Nrf2 slows aging in every cell.

Therefore Nrf2 is one target of the coin of RESILIENCE.

The flip side is reducing autoimmunity that results from inflamaging.

Tails is increasing Vagal tone and activating the cholinergic anti inflammatory pathway via slow paced breathing with or without augmentation by facial cooling.

RESILIENCE includes Nrf2 activation and autoimmunity deactivation.

https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12812

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells - Zamponi - - Aging Cell - Wiley Online Library

Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

Joseph Thomas (Tony) Liverman, Jr.

Save the astrocytes; Save the Neuron, Brain and Person

How does sunlight help cognition and mood?

Sunlight makes UCA urocanic acid which ASTROCYTES converts into  glutamate and then lactate that increases the energy of the neuron via the lactate shuttle.

Urocanic acid is made from L-histidine in the stratium corneum of the skin (sweat) and functions as an endogenous sunscreen, hence it arises from sunlight.

Interestingly, the loss of astrocyte function and structure, damages neurons and is associated with neurodegenerative diseases including depression and dementia.  Activated inflammatory astrocytes are named CA-1  and they increase in percentage in the focal areas of disease.  For example the basal ganglia in Parkinson's disease.

Astrocytes are the "canaries in the mine" because they produce lactate for neurons.  They empty themselves of energy and thereby increase their vulnerability to oxidative stress.  Urocanic acid-glutamate-lactate increases neuron function, hence improved mood and cognition derived from sunlight!

In dementia, NMDA inhibitors (namenda) block glutaminergic overdrive which might be viewed as a normal function of astrocytes that converts glutamate into lactate and neuronal energy.  Namenda also improves depression but does not save astrocytes.  Saving astrocytes is 

1. the job of Nrf2 activation which reduces the activation of astrocytes into CA-1.  It is also 

2. the job of the cholinergic anti-inflammatory pathway that is activated by vagal nerve stimulation. (See DrLiverman. blogspot.com/smokingcessation....)

Sulforaphane is concentrated in astrocytes and provides protection for themselves and their offspring.  Save the astrocytes; save the neuron/brain/person.  Sulforaphane is the most potent Nrf2 activator known. Sulforaphane is concentrated in broccoli sprouts and broccoli sprout extract.

https://www.sciencedirect.com/science/article/pii/S0092867418305075

Highlights

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.

Jo

Telomerase and Antioxidant Capacity Increases Resilience Which Increases IQ

Long telomeres and increased antioxidant capacity is associated with longevity.

Here they are directly proportional and reflect RESILIENCE.

Telomeres are lengthened by telomerase.

Telomerase can only enter the nuclear pore when the cytoplasm is not under oxidative stress.  When there is adequate antioxidant capacity- superoxide dismutase and glutathione telomeres can be repaired.

One can use relative telomere length as a proxy for innate resilience.

I hypothesis that telomere length is directly proportional to HRV index and predicts children who maintain their synaptic connections or brain network which is a predictor for higher IQ, higher income etc.

We likely can improve educational and intellectual success by improving resilience.

Resilience can be predicted by HRV index.

Resilience and brain network preservation is greater than pedagogy for maxims educational attainment.

Nuclear DNA integrity and mitochondrial DNA integrity is therefore permissive when adequate antioxidant capacity and proteostasis is high.

Proteostasis is a function of spermidine.

This blog is aligned with longevity which is directly proportional to RESILIENCE.

This study in mice also explores the resilience of siblings raised in the same environment and discovered resilience is a function of oxidative capacity and telomerase.

https://www.sciencedirect.com/science/article/pii/S0047637417301653

Telomere length, sibling competition and development of antioxidant defense in wild house mice

Antioxidants and telomere length are potential biomarkers for individuals’ exposure and ability to cope with environmental stressors. However, intraspecific variations in antioxidant alterations due to natural, life cycle related stress, have been rarely estimated. We investigated those changes in wild-derived house mice in a longitudinal study with natural sibling competition as a stressor. Blood was used for telomere length measurements at 8-weeks age and for several selected antioxidants at 8-weeks and 6-months age. Our results show that most of the antioxidants increase during that time, indicating that antioxidant-system continues to develop after early development and sexual maturation. In addition females had higher antioxidant-levels than males. Mice with longer telomeres had also higher superoxide dismutase-activity and more glutathione than mice with shorter telomeres, meaning that long telomeres are associated with better antioxidant defense at maturation and during later life. Sibling competition at early age affected superoxide dismutase-levels at 6-months, but only in females. Females, which were lighter than the average of the litter had low superoxide dismutase –activity in later adulthood, indicating delayed negative effect of sibling competition on antioxidant defense. Our results highlight that sex and developmental stage are crucial in intraspecific comparisons of the antioxidant status and its alterations

The Pareto Potential of Fully Pluripotent Stem Cells

Grow one, grow a pair.  All stem cells are not the same.  Pluripotency is a continuum that is lost over development in the same way that reproduction potential declines with aging.  This exciting new discovery may pave the way for brain, lung, renal, liver, pancreas "seeding"with pluripotent stem cells to remodel and regenerate damaged organs.  We do this poorly with  stem cell injections in heart failure and lung failure already with positive but minimal results. Because they are relatively incompetent for the requested outcome.

