Melatonin Use Rationale for Depression and Dementia

Depression (and dementia) is likely due to metabolically unhealthy cells that have reduced number and reduced functioning mitochondria that result from genes being turned off by epigenetic methylation of gene promoter sites.

Considered here is MELATONIN that declines with age and its positive and protective effect on cell metabolic health.

Melatonin increases Sirt1.

Melatonin directly and indirectly reduces inflammation.

Melatonin is integral to all known forms of DNA repair for nuclear and mitochondrial genes.

Melatonin is integral for correct RNA splicing.

Melatonin turns on methylated genes through HDAC inhibition and direct antioxidant effect.

Melatonin reduces oxidative and nitrosative stress.

Melatonin rich cells have increased number and increased function of mitochondria.

Melatonin rich cells have NO and hTert in excess of H2O2 and have lower level pulses of ROS because of increased expression of antioxidant enzymes.

Melatonin rich cells have homeostasis of mitochondrial fission and fusion proteins and the mitochondria are not skinny or fat but lean and fit.

Melatonin rich cells have reduced markers of cell senescence.

Melatonin rich cells have increased functional integrity and function within tissues and organs.

Melatonin rich cells express lower levels of il-beta 1, caspase and downstream homocysteine and C-reactive protein.

Melatonin rich cells have efficient autophagy with fewer autophagosomes because of healthy maintenance and reduced oxidation and protein  and glycosylation aggregates.

Melatonin rich cells cleave APP in a nontoxic way and beta amyloid is reduced in production and cleared.

Melatonin rich cell state occurs in the young and melatonin poor state occurs with aging.

Cognitive and affective decline is caused by lack of metabolic and gene support that could be improved by supplemental melatonin and its functional mimics.

Melatonin should therefore reverse and prevent depression and dementia in the long term.  Antidepressants are  recommended for 6-18 months of initial therapy duration.

Dale Bredesen, MD reports dementia reversal over 6 months in his treatment algorithm.

I conjecture that melatonin should be adjunctive for initial therapy of MDD and provide monotherapy for prevention and maintenance and over all make our current therapies more effective and more sustaining

http://www.sciencedirect.com/science/article/pii/S0278584616303839

Linking the biological underpinnings of depression: Role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition - ScienceDirect

The pathophysiological underpinnings of neuroprogressive processes in recurrent major depressive disorder (rMDD) are reviewed. A wide array of biochemical processes underlie MDD presentations and their shift to a recurrent, neuroprogressive course, including: increased immune-inflammation, tryptophan catabolites (TRYCATs), mitochondrial dysfunction, aryl hydrocarbonn receptor activation, and oxidative and nitrosative stress (O&NS), as well as decreased sirtuins and pathway activity. These biochemical changes may have their roots in central, systemic and/or peripheral sites, including in the gut, as well as in developmental processes, such as prenatal stressors and breastfeeding consequences. Consequently, conceptualizations of MDD have dramatically moved from simple psychological and central biochemical models, such as lowered brain serotonin, to a conceptualization that incorporates whole body processes over a lifespan developmental timescale. However, important hubs are proposed, including the gut-brain axis, and mitochondrial functioning, which may provide achievable common treatment targets despite considerable inter-individual variability in biochemical changes. This provides a more realistic model of the complexity of MDD and the pathophysiological processes that underpin the shift to rMDD and consequent cognitive deficits. Such accumulating data on the pathophysiological processes underpinning MDD highlights the need in psychiatry to shift to a classification system that is based on biochemical processes, rather than subjective 

Fixing Molecular Inflammation

Inflamaging results from decreased antioxidant capacity and thereby decreases resilience.

Integral in this process is ROS that trigger the inflammatory cascade of the inflamasome, the innate immune system.  NLRP3, caspase and il-beta 1 form heteromers of inflammation in conjunction with inflammatory molecules notably the c reactive protein.

Macrophages are the sentinels mentioned below.  Microglia cells in brain.  Muller cells in retina. Kuppfer cells in liver. M1 cells in endothelial linings of arteries and veins, respiratory linings, gastrointestinal linings, pancreatic and biliary duct linings.

The most effective upstream fix to molecular inflamaging is increased antioxidant capacity via Nrf2 activators and spermidine/wheat germ enhancement of proteostasis.

Nrf2 activators include melatonin, hydrogen rich water, sulforaphane, spermidine/wheat germ and Green tea extract.

As critical proof of this concept Reversing Dementia accomplished over a thousand times by Dale Bredesen MD of the Buck Institute SHOUTS special cause variation from usual practice.  It signals a paradigm shift to make cells more resilient and resistant to molecular AND injury related  INFLAMMATION!

