DetOXify Reactive Oxidants to Prevent Nerve Pain and Loss of Function

A study of neuropathy in C eligans has implications for pain and nerve function loss

Here a chemical reaction with a compound increased by increased glucose levels in the cell leads to nonenzymatic glycosylation (like crispy caramelized sauteed onions) and damage of nerves both sensory and motor.

The enzyme that detoxifies nerve metabolic toxins can be unregulated by nrf2 activators.

Hydrogen rich water.

Alpha Lipoic acid.

Ursolic acid.

Sulforaphane.

I suspect this same antioxidant nrf2 pathway activation could reduce pain or nerve hypersensitivity caused by cytokines and likely would prevent nerve damage and neurodegenerative disease (or slow them.). Perhaps arthritis knee pain would decrease!

I think hydrogen rich water is the most effective and most likely to act across the blood brain barrier.  It is also extremely inexpensive at $2.50 per month using 3 hydrogen sticks lasting 6 months and requiring 1 part white vinegar to 3 part water soak once a month to remove magnesium hydroxide and restore hydrogen production efficiency.

http://stke.sciencemag.org/content/9/457/ec286

Reducing nerve-damaging reactive metabolites

1. Annalisa M. VanHook

+ Author Affiliations

If not degraded or modified, reactive metabolites damage cells. One group of reactive metabolites is the α-dicarbonyls (α-DCs), which damage proteins, lipids, and DNA through a nonenzymatic form of glycosylation (glycation). Methylglyoxal (MGO) is an α-DC that accumulates with age and damages nerves and arteries. MGO also accumulates in patients with neurodegenerative disorders and in diabetic patients. In diabetic patients, the accumulation results from increased glycolytic flux, which produces excess MGO. Chaudhuri et al. found that Caenorhabditis elegans lacking the glyoxalase GLOD-4, an enzyme that metabolizes and detoxifies MGO, exhibited MGO accumulation, reduced motility, and neuronal damage. Similar to diabetic patients, who initially experience hypersensitivity and then later loss of sensation, worms deficient in glod-4 were initially hypersensitive to touch but eventually lost sensitivity to touch. Treating wild-type C. elegans with MGO or rearing them on a high-glucose diet phenocopied loss of glod-4. Genetic experiments revealed that accumulation of α-DCs activated the nociceptive transient receptor potential ion channel TRPA-1, which stimulated signaling through the calcium/calmodulin-dependent kinase II (CaMKII) homolog UNC-43 and the p38 mitogen-activated protein kinases PMK-1 and SEK-1 to stimulate activity of the transcription factor SKN-1. SKN-1 is homologous to vertebrate Nrf2, which stimulates the expression genes involved in antioxidant and xenobiotic responses. MGO-induced activation of SKN-1 stimulated the transcription of glod-4 as well as djr-1.1 and djr-1.2, which encode homologs of the human glyoxalase DJ1. Screening a library of natural products for compounds that rescued the phenotypes of glod-4 mutants identified podocarpic acid, a component of the resin of some conifers. Treating glod-4 mutants with podocarpic acid or the NRF2 activator α-lipoic acid stimulated activation of SKN-1 and reduced the accumulation of MGO in a manner that depended on TRPA-1. Experiments in human and rat cultured cells indicated that this α-DC detoxification pathway is conserved in vertebrates and that podocarpic acid can reduce the neurotoxic effects of MGO. This study not only delineates the pathway through which α-DCs induce the machinery necessary for their detoxification, it also demonstrates the usefulness of C. elegans for identifying compounds that could be developed into therapeutics for human patients.

Telomerase first in health, telomere length is second priority

In humans, circulating telomerase activity rather than telomeres length is inversely associated with the major cardiovascular disease risk factors.  See below.

In the nucleus, telomerase promotes telomere "stability."

In the cytoplasm, telomerase has preservation of mitochondria and antioxidant maintenance as its priority and hTert is actually blocked from translocating to the nucleus.

Beta hydroxybutyrate from lifestyle choices causes telomerase et al of the starvation gene set to be expressed.  Telomerase, BDNF, p53-pgc etc.

E.g..  Weekly 24 hour fasting improved age related heart failure EF from 30% to 60% over 8 weeks in mice.  BDNF of 30% increased to 100% of normal.  BDNF is a proxy biomarker for the starvation gene set expression and by extension telomerase.  Therefore fasting weekly increased beta hydroxybutyrate gene transcription of restorative genes including telomerase, a major biomarker of cardiovascular mortality.

Number needed to treat in the mouse study to restore EF and presumptively to reduce "hospitalization and mortality?"

One.

Conclusion of article wrongly emphasizes eating however when we eat and by extension when we do not eat alone produces beta hydroxybutyrate, a ketone from low insulin intervals and increased fat metabolizing intervals.  Insulin stores glucose and inhibits lipolysis.

80% of metabolic health is when we eat or how well we metabolize fats and produce beta hydroxybutyrate.  Insulin sensitive, exercise, fasting and ppar alpha agonists (such as ursolic acid) consuming persons are metabolically healthy and age slower than their opposites.

It appears logical to the extreme to promote 12 hours daily fasting, 24 hour weekly fasting, exercise and possibly ursolic acid 200mgs  for secondary prevention of cardiovascular disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761710/

Nutrition and lifestyle in healthy aging: the telomerase challenge

In contrast to stem cells which constitutively express low levels of telomerase, normal somatic human cells repress its expression immediately after birth [-]. Thus, for a long time, telomere length has been considered as an indicator of cellular senescence, and a potential biomarker of human aging, but studies supporting this role are still contradictory and inconclusive [,,]. More recent genetic studies in animal models have demonstrated that short telomeres rather than average telomere length are associated with age-related diseases and, their rescue by telomerase is sufficient to restore cell and organismal viability [30,31]. In humans, circulating telomerase activity rather than telomeres length is inversely associated with the major cardiovascular disease risk factors [32]. Thus, another concept is coming up, the “telomere stability”, a quite different concept from telomere length. For example, patients with Alzheimer's disease do not invariably have shorter telomeres, but their telomeres have significant signs of dysfunction [33-38]. Improving the activity of telomerase enzyme -that can add length back to shorter telomeres, and, in the meantime, protect longer telomeres to ensure stability- seems a way to actually turn back the biological clock. Telomerase has also extra-telomeric functions influencing various essential cellular processes, such as gene expression, signaling pathways, mitochondrial function as well as cell survival and stress resistance [40,41]. Therefore, the presence of active telomerase in stem cells, and potentially in all cells, may be helpful for longevity and good health.

