Mitochondrial Health, Happiness and Signaling in Neurodegeneration and Aging

If the mitochondria are not happy the cell is not happy and SIGNALS this to the cell and is the cause of neurodegeneration.

The mitochondria is happy in the absence of toxins and the presence of autophagy, Mitophagy and normally functioning cell and organelles quality control mechanisms.

Lifestyle that promotes this happy environment give a maximum clock determined health and life span.  Sulforaphane supports this controlled oxidative flux state.

Spermidine reverses the aging clock mechanism and had the potential to extend our predetermined maximum health and life span.  It prevents the steady erosion of proteostasis.

http://link.springer.com/chapter/10.1007/978-3-319-28637-2_5

Mitochondrial Signaling and Neurodegeneration

Abstract

The endosymbiosis of mitochondria and the resulting increase in energy supply thus conferred upon the eukaryotic cell enabled the evolution of multicellular organisms and complex organs, such as the brain. As a result, the brain and other organs with high energy demands, depend heavily upon mitochondrial metabolism for normal function, and as a consequence, defects in mitochondrial function lead to neurodegenerative disorders. However, the mechanisms linking mitochondrial defects to hallmarks of neurodegeneration, such as the protein aggregates are also extracellular epigenetic alterations, abnormal gene expression, systemic inflammation, and protein aggregates, remain unclear.

Emerging evidence demonstrates that mitochondria are not only power-generating organelles, but also engage in signaling at multiple levels. During the bioenergetic decline associated with aging, dysfunctional mitochondria generate signals of stress (SOS) that can trigger and/or amplify neurodegenerative processes. In this chapter, we describe emerging mechanisms for mitochondrial signaling at four different levels. Mitochondria communicate (1) with each other via fusion and specialized inter-mitochondrial junctions, (2) with cytoplasmic components via posttranslational modifications that shift signaling pathways and promote protein aggregation, (3) with the nucleus to regulate epigenetic modifications and gene expression, and (4) with the systemic environment where they alter neuroendocrine and inflammatory processes that impact neuronal function. The relevance of mitochondrial signaling to neurodegeneration is discussed.

Joseph Thomas (Tony) Liverman, Jr.

Unopposed Oxidative Stress Leads to Pro-inflammatory Phenotype.. Metabolic Cellular Health Produces and Maintains Anti-inflammatory Phenotype..

Here is a discussion of beta hydroxybutyrate mechanisms of action in part listing some of the "starvation gene set" stimulated by nuclear beta hydroxybutyrate.  It further emphasizes the strategic goal of protecting against oxidative stress.  This, in effect, prevents cellular drift to pro-inflammatory senescent cells which prevents stem cell replacement.

The result?

Beta hydroxybutyrate is anti-aging anti-inflammatory and prevents phenotypic pro-inflammatory senescent cell drift and promotes stem cell replacement to maintain tissue integrity and function.

Metabolic cell health practices and supplements strategically and tactically achieves the young anti-inflammatory cell phenotype that simultaneously builds and maintains vigorous stem cell.

Maintaining a clean senescent reduced anti-inflammatory environment and resilient stem cells allows biological age to greatly lag chronological age.  It prevents inflamaging and other diseases derived from various oxidative stresses.

https://www.ncbi.nlm.nih.gov/pubmed/28371201

Ketone bodies mimic the life span extending properties of caloric restriction.

The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP₃ ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.

Joseph Thomas (Tony) Liverman, Jr.

Aging, in the Absence or Presence of Spermidine Affects Mitochondria and its Intimate Relationship with the Endoplasmic Reticulum

Complex folded proteins are processed by the ER which is the likely target of spermidine.  The ER is adjacent and joined to mitochondria by the MAM mitochondrial membrane. A common membrane allows intimate and targeted exchange of compounds for mutual and symbiotic benefit. "I'll scratch your back if you'll scratch mine."

