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