Lifestyle factors known to modulate aging and age-related diseases might also affect telomerase activity. Obesity [42], insulin resistance [43,44], and cardio-vascular disease processes [45,46], which are related to oxidative stress and inflammation, have all been linked to shorter telomeres. Smoking, exposure to pollution, lower physical activity, psychological stress, and unhealthy diet significantly increase the oxidative burden and the rate of telomere shortening [47-53]. So, what a better way to counteract the “biological clock” by reactivating telomerase trough diet and lifestyle interventions? There is a recent paper showing that with intensive lifestyle modification, with a low fat diet, regular physical activity, and mental stress reduction (by yoga and meditation), telomerase activity increases significantly in peripheral blood mononuclear cell (PBMC) [54]. Again, people living in the Mediterranean countries have longer and healthier life as compared with people living in other industrialized countries, and we previously demonstrated that they have also claim longer telomeres and higher telomerase activity in PBMC [55]. It is still unclear if there is a single nutrient or a factor responsible of Mediterranean diet anti-aging properties or the whole, single ingredient foods and lifestyle are the key to “healthspan”.

Today, researchers are struggling to find a compound or an “elixir” for long life, while common people are taking dietary supplements with the intent to preserve mental, physical, and emotional health into old age. Most dietary supplement programs include combinations of vitamins, antioxidants, and other constituents, some of which have been shown to have significant health benefits in controlled clinical studies. Specific nutrients provide all the necessary building blocks to support telomere health and extend lifespan. This is the case of folate [56,57], vitamins (B, D, E, C) [58] zinc [59] and polyphenol compounds such as resveratrol [60], grape seed extract and curcumin [61]. Several foods -such as tuna, salmon, herring, mackerel, halibut, anchovies, cat-fish, grouper, flounder, flax seeds, sesame seeds, kiwi, black raspberries, green tea, broccoli, sprouts, red grapes, tomatoes, olive fruit- are a good source of antioxidants. These, combined with a Mediterranean type of diet containing fruits, vegetables and whole grains would help protect our chromosome ends [62-70].

In conclusion, what we eat, how we eat and how much we eat, together with lifestyle significantly, can affect our telomerase/telomere system with a great impact on healthspan. “Similes cum similibus curantur” and in nature is still hidden the secret of healthy and long life whereas telomerase could represent the distinctive target.

Starvation Genes Improve and Restores the Failing Heart

In this sepsis induced cardiomyopathy model, carvedilol improves recovery by improving the telomere-p53-pgc signaling.

These 3 gene products are alsoincreased by ursolic acid presumptively by beta hydroxybutyrate.  They are among the 44 starvation genes.

I have previously written how telomerase angiotensin 1-7 are starvation genes that promote metabolically healthy flow mediated dilation which improves small vessel circulation to the healing heart post insult.

See bolded below

http://circ.ahajournals.org/content/134/Suppl_1/A17642.short

Abstract 17642: Carvedilol Improves Prognosis in Sepsis-induced Cardiomyopathy Through the Activation of “telomere-p53-pgc Signaling"

Abstract

Background: Stress-induced cardiomyopathy is a complication of severe sepsis. It is characterized by left ventricular dilatation and depressed ejection fraction. Recent meta-analysis suggested that the mortality depends on the heart hyperkinetic. However, the crucial mechanism of sepsis induced cardiomyopathy and the treatment are still unknown. It has been reported that telomere length has inverse correlation to severity of heart failure and infectious disease. Moreover, it is suggested that dysfunction of “telomere-p53-PGC axis” reduces a mitochondrial function, and as a result, it develops to heart failure.

Purpose: We investigated the therapeutic potential of carvedilol which improves prognosis in preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis.

Methods and Results: C57BL/6 male mice were evaluated blood pressure, heart rate and cardiac function followed by CLP surgery and 1mg/kg carvedilol (BB) or saline (CT) was administered for 7days after surgery. 7days after induction of sepsis, BB significantly attenuated blood pressure (101.7±6.0 vs 109.8±57.4mmHg, p<0.05) and heart rate (405.6±18.0 vs 431.6±13.2bpm, p<0.05) as compared to CT. BB also reduced LV dilatation (LVEDV; 53.5±18.5 vs 66.9±15.1uL, p<0.05) and LVEF depression. (61.1±9.9 vs 53.3±7.9%, p<0.05). Kaplan-Meier analysis showed that the 7days mortality significantly reduced in BB group. Telomere shortening of white blood cells seen for sepsis was attenuated in BB by Q-FISH analysis (10.9±1.4 vs 6.8±1.4 telomere fluorescence unit; TFU, p<0.01) Moreover, as compared to CT, BB showed higher expression of tert, PPARγ co-activator (PGC)-1 alpha which promote mitochondrial biogenesis and lower expression of p53 by PCR in heart tissue. Body weight loss was reduced in BB group.

Conclusions: Carvedilol improved sepsis induced cardiomyopathy through the attenuation of telomere shortening due to the enhancement of telomere-p53-PGC axis and reducing mortality resulting from sepsis.

Autophagy Mitophagy controls autoimmune disease

Here below explained is that toxic mitochondria signals the sterile inflammation characteristic of autoimmune disease and aging.

Autophagy (cell recycling) and Mitophagy (mitochondrial recycling or replacement) reduce the inflamasome initiator, NLRP3 the innate cell immune system, activation by their triggers.

It is a reasonable assumption that factors that increase those recycling processes reduce the degree of autoimmune disease.