See his YouTube talk and review his book.  His results are not chance alone.  They are reproducible and have relevance to every organ based specialist and organ based disease model of modern medicine.

http://www.fasebj.org/content/31/5/1787.short

It’s time to redefine inflammation

Maria Antonelli and

+ Author Affiliations

1. ↵1Correspondence: Division of Rheumatology, Case Western Reserve University at MetroHealth Medical Center, 2500 MetroHealth Dr., Cleveland, Ohio, 44109 USA. E-mail: ixk2@case.edu

Abstract

Inflammation has been defined for many years as the response to tissue injury and infection. We are now forced to reconsider this definition by the avalanche of reports that molecules and cells associated with inflammation are activated or expressed in high concentration in a large variety of states in the absence of tissue injury or infection. Modest increases in concentration of C-reactive protein, a circulating marker of inflammation, have been reported to be associated with an astounding number of conditions and lifestyles felt to be associated with poor health; these conditions represent or reflect minor metabolic stresses. In recent years we have learned that inflammation is triggered by sentinel cells that monitor for tissue stress and malfunction—deviations from optimal homeostasis—and that molecules that participate in the inflammatory process play a role in restoring normal homeostasis. Accordingly, we suggest that inflammation be redefined as the innate immune response to potentially harmful stimuli such as pathogens, injury, and metabolic stress.—Antonelli, M., Kushner, I. It’s time to redefine inflammation.

• C-reactive protein
• unfolded protein response
• homeostasis
• Claude Bernard
• innate immunity

Abbreviations:

CREBH

cyclic AMP response element-binding protein-H

CRP

C-reactive protein

ER

endoplasmic reticulum

TLR

Toll-like receptor

UPR

unfolded protein response

• Received December 12, 2016.
• Ac.

Translational Health Will Likely Become a TwentyFirst Paradigm for Medicine

Does this sound promising to you?

Essentially metabolic health improves resilience to illness and disease.

Strategic change, paradigm change?. 

Cell heal thyself.  Instead of increasing war on threats to health, increase the non war activities of cell building and regeneration.  This acknowledges that the capacity to be resilient and regenerate is magnitudes stronger than powerful medicine.  Properly understood medicines allow the body to recover and thrive post war. Resilience and recovery is an infinite game rather than a finite game that leads to nursing home care.

"Abstract

Advances in geroscience are allowing scientists and clinicians, for the first time, to consider interventions aimed at directly targeting the hallmarks of aging. Unlike disease-specific approaches, such interventions have the potential to prevent multiple diseases of aging simultaneously, thereby greatly enhancing healthspan for most individuals. Initial clinical data indicates that geroprotective compounds such as rapamycin and metformin may be effective at delaying or reversing age-related disease in otherwise healthy elderly people and companion animals. Here I will provide an overview of the field of translational geroscience, which I believe will become the paradigm for the practice of medicine in the 21st century."

My study of cell science strongly indicates that Nrf2 activators and proteostasis activators via appropriate and signaled pathways that ultimately leads to autophagy or cell quality control, Mitophagy and reduced Endoplasmic Reticulum stress will regenerate and optimize resilience to oxidative stress and age related pleiotropic disorders.

The best example of this is the work of Dale Bredesen MD who in the YouTube video Reversing Alzheimer s has reversed dementia in 1000s of patient.  That is too many magnitudes of Lazarus walking out of their tombs of dementia to be chance alone.

Dr. Bredesen eschews the single drug therapy for root cause correction and developed the right strategy, right tactics and right projects to provide a powerful proof of concept.

I think this approach will impact humanity like Tesla's alternating current. (Analogy intended)

Cell power is the flow of electrons and it's safe production.  Not too hot and not to cool, just right.

Horse power is electron power in all its forms.

http://www.sciencedirect.com/science/article/pii/S2468501117300081

Nrf2 Activation Prevents and Reverses Dementia in Conjunction with BDNF

Nrf2 sufficiency should reduce Alzheimer's disease.

Aging produces Nrf2 deficiency.

Nrf2 knock out mimic Alzheimer's APP and TAU protein aggregates.

Nrf2 deficiency allows protein aggregates to damage.  

Nrf2 sufficiency prevents damage, improves proteostasis and promotes autophagy to reduce the aggregates.

Remember that soluble beta amyloid induces oxidative stress, neutralized by Nrf2, that damages brain networks in Nrf2 deficiency.

Nrf2 can be stimulated by hydrogen rich water, sulforaphane, melatonin, wheat germ/spermidine and Green tea extract.

http://www.sciencedirect.com/science/article/pii/S2213231717303993

NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology

APP/TAU-induced oxidative and inflammatory stress is exacerbated by NRF2-deficiency.

Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.

Joseph Thomas (Tony) Liver

Improve Diabetes and Bipolar Diseases With Increased Net Total Antioxidant Capacity

Diabetics on insulin are controlled (not cured) but have impaired thioredoxin (and increased TXPIN.)

Manic patients on therapy are controlled (not cured) but have impaired thioredoxin (and increased TXPIN.)

BOTH have either/or both increased oxidative stress or reduced antioxidant capacity.

Could we improve control in both of these "metabolic illnesses?"

How.

1.  Control of symptoms and consequences.  Normalize affect and elevated glucose.

2.  Increase net total antioxidant CAPACITY by activating the Nrf2 pathway with hydrogen rich water, sulforaphane, melatonin and wheat germ in conjunction with 12 hours of daily fasting, four minutes of Tabata high intensity interval exercise and two minutes of slow paced breathing twice daily.