I suspect that enzymes critical for transport of fuel substrates into mitochondria (and their subsequent conversion into ATP energy) are produced by ER.  Therefore oxidative stress, in the absence of spermidine, impedes the efficiency of mitochondria, a hallmark of aging that would not compensate with larger numbers of mitochondria that would come at a cost of even greater oxidative stress.

Only fasting, autophagy, sulforaphane induced greater endogenous antioxidants production and increased spermidine improved proteostasis that works via greater autophagy and reduced mitochondrial/ER oxidative stress would restore efficiency and normalize the increased oxidative stress of aging.

http://www.sciencedirect.com/science/article/pii/S0891584917301855

The Endoplasmic Reticulum: A Hub of Protein Quality Control in Health and Disease

Review article

• Lisa Vincenz-Donnelly
• Mark S. Hipp

Abstract

One third of the eukaryotic proteome is synthesized at the endoplasmic reticulum (ER), whose unique properties provide a folding environment substantially different from the cytosol. A healthy, balanced proteome in the ER is maintained by a network of factors referred to as the ER quality control (ERQC) machinery. This network consists of various protein folding chaperones and modifying enzymes, and is regulated by stress response pathways that prevent the build-up as well as the secretion of potentially toxic and aggregation-prone misfolded protein species. Here, we describe the components of the ERQC machinery, investigate their response to different forms of stress, and discuss the consequences of ERQC break-down.

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FOXO, Fasting and Slowing Senescent Cell Growth Arrest

Senescent cells accumulate with aging and function poorly, like sleeping growth arrested babies, in producing more waste than work.  They are one putative "cause" of aging.

Moreover senescent growth arrested cells are toxic to the environment of regional cells.

Senescent cell development is  countered by FOXO genes which are inhibited by insulin and insulin growth factor during feeding and released to work during fasting.

Fasting 12 hours daily allows FOXO and autophagy to repair and remove waste.  

It allows a new start, the forgiveness of metabolic debts and a roll back of the aging odometer.

In a balanced cell environment then, why does aging and senescent cells still accumulate albeit much slower?

Clock genes.  Spermidine synthetase winds down and slows proteostasis.  This slow down may be slowed down itself by microbiome or dietary supplementation with spermidine/wheat germ.  In effect, spermidine stops or reverses the clock and let's the game continue.  This was the effect represented in the movie Adeline, in which Blake Lively no longer aged until the clock was restarted.

Would one live forever if this was operational? No.  Injury, acute and subacute, would sufficiently damage cell function ultimately.  Nonetheless, Sulphoraphane which stimulates the antioxidant response element would reduce the magnitude and rate of accumulated oxidative stresses produced by the environment.

Once again we arrive at anti-aging being Autophagy, Sulphoraphane and Spermidine; a strategy to prevent inflamaging and improve resilience.

http://www.sciencedirect.com/science/article/pii/S1471491416301721

The Fountain of Youth by Targeting Senescent Cells?

The potential to reverse aging has long been a tantalizing thought, but has equally been considered mere utopia. Recently, the spotlights have turned to senescent cells as being a culprit for aging. Can these cells be therapeutically eliminated? When so? And is this even safe? Recent developments in the tool box to study senescence have made it possible to begin addressing these questions. It will be especially relevant to identify how senescence impairs tissue rejuvenation and to prospectively design compounds that can both target senescence and stimulate rejuvenation in a safe manner. This review argues that to fulfill this niche, cell-penetrating peptides may provide promising therapeutics. As a candidate approach, the author also highlights the potential of targeting individual FOXO signaling pathways to combat senescence and stimulate tissue rejuventaion.

Semigenetic clearance of senescent cells delays features of aging in fast and naturally aged mice establishing senescence as their underlying cause.

Viability screens with existing compounds lead to discovery of the first generation of antisenescence compounds as quercetin/dasatinib and pan-BCL inhibitors. Further optimization is required due to suboptimal selectivity or toxicity.

Cell-penetrating peptides can steer very specific protein–protein interactions and have been successful in various clinical trials. They are a potent option for forward design of antisenescence therapies.