12 hours of daily fasting. Autophagy.
24 hours of weekly fasting. Mitophagy.
Melatonin 3-6 mgs at night. Autophagy and antioxidant.
DHA 1000 mgs daily. Inhibits Il B a component of activated inflamasome.
Ursolic acid 200 mgs 1-3 times daily promotes metabolism of toxic LPS and promotes fatty acid metabolism and production of beta hydroxybutyrate which promotes the transcription of 44 starvation gene set proteins that repair the cell.
Ubiquinol 100 mgs.  Improves mitochondria.
PQQ 20mgs.  Promotes mitochondrial biogenesis and lowers ROS production, a toxic side effect of mitochondrial oxidative phosphorylation.

The key idea above is that beta hydroxybutyrate,a ketone, promotes repair inclusive of autophagy Mitophagy and their gene initiators expression.
This improves age related inflamaging and autoimmune diseases like PSS, RA etc.

This is the same set of therapeutic interventions that Dr. Dale Bredson used to reverse dementia in 9 of 10 apoE positive patients with cognitive decline!

http://www.clinexprheumatol.org/article.asp?a=10865

Healthy Cells Use Better Pathways For Flow Mediated Dilation

Flow mediated dilation with NO generated by angiotensin and telomerase is healthy because it does not signal or activate the inflamasome.

The metabolic unhealthy cell lacks beta hydroxybutyrate transcription of the starvation gene set which includes telomerase and accordingly alternatively activates the H2O2 pathway which activates the inflamasome and leads to atherosclerosis, fibrosis and apoptosis.

MET epithelial mesenchymal transition is important in cancer metastasis, Barretts esophagus and endothelial dysfunction or atherosclerosis. 

The lack of NO/telomerase, angiotensin 1-7 pathway is the probable cause of diabetes related ED, renal failure, retinopathy, neuropathy and microvascular complications

Below are 2 models of liver fibrosis worsened by inflamasome activation by the hydrogen peroxide pathway and alleviated by NO/telomerase, angiotensin 1-7 pathway. One simultaneously promotes both flow mediated dilation and activates inflamasome induced fibrosis.  

If the small scale cellular injury is ischemia reperfusion injury and the proper response is increased flow through flow mediated dilation then the most resourceful pathway in a healthy cell is NO/telomerase, angiotensin 1-7 pathway that is supported by beta hydroxybutyrate generated starvation set gene expression.  In unhealthy inflamed or age inflamaged cells the less resourceful H2O2-activated pathway is the default which leads to fibrosis.

http://www.sciencedirect.com/science/article/pii/S0891584916303343

Angiotensin(1–7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1β/Smad circuit

• •
  Ang II activates NLRP3 inflammasome mediated by NOX-derived H2O2 in hepatocytes.
• •
  Ang II initiates hepatocyte EMT by activating the NOX-derived H2O2-mediated NLRP3 inflammasome/IL-1β/Smad circuit.
• •
  Ang-(1–7) attenuates Ang II-induced hepatocyte EMT by inhibiting NLRP3 inflammasome activation.

Epithelial-mesenchymal transition (EMT) is correlated with NAPDH oxidase (NOX)-derived reactive oxygen species (ROS). The ROS-induced NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a novel mechanism of EMT. Angiotensin II (AngII) induces EMT by regulating intracellular ROS. Nevertheless, it has not been reported whether AngII could induce hepatocyte EMT. Angiotensin-(1–7) [Ang-(1–7)] can inhibit the effects of AngII via a counter-regulatory mechanism. However, whether Ang-(1–7) attenuated the effects of AngII on hepatocyte EMT remains unclear. The aim of this study was to determine whether Ang-(1–7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived ROS-mediated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, two animal models were established. In the first model, rats were infused AngII. In the second model, Ang-(1–7) was constantly infused into double bile duct ligated (BDL) rats. In vitro, hepatocytes were pretreated with antioxidant, NLRP3 siRNA, NOX4 siRNA, or Ang-(1–7) before exposure to AngII. In vitro, AngII induced hepatocyte EMT, which was inhibited by N-acetylcysteine (NAC), diphenylene iodonium (DPI), and NOX4 siRNA. NLRP3 inflammasome, which was activated by hydrogen peroxide (H₂O₂), mediated AngII-induced hepatocyte EMT. Ang-(1–7) suppressed AngII-induced EMT by inhibiting the NOX-derived H₂O₂-activated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, infusion of AngII induced activation of H₂O₂-correlated NLRP3 inflammasome in rat livers and accumulation of α-collagen I (Col1A1) in hepatocytes. Infusion of Ang-(1–7) alleviated BDL-induced liver fibrosis and inhibited the expression of Col1A1 and the activation of NLRP3 inflammasome in hepatocytes. Ang-(1–7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived H₂O₂-activated NLRP3 inflammasome/IL-1ß/Smad circuit.

Fructose Cost Metabolic Health Greatly, Beta Hydroxybutyrate Pays the Debt

Table sugar or 50% fructose is harmful to the cell metabolism.  It pushes metabolic syndrome effects and has the opposite effect of fat burning beta hydroxybutyrate.

The obvious question is how much suppression of beta hydroxybutyrate and starvation gene transcription is prevented?  

Can 12 hours of daily fasting, exercise and their mimetics like Ursolic acid recover starvation gene expression and restore cellular metabolic health?

I think every debt can be paid, every sin forgiven with the penance of 12 hours of beta hydroxybutyrate augmented recovery.

I further conjecture that young cells that are metabolically healthy are more resilient and recover easier in the same way a young adult with good health recovers faster from pneumonia compared to an older adult.