Level of plasma thioredoxin in male patients with manic episode at initial and post-electroconvulsive or antipsychotic treatment

http://onlinelibrary.wiley.com/doi/10.1111/pcn.12244/full

Klotho AND Nrf2 for Health and Wealth

Klotho gene acts by activating Nrf2 pathway negating angiotensin 2 related oxidative stress.

Sulforaphane, hydrogen rich water and melatonin activate Nrf2.

Green tea extract reduces Keap1, the antagonist for Nrf2.

Klotho variant improves longevity and IQ by making GluN2b more sensitive to BDNF.

BDNF activity is inversely related to depression and suicide.

BDNF is directly related to school performance, life success and metabolic cell health.

Would Sulforaphane, hydrogen rich water, melatonin and green tea extract improve the following?

School performance.

Life performance.

Metabolic health and tissue and organ function.

Depression.

Suicide.

How much?

Targeting Klotho (for GluN2b) AND Nrf2 (for BDNF and reduced oxidative stress, gene repair and epigenetic gene expressing restoring.)

Healthy kidneys express Klotho which targets the hippocampus GluN2b expression upon which BDNF works.

The anti-ageing hormone klotho induces Nrf2-mediated antioxidant defences in human aortic smooth muscle cells

http://onlinelibrary.wiley.com/doi/10.1111/jcmm.12996/full

Melatonin and TNPIX Modulates ROS IN Acute and Chronic Oxidative Stress

This first paragraph implies that cleaning up oxidative stress inhibits or reverses malignancy, diabetes, neurodegenerative diseases and aging.

It further shows that TNPIX is elevated in oxidative stress.

No stress low TNPIX.

Challenging stress low levels.

Overwhelming stress high levels.

TNPIX modulates ROS signaling AND has both pro oxidant and antioxidant effects dependent on level. (Interestingly melatonin has that same duality and may imply it shares TNPIX ROS modulation function.)

The article implicitly states that TNPIX declines with age.

It is firmly established that Melatonin declines with age.

High levels are associated with growth arrest and tumor suppression.

In diabetes formation TNPIX is elevated and beta cells decline (arrested.)

Challenging levels signal that "more antioxidant capacity" is needed.

Oxidative stress accelerates aging and reduces stem cells number and quality leading to stem cell exhaustion.

Does treating oxidative stress with hydrogen rich water, sulforaphane, melatonin, wheat germ spermidine reduce both aging and cancer?

Sepsis (and cardiac or respiratory failure ) is a major acute oxidative stressor.  Antioxidant rescue of sepsis model animals that targets mitochondria increase survival and organ function survival acutely.

Does increasing net total antioxidant capacity protect against age related chronic oxidative stress including diabetes, neurodegenerative disease and malignancy?

http://www.cell.com/cell-metabolism/fulltext/S1550-4131(13)00245-3?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413113002453%3Fshowall%3Dtrue

TXNIP Maintains the Hematopoietic Cell Pool by Switching the Function of p53 under Oxidative Stress

Oxidative stress occurs mainly due to excessive accumulation of cellular reactive oxygen species (ROS) or deficiency of antioxidant defense system. Oxidative stress often leads to pathologic diseases such as diabetes, neurodegenerative diseases, and cancer (Hole et al., 2011, Sinha et al., 2013). There is growing evidence that balanced regulation of ROS is critical for hematopoiesis. Hematopoietic cells are vulnerable to oxidative stress, and malignancy of hematopoietic tissues is observed in the presence of chronic oxidative stress (Ghaffari, 2008). Homeostatic regulation of redox status in hematopoietic tissues is important for normal hematopoiesis.

Thioredoxin-interacting protein (TXNIP) is a 397 amino acid, 50 kDa protein that belongs to the arrestin family, and Txnip^−/− mice show a high incidence of hepatocellular carcinoma (HCC) (Jeong et al., 2009, Kwon et al., 2011, Lee et al., 2005, Song et al., 2003). TXNIP expression is reduced in many types of tumors, and TXNIP overexpression inhibits tumor growth by blocking cell-cycle progression (Han et al., 2003). The numbers of natural killer (NK) cells in the bone marrow (BM) of Txnip^−/− mice are reduced, and the long-term reconstituting HSC population shows an exhausted phenotype and is reduced in frequency (Jeong et al., 2009, Lee et al., 2005).

The tumor suppressor p53 plays a key role in restricting the expansion of abnormal cells through either growth arrest or apoptosis in response to genotoxic stresses (Olovnikov et al., 2009, Sablina et al., 2005). The p53 pathway is regulated by mouse double minute 2 (MDM2), an E3 ubiquitin ligase that targets the p53 protein for proteasomal degradation (Sasaki et al., 2011). p53 engages powerful prosurvival pathways by inducing the expression of antiapoptotic or antioxidant genes (Bensaad and Vousden, 2007, Jänicke et al., 2008). In addition, p53 is a critical regulator of HSC quiescence through its target genes (Liu et al., 2009). Previous reports imply that the protective or antiaging effects of TXNIP are important in maintaining hematopoietic cell pool (Jeong et al., 2009, Kim et al., 2007).