Senescent cells can impair their environment through juxtacrine and paracrine signaling of SASP factors. This may be caused by keeping neighboring cells permanently locked in a state of dedifferentiation (Figure 3), leading to reduced tissue rejuvenation potential.

FOXOs regulate p21^Cip1, a prominent factor in senescence growth arrest, and they inhibit the stemness regulator β-catenin. As such, they could be ideal therapeutic targets to counter senescence, while promoting tissue rejuvenation.

Longevity and Increased Healthspan: A Strategy with Strong Evidence

Interesting article showing that autophagy promotion reduces sarcopenia and improves muscle strength function.  Autophagy inhibition promotes sarcopenia and reduces muscle strength function.

Spermidine, fasting and exercise directly promotes autophagy and without autophagy their actions are blocked.

Sulphoraphane by stimulating ARE antioxidant response element counters oxidative stress and reduces the damaged proteins and DNA that require autophagy and replacement or repair and indirectly aids autophagy.

That is likely the anti-aging effect of these lifestyle and supplements.  The magnitude of all combined should be greater than 30% Healthspan and lifespan as that had been proved with either supplement alone.

http://www.sciencedirect.com/science/article/pii/S1471489216300959

Macrophage Activation by Fructose Prevented by Antioxidant Sufficiency Blocks TXNIP Conversion of M2 into M1

What we were talking about recently.  Inflamasome activation converts anti inflammatory macrophage 2 into pro inflammatory macrophage 1.  This macrophage activation is the putative cause of asthma and diabetes.  Blocking the NLRP3 inflamasome prevents cell damage and death.  Sepsis and ischemia reperfusion injury activate the inflamasome.  Too much fructose leading to too much oxidative stress causes damaging pro inflammatory TXNIP to be increased.  Verapamil can directly inhibit TXNIP but then oxidative stress directly damages cells.  The solution is safer antioxidants.

Sepsis is an increased oxidative stress, NLRP3, increased TXNIP condition.  Studies show a 30% reduction of mortality with Vitamin C in animal models.

Generally endogenous antioxidants  superoxide dismutase and glutathione are superior to direct antioxidants like vitamin c.

This should prevent loss of beta cell function and progression of diabetes.  This should prevent or decrease asthma exacerbation teiggered by infections that promote oxidative stress.

I prefer to use sulforaphane from broccoli sprouts and spermidine from wheat germ to achieve increased antioxidant, increased energy production and inhibition of toxic inflammatory TXNIP.

http://link.springer.com/article/10.1007/s10753-017-0542-4

Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines

22 March 2017

The aim of this study was to identify the role of thioredoxin-interacting protein (TXNIP) and its interaction with antioxidants in the activation of the fructose-induced NOD-like receptor protein 3 (NLRP3) inflammasome in human macrophages. The study was performed with U937 and THP-1 macrophage cell lines. Total reactive oxygen species (ROS) were measured by flow cytometry. Interleukin-1β (IL-1β), IL-18, NLRP3, TXNIP, and caspase-1 protein expression was detected using western blotting. Quantitative real-time polymerase chain reaction was used to detect IL-1β, IL-18, and caspase-1 gene expression. Intracellular shuttling of TXNIP was assessed by immunofluorescent staining with MitoTracker Red. Increased production of ROS and expression of IL-1β, IL-18, and caspase-1 genes and proteins were observed in U937 and THP-1 cells incubated with fructose and were effectively inhibited by quercetin and ascorbic acid. Intracellular shuttling of TXNIP from the nucleus into the mitochondria was detected under stimulation with fructose, which was also attenuated by antioxidants quercetin and ascorbic acid but not butylated hydroxyanisole. Treatment of macrophages with fructose promoted the association between TXNIP and NLRP3 in the cytosol, sequentially resulting in the activation of the NLRP3 inflammasome. This study revealed that intracellular TXNIP protein is a critical regulator of activation of the fructose-induced NLRP3 inflammasome, which can be effectively blocked by the antioxidants quercetin and ascorbic acid.