When performed with autologous completely pluripotent stem cells, organ regeneration will definitely be possible even before limb regeneration..

Create in me a new heart, O Lord?

This also comforms with the pareto principle that the square root of a population are responsible for 50% of productivity.  These cells are "pareto" special because of their potential for pluripotent productivity.

Loss of stem cell capability and function, stem cell exhaustion, is the ultimate cause of disease, disability and nontraumatic deaths.  Multicellular biology may make medicine more like farming, creating an environment that favors exponential yields from "seeds and seedlings.". This gives a new meaning for GMO.

http://www.kurzweilai.net/research-suggests-that-humans-could-one-day-regrow-limbs

Research suggests that humans could one day regrow limbs

Scientists have identified the specific type of planaria flatworm pluripotent stem cell that is capable of regenerating an entire organism

Melatonin Sirt-1 for longevity and normal endothelial function

Melatonin is  an exercise mimetic.

Melatonin increases insulin sensitivity.

Melatonin increases Sirt1.

Sirt1 is a nutrient sensor BUT it  also rises with melatonin.

Melatonin increases mitochondrial biogenesis, the volume of cellular mitochondria.

Nutrient sensing must signal relative to mitochondria volume.

Melatonin effects on metabolic signaling may be relative to mitochondrial volume.

Age and disease decrease melatonin.

The sickest persons due to metabolic syndrome, aka endothelial dysfunction, improve the most with calorie restriction indicating that "relative" melatonin, relative Sirt1 to mitochondrial volume improves flow mediated dilation or endothelial function.

Melatonin declines with aging.

Melatonin is high in nuts and olives oil.

Meat rich diet plus one oz of nuts reduce CAD coronary artery disease odds ratio from 1.6 to O.6.

Melatonin concentrates in mitochondria.

The DASH and Mediterranean diet lower blood pressure 10-14 points.

Is this due to melatonin, Sirt1 or Nrf2 activation which follows either melatonin or Sirt1 increases.

Increasing relative melatonin/sirt-1/mitochondrial volume improves health and longevity.

Persons with high levels of Sirt1 have proved increased longevity.

Higher Sirt1 due to gene polymorphism AND/OR calorie restriction, exercise and exercise mimetics.

Heat is an exercise mimetic, sauna, steam or immersion.

http://www.mdpi.com/1422-0067/19/3/751

Caloric Restriction and Its Effect on Blood Pressure, Heart Rate Variability and Arterial Stiffness and Dilatation: A Review of the Evidence

Rachel Nicoll

Abstract 

Essential hypertension, fast heart rate, low heart rate variability, sympathetic nervous system dominance over parasympathetic, arterial stiffness, endothelial dysfunction and poor flow-mediated arterial dilatation are all associated with cardiovascular mortality and morbidity. This review of randomised controlled trials and other studies demonstrates that caloric restriction (CR) is capable of significantly improving all these parameters, normalising blood pressure (BP) and allowing patients to discontinue antihypertensive medication, while never becoming hypotensive. CR appears to be effective regardless of age, gender, ethnicity, weight, body mass index (BMI) or a diagnosis of metabolic syndrome or type 2 diabetes, but the greatest benefit is usually observed in the sickest subjects and BP may continue to improve during the refeeding period. Exercise enhances the effects of CR only in hypertensive subjects. There is as yet no consensus on the mechanism of effect of CR and it may be multifactorial. Several studies have suggested that improvement in BP is related to improvement in insulin sensitivity, as well as increased nitric oxide production through improved endothelial function. In addition, CR is known to induce SIRT1, a nutrient sensor, which is linked to a number of beneficial effects in the body. View Full-Text

Keywords: blood pressure;  heart rate variability;  arterial stiffness;  flow-mediated dilatation;  caloric restriction fasting

Joseph Thomas (Tony) Liverman, Jr.

PCOS Treatment of Immunologic Inflammatory Macrophage Shift

PCOS is not solely endocrine related to higher androgen production.  Inflammation is also significant.

PCOS has an immunological basis.  Increased pro-inflammatory M1 macrophages and decreased anti inflammatory M2 macrophages.