In this study, we demonstrate that Txnip^−/− hematopoietic cells had defects in the regulation of ROS levels and were more sensitive than wild-type cells to oxidative stress. We also demonstrated that TXNIP exerted its antioxidant effects in hematopoietic cells by stabilizing p53 under oxidative stress. Our findings suggest that TXNIP plays a critical role in the antioxidant defense mechanisms of hematopoietic cells by activating the p53 pathway during oxidative stress.

To investigate the effects of TXNIP deficiency on hematopoiesis, we analyzed the frequency of hematopoietic stem cells (HSCs) and hematopoietic progenitors from young (12 weeks) and old (22–23 months) Txnip^+/+ (wild-type [WT]) and Txnip^−/− (KO) mice. Consistent with previous reports (Geiger and Van Zant, 2002, Sudo et al., 2000), old WT mice showed much higher frequencies of HSCs and hematopoietic progenitors, but old KO mice showed relatively decreased frequencies (Figure 1A). Next, we performed a competitive repopulation assay and a serial bone marrow transplantation (BMT) experiment (Figure 1B). We transplanted lineage⁻c-Kit⁺Sca-1⁺ (LKS) cells or WBM (whole bone marrow) cells from young (12 weeks) and old (22–23 months) mice (CD45.2⁺) with competitor WBM cells (CD45.1⁺) into congenic recipients (CD45.1⁺). Donor-derived cell populations of old WT LKS or WBM cell-transplanted recipients showed little change, but those of old KO LKS or WBM cell-transplanted recipients were markedly decreased (Figure 1C and Figure S1A available online). Also, WBM cells of recipients from young and old KO mice showed a greater reduction in donor-derived cell populations of HSCs and progenitors than those from WT mice (Figures 1D, S1B, and S1C), mostly due to the reduced frequency of HSCs and progenitors in donor WBM or LKS as shown in Figure 1A. Next, we performed a serial BMT experiment. Donor-derived CD45.2⁺ cells were dramatically decreased in the KO-derived recipient cells (Figures 1E and 1F).

The exhaustion of primitive HSCs is believed to result from increased ROS accumulation following serial transplants, which are a critical determinant of HSC pool maintenance (Abbas et al., 2010, Ito et al., 2006). We found dramatically increased ROS levels in old KO BM cells compared with those from WT littermates (Figure 2A). To assess the effects of the intrinsic increase in ROS on the maintenance of KO BM cells, we transplanted WBM cells (CD45.2⁺) into lethally irradiated WT congenic (CD45.1⁺) recipients. After 9 months, we confirmed higher levels of ROS in the KO-derived BM cells (Figure 2B). Our observations suggested that TXNIP plays a critical role in hematopoietic cell antioxidant defense through mechanisms other than its known prooxidant function as an inhibitor of thioredoxin (Trx) (Lee et al., 2005, Patwari et al., 2006, Schulze et al., 2002).

To examine the specificity of antioxidant defense by TXNIP in hematopoietic cells, we analyzed the levels of ROS in WT and KO mouse embryonic fibroblast (MEF) and lung fibroblast cells under oxidative stress. Interestingly, WT MEF and lung fibroblast cells showed the prooxidant function of TXNIP following oxidative stress (Figures S2A–S2D), indicating that TXNIP regulates ROS levels in a cell-type-specific manner. Next, to validate the antioxidant function of TXNIP in hematopoietic cells under oxidative stress, we intraperitoneally (i.p.) injected paraquat (PA), a strong oxidative stress inducer, into young mice. Consistent with our observations of old KO mice, young KO mice showed higher ROS levels and increased cell death in BM cells following PA challenge (Figures 2C and 2D). KO HSCs showed lower ROS levels than nonprimitive cells but also hypersensitivity under oxidative stress. KO HSCs entered into the cell cycle at an early time (0–12 hr) but showed decreased proliferating rates and frequencies at a late time (48–96 hr) following PA challenge (data not shown) (Macip et al., 2003). Taken together, the above data indicate that TXNIP shows cell-type-specific antioxidant function and plays an important role in the maintenance of both HSCs and nonprimitive hematopoietic cells by regulating ROS and cell death following oxidative stress.

Joseph Thomas (Tony) L

Prevent Osteoarthritis (and Diabetes) by Increasing Net Antioxidant Capacity

Aging is a risk factor for osteoarthritis.

Diabetes is a risk factor for osteoarthritis.

Diabetes accelerates aging.

Why?

Net total antioxidant capacity decreases with both aging and diabetes.

Nrf2 increases net total antioxidant capacity.

In this study bolded  text showing DM vs DM- OA varied according to Nrf2 status and therefore net total antioxidant capacity varied!

How?