Action:  limit fructose and maximize beta hydroxybutyrate in your daily cycle.  Remember that debt can be paid for health maintenance.  It is also true that resilience or health building is when debts are less than income, costs less than capital reserves.  The evidence of healthy reserves is fidelity of cellular genetic code, stable telomere length, reduced markers of inflammasome activity, increased numbers of mitochondria producing manageable ROS levels and effective cell quality control activities like autophagy and mitophagy.

http://jcb.sagepub.com/content/36/5/941.short

Dietary fructose aggravates the pathobiology of traumatic brain injury by influencing energy homeostasis and plasticity

Fernando Gomez-Pinilla, Department of Integrative Biology and Physiology, University of California Los Angeles (UCLA), 621 Charles E. Young Drive South, Los Angeles, CA 90095, USA. Email: fgomezpi@ucla.edu

Fructose consumption has been on the rise for the last two decades and is starting to be recognized as being responsible for metabolic diseases. Metabolic disorders pose a particular threat for brain conditions characterized by energy dysfunction, such as traumatic brain injury. Traumatic brain injury patients experience sudden abnormalities in the control of brain metabolism and cognitive function, which may worsen the prospect of brain plasticity and function. The mechanisms involved are poorly understood. Here we report that fructose consumption disrupts hippocampal energy homeostasis as evidenced by a decline in functional mitochondria bioenergetics (oxygen consumption rate and cytochrome C oxidase activity) and an aggravation of the effects of traumatic brain injury on molecular systems engaged in cell energy homeostasis (sirtuin 1, peroxisome proliferator-activated receptor gamma coactivator-1alpha) and synaptic plasticity (brain-derived neurotrophic factor, tropomyosin receptor kinase B, cyclic adenosine monophosphate response element binding, synaptophysin signaling). Fructose also worsened the effects of traumatic brain injury on spatial memory, which disruption was associated with a decrease in hippocampal insulin receptor signaling. Additionally, fructose consumption and traumatic brain injury promoted plasma membrane lipid peroxidation, measured by elevated protein and phenotypic expression of 4-hydroxynonenal. These data imply that high fructose consumption exacerbates the pathology of brain trauma by further disrupting energy metabolism and brain plasticity, highlighting the impact of diet on the resilience to neurological disorders.

Does Beta Hydroxybutyrate Increase FOXO1 and Telomerase?

I have rewritten the bolded paragraph below to reveal the central idea.

The present studies suggest that FoxO1 plays beneficial roles by inducing genes involved in telomerase activity, as well as anti-oxidant, autophagic, and anti-apoptotic genes under conditions of increased beta hydroxybutyrate promotion of starvation gene set, and suggest that FoxO1 signaling may be an important mediator of metabolic equilibrium during conditions of increased beta hydroxybutyrate promotion of starvation gene set.

Calore restriction is equal to conditions of increased beta hydroxybutyrate promotion of starvation gene set.

FOXO1 is elevated when insulin and IGF1 is low or when fasting.  These studies are performed best in single celled organism that do not exercise.  One could prove this by adding a PPAR alpha agonist such as Fenofibrate or Ursolic acid to cell culture without calorie restriction.

One usually has ejaculation a sympathetic action usually with erections a parasympathetic activity.  Only in ED do you find ejaculation separately.  In nature fasting creates beta hydroxybutyrate but so does exercise.  Would exercise or its chemical mimetic BHB induce FOXO1 effect on telomerase just as fasting.  My conjecture is yes?  Both pathways can be expressed simultaneously but perhaps with or without synergy.

http://link.springer.com/article/10.1007/s11010-015-2615-8

FoxO1 signaling plays a pivotal role in the cardiac telomere biology responses to calorie restriction

This study examined whether the forkhead transcription factors of O group 1 (FoxO1) might be involved in telomere biology during calorie restriction (CR). We used FoxO1-knockout heterozygous mice (FoxO1^+/−) and wild-type mice (WT) as a control. Both WT and FoxO1^+/− were subjected to ad libitum (AL) feeding or 30 % CR compared to AL for 20 weeks from 15 weeks of age. The heart-to-body weight ratio, blood glucose, and serum lipid profiles were not different among all groups of mice at the end of the study. Telomere size was significantly lower in the FoxO1^+/−-AL than the WT-AL, and telomere attrition was not observed in either WT-CR or FoxO1^+/−-CR. Telomerase activity was elevated in the heart and liver of WT-CR, but not in those of FoxO1^+/−-CR. The phosphorylation of Akt was inhibited and Sirt 1 was activated in heart tissues of WT-CR and FoxO1^+/−-CR. However, the ratio of conjugated to cytosolic light chain 3 increased and the level of p62 decreased in WT-CR, but not in FoxO1^+/−-CR. A marker of oxidative DNA damage, 8-OhdG, was significantly lower in WT-CR only. The level of MnSOD and eNOS increased, and the level of cleaved caspase-3 decreased in WT-CR, but not FoxO1^+/−-CR. Echocardiography showed that the left ventricular end-diastolic and systolic dimensions were significantly lower in WT-CR or FoxO1^+/−-CR than WT-AL or FoxO1^+/−-AL, respectively. The present studies suggest that FoxO1 plays beneficial roles by inducing genes involved in telomerase activity, as well as anti-oxidant, autophagic, and anti-apoptotic genes under conditions of CR, and suggest that FoxO1 signaling may be an important mediator of metabolic equilibrium during CR.

Rejuvenation of Metabolic Health Reverses Biological Aging

The sum of the words below means that activating the 44 starvation gene sets with BHB promotes mtDNA repair, metabolic Health and lengthening and stabilization of telomeres leading to reversing cell aging.

Also note that Ursolic acid activates Sirt-1 and peroxisome proliferator-activated receptor gamma co-activator 1α/β (PGC-1α/β).

http://link.springer.com/article/10.1007/s10522-015-9609-5

Mitochondrial metabolic failure in telomere attrition-provoked aging of bone marrow mesenchymal stem cells

The proliferation and differentiation potential of bone marrow mesenchymal stem cells (BMMSCs) declines with age and with in vitro passages. However, the underlying mechanisms and putative approaches to maintain their function are not fully understood. Recent studies have revealed telomere attrition as the core initiator determining functional decline in aging of BMMSCs. Telomere attrition activates downstream p53 signaling and compromises mitochondrial metabolism via the peroxisome proliferator-activated receptor gamma co-activator 1α/β (PGC-1α/β), a key process possesses peculiarities in BMMSCs distinct from other stem cells and their mature derivatives. Despite of the shortened telomere, the mitochondrial failure could be overcome through metabolic regulation by caloric restriction (CR) and its mediator Sirtuin 1 (SIRT1). Researches have shown that mitochondrial metabolic reprogramming by CR and SIRT1 alleviates functional decline of BMMSCs in aging. In this review, we intend to summarize our understanding about how telomere attrition initiates and induces mitochondrial compromise in functional decline of BMMSCs in aging, and the potential therapeutic strategies based on metabolic reprogramming.

