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

.