See preceding posts.

http://www.jbc.org/content/early/2017/07/06/jbc.M117.802157.short

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes-associated osteoarthritis

Carlos Vaamonde-Garcia1,

1. Alice Courties2, 
2. Audrey Pigenet3, 
3. Marie-Charlotte Laiguillon3, 
4. Alain Sautet2, 
5. Xavier Houard3, 
6. Saadia Kerdine-R&oumlmer4, 
7. Rosa Meijide5, 
8. Francis Berenbaum2* and 
9. J&eacuter&eacutemie Sellam2

+ Author Affiliations

1. ↵* Corresponding author; email: francis.berenbaum@sat.aphp.fr

1. Author contributions: CV-G, AC, M-CL, XH, SK-R, RS, FB and JS were responsible for the study design, manuscript preparation, and data interpretation. AS organized and collected the human tissue samples and participated in designing the experiments with human tissue and in data interpretation. CV-G, AC and AP performed the experiments. SK-R was responsible for generating the Nrf-2-/- mice and was involved in data interpretation. All authors reviewed and approved the final manuscript.

Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients, as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM vs. non-T2DM OA cartilage (0.57-fold [Nrf-2] and 0.34-fold [HO-1]), and prostaglandin E₂ (PGE₂) release was increased in samples with low HO-1 expression. HG-exposed, IL-1β-stimulated chondrocytes had lower Nrf-2 levels in vitro, particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin-IX more efficiently attenuated PGE₂ and IL-6 release in HG+IL-1β-treated cells than in NG+IL-1β-treated cells. A greater reduction in HO-1 expression and increase in PGE₂/IL-6 production were observed in HG+IL-1β-stimulated chondrocytes from Nrf-2^-/- mice than in chondrocytes from wild type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients.

Aging and Age Reversal Explained by Combination of Two Theories of Aging

A combo of two theories explain aging.

1.  Oxidative damage.

2.  Impaired proteostasis.

How can "aging" be measured?

1.  Methylation of genes accumulate signifying genes are epigenically turned off.

2. Percentage or accumulation of senescent cells signifying survival without quality control mechanisms such as proteostasis.  A subset of these senescent growth arrested cells become cancer or contribute to neurodegenerative changes.

What proof is known?

1.  Cell, tissue and organ function is inversely related to methylation counts or "biological age."

2.  Cell penetrating protein that kills senescent cells allows stem cells to replace the non functioning cell with a fully functioning and non toxic cell.

Senescent cells arise when pro oxidant forces exceed antioxidant and proteostasis forces.

Proteostasis is impaired by clock gene reduction of spermidine synthesis and reduction of dietary Spermidine supplements.

Antioxidant forces are reduced by methylation of ARE antioxidant response element gene due to pro oxidation forces.

Therefore, accumulation of senescent cells and abnormal protein aggregates in cells indicate inadequate autophagy, proteostasis.

What is the solution to biological AND chronological aging?

Hydrogen rich water, sulforaphane, melatonin and wheat germ/spermidine that activate Nrf2 that stimulates ARE and increases protective antioxidant capacity and restores proteostasis/autophagy.  

Cell, tissue, organ and organism quality control is restored and aging slowed down until agents that promote senescent cells to die via apoptosis can restore a young phenotype is available.

http://www.sciencedirect.com/science/article/pii/S2213231716303512

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset.

Speculation About Hypometylation in Autism and Aging

This article shows two changes from normal in autism.

1.  Reduced antioxidant capacity.  Sulforaphane an Nrf2 agonist increases antioxidant capacity and improved behavior in autistic children.

2.  Hypomethylation of gene promoter sites which also occurs in aging and is associated with methylation of histone gene promoter sites.  I suspect that gene specific methylation of histone production dysregulates normal epigenetic control of acetylation deacetylatoon of genes.  Without adequate histones production, methylated CpG gene promoter sites cannot lay down histone to fully block gene transcription, therefore control of gene expression is haphazard and incomplete.  Melatonin through its HDAC INHIBITIONS and ANTIOXIDANT functions might demethylate the histone gene promoter site and restore histone gene function and thereby return command and control for non impaired epigenetic control of cellular functions.  It should be stated that methylation is a dimmer not a light switch because of redundancy of gene copies to express certain products. HIIE and fasting produced beta hydroxybutyrate is also an HDAC INHIBITOR.

CONJECTURE:. HRW, sulforaphane, spermidine, melatonin and lifestyle changes could ameliorate autism through epigenetic change and return to normal command and control of gene expression.

It also follows that hypomethylation secondary to aging related methylation or acetylation of histone CpG gene promoter site would be more and better regulated! This is the reason that heterochromic parabiosis results in a plasma transfer of a youthful factor to the older mouse and an aging factor to the younger mouse with conjoined circulation.  The aging clock genes express a ratio of protein products that stimulate and inhibit histone expression in the elderly cell that mimics histone gene promoter site methylation in the young "autistic" cell.

The hypomethylation of aging increases exponentially and is counterintuitive to epigenetic aging measures of biological aging based on number of methylated genes in peripheral blood.  I interpret this to mean that epigenetic biological aging is directly proportional to methylated gene CpG promoter sites to mortality predictions with a 96% correlation before histone gene promoter methylation that causes exponential increases in its opposite, hypomethylation. 