This leads to fibrosis and is a significant part of obesity related inflammatory tissues changes throughout the body tissues.

How can one treat and reverse the macrophage inflammatory shift and reverse the M1/M2 ratio?

1.  Melatonin reverses PCOS due to antioxidant and Nrf2 activation.

2.  Vagal reflex activation stimulates the cholinergic anti-inflammatory pathway and shifts the phenotype of M1 towards M2.  Acetylcholine is released into the bloodstream and binds the nicotine acetylcholine receptors in macrophages to cause this shift.  

3.  Because organs such as spleen, pancreas, liver and ovaries are cloistered behind blood brain barriers, one can better address the cholinergic tone within the organs by the Wim Hot breathing technique that uses hyperventilation to raise both pH and bicarbonate which directly activates acetylcholinesterase inhibition by acting on mesothelial cells.

This is entirely logical because testosterone is associated with abdominal visceral body fat while estrogen inhibits visceral body fat in favor of "pear shaped" peripheral body fat.  PCOS is an estrogen producing female with elevated testosterone production.  The relative increase in visceral body fat promotes inflammation that drives increased abdominal body fat and insulin resistance.  Block the inflammation AND block the increased oxidative stress to broadly treat the syndrome.

https://academic.oup.com/biolreprod/advance-article-abstract/doi/10.1093/biolre/ioy096/4983117

Polycystic ovary syndrome: possible involvement of androgen-induced, chemerin-mediated ovarian recruitment of monocytes/macrophages

Polycystic ovary syndrome (PCOS) is a continuum of endocrine and reproductive disorders characterized by hyperandrogenism, antral follicle growth arrest and chronic inflammation. Macrophages play key role in inflammation and the balance between M1 (inflammatory) and M2 (anti-inflammatory) macrophages determines physiological/pathological outcomes. Here, we investigated if hyperandrogenism increases ovarian chemerin altering the balance of M1 and M2 macrophages and the granulosa cell death. Ovarian chemerin was up-regulated by 5α-dihydrotestosterone (DHT) in lean and overweight rats; while increased serum chemerin levels were only evident in overweight rats, suggesting that the serum chemerin may be reflective of a systemic response and associated with obesity, whereas increased ovarian chemerin expression is a localized response independent of the metabolic status. DHT altered follicle dynamics while increased the M1: M2 macrophages ratio in antral and pre-ovulatory follicles. While ovarian M1 macrophages expressing chemokine-like receptor 1 (CMKLR1) were increased, CMKLR1 + monocytes, which migrated towards chemerin-rich environment, were markedly decreased after 15 days of DHT. Androgen-induced granulosa cell apoptosis was dependent on the presence of macrophages. In humans, chemerin levels in follicular fluid, but not in serum, was higher in lean PCOS patients compared to BMI-matched controls and was associated with increased M1: M2 ratio. Our results support the concept that in PCOS, hyperandrogenemia increases chemerin expression while promotes CMKLR1 + monocytes recruitment and deregulates the immunological niche of ovaries. This study established a new immunological perspective in PCOS at the ovarian level. Hyperandrogenism is associated with up-regulation of chemerin and macrophage unbalance in the ovaries.

Smoking Cessation Addiction Cessation Trial

Subjects:. Smokers without cardiovascular morbidities less than 50 years of age.

Methods:. Apply refrigerated cold pack to upper two thirds of face for 120 seconds while bending forward to produce mild valsalva maneuver and breathing in 5 seconds and out for 5 seconds for the 120 seconds.  Perform at least twice daily and add lib if urge to smoke.

Endpoint:. Complete Smoking cessation for 6 weeks.  Follow up for 3-6 months.

Rationale and discussion.  
Vagal exhaustion or reduced vagal tone is associated with autonomic symptoms of depression, hopelessness, anxiety, poor concentration, appetite change and sleep change.  
All these symptoms are subjectively improved by smoking and worsened by nicotine withdrawal.
Nicotine activates the Nicotinic acetylcholine receptor.
Chantix activates a subtype of Nicotinic receptor where it's binding produces agonist activity, while simultaneously preventing nicotine binding to alpha 4 beta 2 receptor.
Nicotine and chantix activate a cholinergic receptor to either maintain smoking benefits or taper off.
A more enduring taper and maintenance program would therefore activate the cholinergic peripheral receptors independent of nicotine or chantix.
The diving reflex activates the cholinergic anti inflammatory pathway peripherally and restores vagal tone.
The cholinergic anti inflammatory pathway corrects autonomic symptoms of depression, hopelessness, anxiety, poor concentration, appetite change and sleep change.  
Therefore a healthy and effective substitute is available that restores resilience into recovery by restoring autonomic vagal nerve tone that makes one resilient to ADDICTIONS.