Healthy Longevity Depends on Mitochondrial Fitness and Number

Interesting article below with the following implications.

Timed eating less than half the day allows for recovery and adaptation of mitochondria in the fasting half of the day preventing mitochondrial exhaustion.

Mitochondria numbers are increased by biogenesis and decreased by inflamaging.

More biogenesis means more mitochondria and less stress per mitochondria, therefore exercise, fasting, MCT oil and Ursolic acid promotion of increased mitochondria is better for health.

Decreased inflamaging through melatonin, Dha, COq10 and PQQ etc promotes recovery from metabolic stress and is better for health.

More mitochondria and less stress per mitochondria equals health and longevity.

Just another way to state that health equals autophagy,mitophagy minus inflammasome.

See example physician patient video below as example.

See Minding your mitochondria Dr. Terry Wahls at Ted.com as validation of this concept.  She did not document her calorie restriction or her time of fasting but this can be derived from her diet.

This disabled multiple sclerosis patient fully recovered with perfect nutrition targeting inflamaging and avoiding over nutrition and promoting mitochondrial rich nutrition.  She recovered from bed rest and moterized wheelchair to biking and horseback riding over the course of one year.

I am less motivated and , I believe, more resilient at baseline than the resourceful and recovered MS physician/patient who healed her mitochondria in order to reverse MS changes, and I strive to do the following:

Fast 12 hours per day.

Fast 24 hours per week.

Exercise.

Slow paced breathing twice daily.

Ursolic acid.

Melatonin.

DHA.

B complex vitamins.  Because I, like 30% of persons, am MTHFR heterozygous (from gene testing) I augment with L-methyl folate, methylB12 and Activated B6.

Highlights

• •
  Time-controlled fasting improves mitochondrial metabolism of fat cells.
• •
  Mitochondrial flexibility maintains adipose tissue functionality.
• •
  Transient ^mtROS flux, FoxO1 and AMPK promote healthy aging.

http://www.sciencedirect.com/science/article/pii/S1568163716300861

Feast and famine: Adipose tissue adaptations for healthy aging

Abstract

Proper adipose tissue function controls energy balance with favourable effects on metabolic health and longevity. The molecular and metabolic asset of adipose tissue quickly and dynamically readapts in response to nutrient fluctuations. Once delivered into cells, nutrients are managed by mitochondria that represent a key bioenergetics node. A persistent nutrient overload generates mitochondrial exhaustion and uncontrolled reactive oxygen species (^mtROS) production. In adipocytes, metabolic/molecular reorganization is triggered culminating in the acquirement of a hypertrophic and hypersecretory phenotype that accelerates aging. Conversely, dietary regimens such as caloric restriction or time-controlled fasting endorse mitochondrial functionality and ^mtROS-mediated signalling, thus promoting geroprotection. In this perspective view, we argued some important molecular and metabolic aspects related to adipocyte response to nutrient stress. Finally we delineated hypothetical routes by which molecularly and metabolically readapted adipose tissue promotes healthy aging.

Joseph Thomas (Tony) Liverman, Jr.

Autophagy and Sirt-1 Stimulation Reduced Endothelial Injury or Unstable Atherosclerosis Plaque

Ursolic acid, like reservatrol, increases Sirt-1 and restores the normal rate of autophagy from inhibition from oxidized LDL the toxic lipoprotein residue of foam cells and early atherosclerosis.  Calcium and urate are the other toxic residues that increase NLRP3 and inhibits autophagy within atheromatous plaques.

Taken together Reservatrol and Ursolic acid increases  (Sirt-1 and autophagy) and negates the effect of oxidized LDL or reduced calcium and urate thereby stabilizing or reversing unstable atheromatous plaques.

Though not stated, uric acid reduction should also have a similar effect.

Sirt-1 is a longevity gene.  Autophagy and mitophagy are longevity processes.  Of course, homeostasis is the goal and too little is the more common defect from inhibitors such as oxidized LDL, calcium and urate, over nutrition, under exercise.  There are examples of too much autophagy such as in Charcot Marie tooth disorder.

Take home message is once again; Health plus autophagy,mitophagy minus inflamasome.

http://www.hindawi.com/journals/omcl/2016/7589813/abs/

Resveratrol Enhances Autophagic Flux and Promotes Ox-LDL Degradation in HUVECs via Upregulation of SIRT1

Copyright © 2016 Yanlin Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oxidized low-density lipoprotein- (Ox-LDL-) induced autophagy dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis (AS). Resveratrol (RSV) protects against Ox-LDL-induced endothelium injury. The objective of this study was to determine the mechanisms underlying Ox-LDL-induced autophagy dysfunction and RSV-mediated protection in human umbilical vein endothelial cells (HUVECs). The results showed that Ox-LDL suppressed the expression of sirtuin 1 (SIRT1) and increased LC3-II and sequestosome 1 (p62) protein levels without altering p62 mRNA levels in HUVECs. Pretreatment with bafilomycin A1 (BafA1) to inhibit lysosomal degradation abrogated the Ox-LDL-induced increase in LC3-II protein level. Ox-LDL increased colocalization of GFP and RFP puncta in mRFP-GFP-tandem fluorescent LC3- (tf-LC3-) transfected cells. Moreover, Ox-LDL decreased the expression of mature cathepsin D and attenuated cathepsin D activity. Pretreatment with RSV increased the expression of SIRT1 and LC3-II and increased p62 protein degradation. RSV induced RFP-LC3 aggregation more than GFP-LC3 aggregation. RSV restored lysosomal function and promoted Ox-LDL degradation in HUVECs. All the protective effects of RSV were blocked after SIRT1 was knocked down. These findings demonstrated that RSV upregulated the expression of SIRT1, restored lysosomal function, enhanced Ox-LDL-induced impaired autophagic flux, and promoted Ox-LDL degradation through the autophagy-lysosome degradation pathway in HUVECs.