In effect autistic children lose control of gene expression through methylation of histone gene promoter site.

Aging adults in final descent toward mortality, show clock gene related histone associated down regulation of histone production.

An old gamete  cell or stem cell escapes by turning back the clock genes or increasing the ratio of histone producing/histone inhibiting gene products as highlighted  by Rando in interpreting parabiosis experiments. This reverses replicative aging only.  DNA damage is wear and tear aging and is the homeostasis of gene repair, cell energetics and proteostasis forces working under the histone ratio drag of replicative aging.

https://link.springer.com/article/10.1007/s10803-011-1260-7

Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism

26 April 2011

Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. We investigated the dynamics of an integrated metabolic pathway essential for cellular antioxidant and methylation capacity in 68 children with autism, 54 age-matched control children and 40 unaffected siblings. The metabolic profile of unaffected siblings differed significantly from case siblings but not from controls. Oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls. These data indicate that the deficit in antioxidant and methylation capacity is specific for autism and may promote cellular damage and altered epigenetic gene expression. Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism.

Strategy to Augment Cancer Treatment and Prevention

New strategy to augment cancer prevention and treatment suggested by research showing that cancer is a metabolic disease and is reduced by restoring optimum mitochondrial metabolism.

This article notes that cancer turns off  the enzyme that ultimately converts glucose into fuel for mitochondria.

By depriving the mitochondria of fuel, ROS is reduced.

ROS radical oxygen species kills cancer cells primed for apoptosis.

Blocking or reducing that enzyme directly or indirectly by fasting/ nutrient deprivation results in increased levels of ROS which drives cancer cell death that can be augmented with cancer treatments.

The Warburg Effect is glucose burning without mitochondrial help.  This allows glucose imaging molecules to show cancer like metabolism on PET scans as highly metabolic cells that light up.

It also suggests that increasing mitochondrial metabolism would increase ROS and cancer cell death.  For example the Ketogenic diet.  

If, however, the ketogenic diet is "running hot" with meaningless noise or H2O2 the UPR unfolding protein response dissipates the ROS  produced.

How to run hot with signaling ROS that drives cancer cell death apoptosis without activating the unfolded protein response UFP meant to protect the mitochondria and ER endoplasmic reticulum from harming the non resilient cell?

Clean up noise, ROS, that are unimportant to signaling. (Hydrogen Rich Water)

Block the UPS with mitochondrial/ER specific antioxidant function. (Wheat germ/Spermidine)(sulforaphane)

Add ketones as fuel to produce " important ROS signaling" that kill cancer cells. (Fasting) (modified fasting diet per Valter Longo) (medium chain triglyceride or coconut oil supplements that are metabolized into ketones by the liver- bulletproof coffee)

https://academic.oup.com/jnci/article-abstract/109/11/djx069/3871191/Breaking-Mitochondrial-Fasting-for-Cancer?redirectedFrom=fulltext

Breaking Mitochondrial Fasting for Cancer Treatment: Old Wine in New Bottles

Many malignant cells exhibit the Warburg effect, first described by Otto Warburg in 1924 (1). Since then, this phenomenon has been well documented and characterized by augmented aerobic glucose uptake, glycolytic shift, decreased utilization of pyruvate by mitochondria, and increased lactate production, all of which are mainly controlled by hypoxia-induced factor 1 alpha (HIF-1α) and Myc overexpression in neoplastic cells (1). HIF-1α and Myc attenuate mitochondrial function by activating pyruvate dehydrogenase kinases (PDKs), which phosphorylate and inactivate the pyruvate dehydrogenase complex (PDC). Hence, inhibiting the PDKs can shuttle more pyruvate into mitochondrial oxidative phosphorylation and away from lactate synthesis, resulting in oxidative stress, triggering apoptosis, and augmentating host immuno-surveillance, ultimately leading to diminished tumor proliferation (2). Additionally, the Warburg effect leads to increased lactate in cellular and extracellular compartments....

Preventing Age and Pathological Thrombosis Using Hydrogen Rich Water

Conjecture:. H2S inhibits pathologic platelet activation, adhesion and clots.

Molecular hydrogen has a similar effect as an antioxidant modifier.

H2S is the endogenous gasotransmitter or hydrogen donor.

H2 is the active moiety.

This is analogous to beta hydroxybutyrate the endogenous HDAC inhibitor and starvation gene set gene promoter and Na Butyrate the active moiety that shares the same function in the cell nucleus.

Would molecular hydrogen like H2S prevent clots without increasing bleeding?  Molecular hydrogen reduces oxidative stress without abrogating redox signaling.  It might be a perfect agent for preoperative and postoperative prophylaxis of DVT or adjunctive therapy in DVT.

http://www.sciencedirect.com/science/article/pii/S0014482717303439

Calcium sensing receptor initiating cystathionine-gamma-lyase/hydrogen sulfide pathway to inhibit platelet activation in hyperhomocysteinemia rat

H₂S is involved in protection of ECs and the mediation of anti-thrombotic in HHcy.

