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

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  Ang II activates NLRP3 inflammasome mediated by NOX-derived H2O2 in hepatocytes.
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  Ang II initiates hepatocyte EMT by activating the NOX-derived H2O2-mediated NLRP3 inflammasome/IL-1β/Smad circuit.
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  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

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  Time-controlled fasting improves mitochondrial metabolism of fat cells.
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  Mitochondrial flexibility maintains adipose tissue functionality.
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  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.