Melatonin Increased Autophagy dependent on SIRT1, a Longevity Marker

Melatonin declines with age.

Seborrheic keratosis increase with age.

Autophagy declines with age.

Melatonin activates melatonin flux, increasing autophagy.

Blocking Sirt1 blocked melatonin increased autophagy.

Blocking autophagy directly reduced the protection of melatonin.

Increasing autophagy should block or reverse Seborrheic keratosis formation.

Melatonin and Ursolic acid (which increases Sirt1) might ameliorate age related Seborrheic keratosis.

BHB related to exercise and fasting increases autophagy.

I further conjecture that vitamin d levels affects Seborrheic keratosis as keratinocytes have large numbers of vitamin d receptors.

Fasting.

Exercise.

Melatonin.

Ursolic acid. 

Vitamin D.

The above should be negatively associated with Seborrheic keratosis specifically and aging generally!

http://europepmc.org/abstract/med/26918354

Melatonin protects skin keratinocyte from hydrogen peroxide-mediated cell death via the SIRT1 pathway.

Melatonin (N-acetyl-5-methoxytryptamine), which is primarily synthesized in and secreted from the pineal gland, plays a pivotal role in cell proliferation as well as in the regulation of cell metastasis and cell survival in a diverse range of cells. The aim of this study is to investigate protection effect of melatonin on H2O2-induced cell damage and the mechanisms of melatonin in human keratinocytes. Hydrogen peroxide dose-dependently induced cell damages in human keratinocytes and co-treatment of melatonin protected the keratinocytes against H2O2-induced cell damage. Melatonin treatment activated the autophagy flux signals, which were identified by the decreased levels of p62 protein. Inhibition of autophagy flux via an autophagy inhibitor and ATG5 siRNA technique blocked the protective effects of melatonin against H2O2-induced cell death in human keratinocytes. And we found the inhibition of sirt1 using sirtinol and sirt1 siRNA reversed the protective effects of melatonin and induces the autophagy process in H2O2-treated cells. This is the first report demonstrating that autophagy flux activated by melatonin protects human keratinocytes through sirt1 pathway against hydrogen peroxide-induced damages. And this study also suggest that melatonin could potentially be utilized as a therapeutic agent in skin disease.

Joseph Thomas (Tony) Liverman, Jr.

Promoting autophagy, mitophagy; Inhibiting NLRP3- Reverses Aging, Autoimmune, Trauma and Infectious Cellular Damage

Biggest Picture Yet.

Health plus autophagy,mitophagy minus Inflamasome.

At the largest fractal level thus far revealed by all the blog posts before, the above is the current grand strategy.  Thus there is the same dual aim of increasing the good and inhibiting the bad as cellular homeostasis.

In article below clock gene disruption is related to Sirt-1 decline in ability to deacetylate or inactivate the NLRP3 pathway.

Ursolic acid increases Sirt-1 and Sirt-3 and elevated levels are associated with longevity.

Ursolic acid increases intracellular BHB

Autophagy and mitophagy are increased by BHB.

Autophagy and mitophagy inhibit NLRP3 by removing toxic ROS producing mitochondria.

Melatonin promotes autophagy and mitophagy.

Melatonin counters only sepsis related NLRP3 activation.

BHB and melatonin counter NLRP3 activation in Both aging, sepsis and sterile inflammation from LPS and other triggers of autoimmune disease.

Increasing BHB and melatonin slows aging, neuroinflammation, autoimmune inflammation and degenerative age related diseases likely including cancer, stroke, heart attack, sarcopenia,heart failure, cognitive impairment and dementia.

http://onlinelibrary.wiley.com/doi/10.1111/jpi.12303/full

Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin

The connection between the innate immune system, clock genes, and mitochondrial bioenergetics was analyzed during aging and sepsis in mouse heart. Our results suggest that the sole NF-κB activation does not explain the inflammatory process underlying aging; the former also triggers the NLRP3 inflammasome that enhances caspase-1-dependent maturation of IL-1β. In this way, aged mice enter into a vicious cycle as IL-1β further activates the NF-κB/NLRP3 inflammasome link. The origin of NF-κB activation was related to the age-dependent Bmal1/Clock/RORα/Rev-Erbα loop disruption, which lowers NAD⁺ levels, reducing the SIRT1 deacetylase ability to inactivate NF-κB. Consequently, NF-κB binding to DNA increases, raising the formation of proinflammatory mediators and inducing mitochondrial impairment. The cycle is then closed with the subsequent NLRP3 inflammasome activation. This paired contribution of the innate immune pathways serves as a catalyst to magnify the response to sepsis in aged compared with young mice. Melatonin administration blunted the septic response, reducing inflammation and oxidative stress, and enhancing mitochondrial function at the levels of nonseptic aged mice, but it did not counteract the age-related inflammation. Together, our results suggest that, although with different strengths, chronoinflammaging constitutes the biochemical substrate of aging and sepsis, and identifies the NLRP3 inflammasome as a new molecular target for melatonin, providing a rationale for its use in NLRP3-dependent diseases.

Joseph Thomas (Tony) Liverman,

Infertility Management May Benefit from Both Increased BDNF Lifestyle and Increased PPAR Agonist Activity

Peroxisome Proliferator-Activated Receptors in Female Reproduction and Fertility 

http://downloads.hindawi.com/journals/ppar/2016/4612306.pdf

PPAR system is an amplifier of other nuclear transcription products.  In this review article, the implications of PPAR dysfunction as it affects fertility is discussed.  In essence, PPAR activity is important for stimulation of  2 types of cells in the ovary and is implicated in ova maturation, ova release, luteal cyst formation, trophoblast implantation in early pregnancy.  However, PPAR activity is diminished relatively later during pregnancy and lactation!

What is implied by early high and late low PPAR activity in pregnancy and lactation is my conjecture of the day.