Hyperhomocysteinemia (HHcy, high homocysteine) induces the injury of endothelial cells (ECs). Hydrogen sulfide (H₂S) protects ECs and inhibits the activation of platelets. Calcium-sensing receptor (CaSR) regulates the production of endogenous H₂S. However, whether CaSR inhibits the injury of ECs and the activation of platelets by regulating the endogenous cystathionine-gamma-lyase (CSE, a major enzyme that produces H₂S)/H₂S pathway in hyperhomocysteinemia has not been previously investigated. Here, we tested the ultrastructure alterations of ECs and platelets, the changes in the concentration of serum homocysteine and the parameters of blood of hyperhomocysteinemia rats were measured. The aggregation rate and expression of P-selectin of platelets were assessed. Additionally, the expression levels of CaSR and CSE in the aorta of rats were examined by western blotting. The mitochondrial membrane potential and the production of reactive oxygen species (ROS) were measured; the expression of phospho-calmodulin kinases II (p-CaMK II) and Von Willebrand Factor (vWF) of cultured ECs from rat thoracic aortas were measured. We found that the aggregation rate and the expression of P-selectin of platelets increased, and the expression of CaSR and CSE decreased in HHcy rats. In the ECs of HHcy group, the ROS production increased and the mitochondrial membrane potential decreased markedly, the expression of CSE and the p-CaMK II increased after treatment with CaSR agonist while decreased upon administration of U73122 (PLC-specific inhibitor) and 2-APB (IP₃ Receptor inhibitor). CaSR agonist or NaHS significantly reversed the ECs injured and platelet aggregation caused by hyperhomocysteinemia. Our results demonstrate that CaSR regulates the endogenous CSE/H₂S pathway to inhibit the activation of platelets which concerts the protection of ECs in hyperhomocysteinemia.

Tuning Cellular Power Production with Safety; Direct, Indirect Antioxidants and Proteostasis

Oxidative stress is harmful and increases with age and disease.

Anti oxidant capacity declines with age AND parallels the amount of Nrf2 activation.

In the abstract below showing that antioxidants disappoint in cardiovascular studies they do not acknowledge the importance of ROS as metabolic signaling.  One must increase antioxidant CAPACITY and activity without impacting signaling.

How?

Hydrogen rich water removes noise level oxidants only like a filter in a flow of signal rich electrons.

Secondly, sulforaphane increases antioxidant enzymes for PRN use with activation.

Finally, being able to translate signaling from genes requires proteostasis, making, refolding and removing proteins which is a function of wheat germ spermidine that declines with age in parallel to declining antioxidant CAPACITY.

One can measure direct antioxidant capacity and antioxidant stress in peripheral blood.

But can one measure available potential antioxidant capacity?

This would require a challenge or stress test.

These studies have already been performed in part.

E.g..  The product of order and power or speed parameters of HIIE sprints is increased by hydrogen rich water which preserves safe oxidation independent of baseline VO2 max.  The VO2 is directly proportional to the mass of mitochondria.  It had been shown that HYDROGEN RICH WATER makes each mitochondria more efficient and maintains a higher proton gradient which ultimately translates into POWER.

Homeostasis or balance of oxidative signaling or flux.

http://hyper.ahajournals.org/content/44/3/248.short

Abstract

Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normal conditions the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase–derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies. Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. This article highlights current developments in the field of ROS and hypertension, focusing specifically on the role of oxidative stress in hypertension-associated vascular damage. In addition, recent clinical trials investigating cardiovascular benefits of antioxidants are discussed, and some explanations for the rather disappointing results from these studies are addressed. Finally, important avenues for future research in the field of ROS, oxidative stress, and redox signaling in hypertension are considered.

Nrf2 Reduces Senescent Associated Phenotype; Improves Resilience of Somatic and Stem Cells

Not only does removing senescent cells reduce damage and increase resilience of non-senescent cells, REDUCING the senescent associated phenotype or the expression of destructive enzymes works to improve non- senescent cell function and resilience.

This is one of many studies showing that phytochemicals, in this case Apigenin, REDUCE the SASP phenotype and improve tissue function and resilience.

Sulforaphane shows similar affects.  

Hydrogen rich water shows similar effects. 

Wheat germ/spermidine shows similar effects.  

Melatonin shows similar effects.

All through different entry points but all can be blocked by autophagy blockade.

Which pathway is the driver? 

Nrf2 is the driver.

When autophagy is increased genes such as BDNF and other "starvation gene set" are increased by upregulated transcription, and perhaps by turning these genes back on through the combination of HDAC inhibition and de-methylation of cytosine gene promoter sites.  This reverses oxidative stress and decreased energy related epigenic switched off genes.

The anti-aging anti inflammatory Nrf2 pathway suppresses p38-MAPK, and NF-κB. 

All of the above activate Nrf2 and suppress downstream p38-MAPK, and NF-κB. 