The metabolic health of cells, their resistance to cell death and malignant transformation is directly correlated to BDNF levels directly and other "starvation set" genes by proxy.
Since PPAR genes can only amplify and co promote other nuclear transcription genes, BDNF et al are the genes they promote along with healthy sex hormone and viable eggs and sperm for procreation.  One must have BOTH BDNF et al gene expression for health and procreation AND PPAR  gene expression to amplify these effects for early pregnancy.

Why then is PPAR activity diminished by pregnancy and lactation?
Why is pregnancy an immune suppression state?

My conjecture is that pregnancy occurs to allow a genetically different body to live in the host or mother albeit in a protected environment with placental barrier.  There must be further immune system protections to prevent the rejection of the genetically different baby or allograft.

In addition to down regulated nuclear gene transcription of immune function there is down regulated nuclear transcription of co promoter or amplifiers.  Hence the decreased PPAR activity levels in the time around pregnancy.

ACTION:  BDNF increasing lifestyle should increase fertility and PPAR effects as a team.

Polycystic ovary syndrome is a syndrome of obesity, insulin resistance, ovarian follicular cysts and infertility.  Infertility is treated by reversing insulin resistance, a PPAR action and by use of fertility medications.

I wonder if BDNF et al gene expression would improve metabolic and fertility issues in Polycystic ovary syndrome.  If true, then raising BHB by any means and using PPAR agonists should improve fertility.

BHB is increased by the following:

Fasting. Restricted interval feeding.  ( This is 80% of metabolic health, based on studies including poor diets and limited exercise likely because the time duration of BHB is prolonged in contrast to the BHB time duration of either exercise and MCT oil consumption.)
Exercise,
MCT oil and coconut oil metabolism.
Ursolic acid. (UA increases PPAR alpha nuclear transcription which increases fatty acid metabolism within cells and increases PGC-1 alpha levels.  The latter amplifies the effect of BHB nuclear transcription of BDNF and has a force multiplying effect for fasting, exercise and MCT oil consumption.)

Metabolic Health and Resilience of the Cell is Directly Proportional to BDNF Levels

Previous articles have shown the protective effects of BDNF for nerve cells by directly preventing drug and chemical inflammation and apoptosis of nerve cells and thereby preventing Parkinson's disease and Alzheimer's.

Similarly, this protective effect has now been shown for pancreatic cells.  Pretreatment with BDNF prevented cell inflammation and cell death via toxic drugs used to cause diabetes in vivo.

Cells that are metabolically healthy are not just metabolically heathy, non diabetic cells but have resilience and resistance to cancer transformation.  It is also obvious that metabolic health is associated with BDNF levels and that malignant cells are adversely affected by increasing BDNF or activation of the starvation gene set.

BDNF is one of 44 genes in the starvation set whose nuclear transcription is promoted by BHB.

BHB is increased by the following:

Fasting.

Exercise.

MCT or coconut oil.

Ppar alpha agonists such as Ursolic acid, Reservatrol, and Betain.

Telmisartan, Atorvastatin, Fenofibrate. 

http://www.sciencedirect.com/science/article/pii/S0026049516000317

BDNF protects pancreatic β cells (RIN5F) against cytotoxic action of alloxan, streptozotocin, doxorubicin and benzo(a)pyrene in vitro

Abstract

Objective

The study was conducted to observe whether brain-derived neurotrophic factor (BDNF) has cytoprotective actions against alloxan (AL), streptozotocin (STZ), doxorubicin (DB) and benzo(a)pyrene (BP) compounds in vitro that may account for its beneficial action in diabetes mellitus.

Materials and methods

This in vitro study was performed using rat insulinoma (RIN5F) cells. Possible cytoprotective action of BDNF (using pre-treatment, simultaneous and post-treatment schedules of RIN5F cells with BDNF) against the four chemicals tested was evaluated using MTT and apoptosis assays. Possible mechanism of cytoprotective action of BDNF was assessed by measuring BCl2/IKB-β/Pdx mRNA transcripts and anti-oxidant levels in RIN5F cells. Effect of alloxan, STZ, doxorubicin and BP on the production of BDNF by RIN5F cells was also studied.

Results

Results of the present study revealed that BDNF in the doses (100 ng > 50 ng > 10 ng/ml) has significant cytoprotection (P < 0.001, P < 0.01) on cytotoxic action of AL, STZ, DB and BP against rat insulinoma RIN5F (5 × 10⁴ cells/100 μl) cells in vitro. It was observed that AL, STZ, DB and BP inhibited BDNF production significantly (P < 0.001) in a dose-dependent manner by RIN5F cells (0.5 × 10⁶ cells/500 μl) in vitro, while BDNF not only prevented apoptosis induced by these four chemicals but also significantly increased (P < 0.001) BCl2/IKB-β/Pdx mRNA transcripts and restored anti-oxidant levels (P < 0.01) in RIN5F cells to normal.

Discussion

These results suggest that BDNF has potent cytoprotective actions, restores anti-oxidant defenses to normal and thus, prevents apoptosis and preserves insulin secreting capacity of β cells. In addition, BDNF enhanced viability of RIN 5F in vitro. Thus, BDNF not only has anti-diabetic actions but also preserves pancreatic β cells integrity and enhances their viability. These results imply that BDNF functions as an endogenous cytoprotective molecule that may explain its beneficial actions in some neurological conditions as well

.

Lifestyle and Ursolic Acid Amplifies Energy for Cellular Function and Regeneration.

Exercise and fasting via beta hydroxybutyrate ( signaling, direct priming of oxidative phosphorylation and histone acetylase inhibition to increase BDNF transcription)  increase nuclear transcription factors of BDNF et al and are promoted by PPAR gamma agonist such as Ursolic acid via peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α.

BHB beta hydroxybutyrate is the transcriptional link allowing PGC1α and NCOR1 to co-promote or co-repress oxidative phosphorylation .

More fasting, exercise and high fat low carb diet promotes mitochondrial metabolism via BHB nuclear transcription of BDNF et al and increased PgC1a or decreased NCOR1 an amplifying or silencing partner effecting the mitochondria.