Activate the Nrf2 pathway reduce SASP and increase resilience through appropriate autophagy control and signaling.

One either gains and maintains resilience via autophagy signaling and action OR one loses resilience and drift to senescent somatic and stem cells.  The latter leads to degenerative changes, senescent cells or the consequences of senescence- loss of function or malignant transformation.

https://link.springer.com/article/10.1007/s11357-017-9970-1

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

April 2017

Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells—stressed cells that accumulate with age in mammals—display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelial-mesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

BDNF for All of God's Children, especially ADHD

In this abstract methylphenidate, like opioids, reduced BDNF the memory chemical which was already lower in the evening in ADHD children.

I propose that this decline reduces the effectiveness of stimulant therapy AND combined treatment with stimulant and lifestyle and supplements to increase BDNF would be superior. Lower levels of BDNF were seen in comorbid hyperactivity and conduct disorders. Could these commodities too inattention reduce with elevated BDNF?

It may be that the BDNF gene is epigenically turned down.  If so then melatonin, vitamin D, hydrogen rich water and sulforaphane could reverse the turned off gene and increase BDNF production.

With regard to the paradox of no effect on depression, stimulants in addition to exercise are treatments for depressant.  This treatment may be a cover up like prednisone in rheumatoid joint destruction relieving only symptoms.

https://link.springer.com/article/10.1007/s00213-016-4460-1

BDNF concentrations and daily fluctuations differ among ADHD children and respond differently to methylphenidate with no relationship with depressive symptomatology

January 2017

Abstract

Rationale

Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD).

Objective

We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment.

Method

A total of 148 children, 4–5 years old, were classified into groups as follows: ADHD group (n = 107, DSM-IV-TR criteria) and a control group (CG, n = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0).

Results

Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive–impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms.

Conclusions

Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.

Joseph Thomas (Tony) Liverman, Jr.

A Strategy for Joy, Happiness, Longevity and Primary and Secondary Wealth.

This article merges psychology and medicine writ large to include lifestyle changes.

If money is secondary property that is accumulated by investing primary property the self assets or gifts and TALENTS, the strategic goal should be the accumulation of TALENTS to share or employ for self and others.

BDNF levels are like assets or bank.  Sensitivity to BDNF is like thrift and explains why some individuals can endure and thrive after losing everything, a stressful event that diminishes BDNF asset levels.

BDNF decreases with aging and disease.  It is inversely proportional to addiction, depression and cognitive impairment.  It is directly proportional to joy, happiness, sobriety and longevity.

This strategic frame of why, how and what allows one to augment their counseling and their healthcare toward wholeness with themselves, others and God which implies goodness congruent with the divine design.  This entire blog is directly or indirectly about increasing BDNF and sensitivity to BDNF.

Below is a link to an article:. The Grim Biology of Poverty. I would suggest a subtitle- A Strategy for Joy, Happiness, Longevity and Primary and Secondary Wealth.

http://nautil.us/issue/47/Consciousness/why-poverty-is-like-a-disease

Cell Transfiguration to Ageless Health is an Epigenic Process

Here, an HDAC3 inhibitor (histone deacetylase inhibitor) restores the acetylation of Peroxisome Proliferation–Activated Receptor and Klotho increases and protects kidneys (other tissue and organs!)

Exercise and fasting also performs this function via the action of beta hydroxybutyrate, an HDAC(3) inhibitor.

Aging methylates the Klotho promoter gene.  Hydrogen rich water or endogenous H2S can demethylate the CGG promoter site of Klotho after histone is removed by the HDAC inhibitor.  

The sequential combination action of HDAC and hydrogen turns genes on.  Aging, loss of the solubility ATP provides, may be caused by ATP loss for one of two reasons.  Protection from cell energy failure or cell solubility failure.  (Please note that pioglitazone, a peroxide proliferation gamma agonist promotes fatty acid oxidation, producing beta hydroxybutyrate and restores Klotho gene promoter switch to on.)

Beta hydroxybutyrate, unlike some HDAC inhibitors, also serves as the starvation gene set promoter which increases mitochondrial biogenesis and ATP is directly proportional to mitochondria volume. Thus cell energy and solubility increase and the cell appears to be younger.

Summary: beta hydroxybutyrate AND hydrogen turns genes back on that promote health and youthful epigenic restoration.  

Aging, inflamaging turns genes off.

Restoring gene switches to on optimally occurs when antioxidant capacity is also optimum and proteostasis is optimum.  

Therefore, sulforaphane (antioxidant capacity) and wheat germ (proteostasis) completes the transfiguration into youthful dynamic cells and in numerous species and human cells increases healthspan and lifespan by 30%!

Beta hydroxybutyrate is downstream of Peroxisome Proliferation–Activated Receptor γ and had a direct effect that is also provided by sodium butyrate which is 3% of butter.  The French version of the Mediterranean diet before Paula Dean is full of this HDAC inhibitor!

http://www.sciencedirect.com/science/article/pii/S0085253817301588

Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho (1) expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation–Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A–induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the reduction of CKD progression.