Ursolic acid, amplifies fasting and exercise effects of BDNF leading to increased fatty acid oxidation and energy production by mitochondria.  The effect in muscles is 30% more strength in 8 weeks and I suspect increased nerve and brain metabolism and function.  One important function of brain energy is to protect the brain!  What is the most potent nuclear transcription growth factor to prevent brain disconnection syndrome?  BDNF brain derived neurotrophic factor.  BDNF also inhibit heart and muscle disconnection syndrome that leads to heart failure and age related sarcopenia.

http://www.sciencedirect.com/science/article/pii/S0955067414001410

Introduction

Energy is vital to all living organisms. In humans and other mammals, the vast majority of energy is produced by oxidative metabolism in mitochondria [1]. As a cellular organelle, mitochondria are under tight control of the nucleus. Although the majority of mitochondrial proteins are encoded by nuclear DNA (nDNA) and their expression regulated by the nucleus, mitochondria retain their own genome, mitochondrial DNA (mtDNA), encoding 13 polypeptides of the electron transport chain (ETC) in mammals. However, all proteins required for mtDNA replication, transcription, and translation, as well as factors regulating such activities, are encoded by the nucleus [2].

The cellular demand for energy varies in different cells under different physiological conditions. Accordingly, the quantity and activity of mitochondria are differentially controlled by a transcriptional regulatory network in both the basal and induced states. A number of components of this network have been identified, including members of the nuclear receptor superfamily, the peroxisome proliferator-activated receptors (PPARs) and the estrogen-related receptors (ERRs) [3, 4 and 5].

The Yin-Yang co-regulators

A well-known inducer of mitochondrial oxidative metabolism is the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) [6], a nuclear cofactor which is abundantly expressed in high energy demand tissues such as heart, skeletal muscle, and brown adipose tissue (BAT) [7]. Induction by cold-exposure, fasting, and exercise allows PGC1α to regulate mitochondrial oxidative metabolism by activating genes involved in the tricarboxylic acid cycle (TCA cycle), beta-oxidation, oxidative phosphorylation (OXPHOS), as well as mitochondrial biogenesis [6 and 8] (Figure 1).

Figure 1. PPARs and ERRs are major executors of PGC1α-induced regulation of oxidative metabolism. Physiological stress such as exercise induces both the expression and activity of PGC1α, which stimulates energy production by activating downstream genes involved in fatty acid and glucose metabolism, TCA cycle, β-oxidation, OXPHOS, and mitochondrial biogenesis. The transcriptional activity of PGC1α relies on its interactions with transcriptional factors such as PPARs (for controlling fatty acid metabolism) and ERRs (for regulating mitochondrial OXPHOS).

The effect of PGC1α on mitochondrial regulation is antagonized by transcriptional corepressors such as the nuclear receptor corepressor 1 (NCOR1) [9 and 10]. In contrast to PGC1α, the expression of NCOR1 is suppressed in conditions where PGC1α is induced such as during fasting, high-fat-diet challenge, and exercise [9 and 11]. Moreover, the knockout of NCOR1 phenotypically mimics PGC1α overexpression in regulating mitochondrial oxidative metabolism [9]. Therefore, coactivators and corepressors collectively regulate mitochondrial metabolism in a Yin-Yang fashion.

However, both PGC1α and NCOR1 lack DNA binding activity and rather act via their interaction with transcription factors that direct the regulatory program. Therefore the transcriptional factors that partner with PGC1α and NCOR1 mediate the molecular signaling cascades and execute their inducible effects on mitochondrial regulation.

Joseph Thomas (Tony) Liverman, Jr.

Time Restricted Feeding née Intermittent Fasting Increases Fat Metabolism, Prevents Obesity and Reduces Inflammatory Cytokines

Time restricted feeding of calories for 8 or 12 hours of a high fat diet resulted in lower obesity rates in mice.

Insulin levels were reduced (and therefore less needed) by time restricted feedings.  The respiratory exchange ratio of the time restricted feeding high fat diet group was lower than the normal diet group meaning greater fat metabolism despite less energy expenditure.  They burned more fat and more calories with less exercise and less fat gain.  (Lower insulin increased fat burning and metabolic rate independent of exercise.)

Diabetic humans who fast 12 or more hours daily despite a crappy diet and no exercise should have better A1c, less obesity and less inflammatory cytokines.

Circadian metabolic clock genes cycle from the first bite of food for approximately one half of the circadian light dark cycle.

Conjecture:  time restricted feeding is 80% of obesity prevention, 10% calorie restriction and 10% exercise.

http://www.sciencedirect.com/science/article/pii/S0271531716000464

Time-restricted feeding reduces adiposity in mice fed a high-fat diet

Disruption of the circadian rhythm contributes to obesity. This study tested the hypothesis that time-restricted feeding (TRF) reduces high-fat diet–induced increase in adiposity. Male C57BL/6 mice were fed the AIN93G or the high-fat diet ad libitum (ad lib); TRF of the high-fat diet for 12 or 8 hours during the dark cycle was initiated when high-fat diet–fed mice exhibited significant increases in body weight. Energy intake of the TRF 12-hour group was not different from that of the high-fat ad lib group, although that of the TRF 8-hour group was slightly but significantly lower. Restricted feeding of the high-fat diet reduced body fat mass and body weight compared with mice fed the high-fat diet ad lib. There were no differences in respiratory exchange ratio (RER) among TRF and high-fat ad lib groups, but the RER of these groups was lower than that of the AIN93G group. Energy expenditure of the TRF groups was slightly but significantly lower than that of the high-fat ad lib group. Plasma concentrations of ghrelin were increased in TRF groups compared with both AIN93G and high-fat ad lib groups. Elevations of plasma concentrations of insulin, leptin, monocyte chemoattractant protein-1, and tissue inhibitor metalloproteinase-1 by high-fat ad lib feeding were reduced by TRF to the levels of mice fed the AIN93G diet. In conclusion, TRF during the dark cycle reduces high-fat diet–induced increases in adiposity and proinflammatory cytokines. These results indicate that circadian timing of food intake may prevent obesity and abate obesity-related metabolic disturbance.