What to eat during the 8-hour feeding window , whole-8-hour

We aspire to have adequate sleep at night so that we can be productive during the day. We need the energy and motivation to stay in our healthy weight. We don’t want to deprive our bodies with our favorite dish but wanted to do some cleansing to get rid of toxins we have accumulated over the years (too much alcohol, junk foods, stress, others).

If we plan to fast or not eat heavy meal during the 16 hour period and graze or eat a good healthy meal during the 8-hour period (9am to 5pm or 10am to 6pm, 8am to 4pm), what can we do to follow this regimen to have the health we deserve without dieting but feeling our satiety and conscious of each food we chew?

1. Whole foods
We can pair plants and healthy protein, drink your favorite (1) cup of coffee or tea during the day, and      explore more whole foods to pair with our favorite dishes.
2. Protein in the morn 9-5 ; 1 or 2 boiled eggs , boiled ginger with lemon and our favorite herbs or tea.
3. Apple at night, small protein (half a tsp of peanut butter). Choose bananas or fruits that are not over rip. Create an avocado dip for your carrots or celery stick.
4. Fibers during the day
Fiber helps encapsulate the fat and sugar out of our bodies.
5. Drink 30 minutes before full lunch and 30 minutes after lunch.
6. Take time to chew your food, to meditate, to give thanks. Your positive spirit will guide you in nourishing your body.
7. Rest and deep breathing in between (5 minutes, will help you arrive at good decisions and fill up your minds with happy thoughts)
8. Love foods, healthy ones and observe the benefits derived from your food choices.
Say No to unhealthy foods. Happy foods are eggs, yams and fruits.
9. Celebrate each day by noticing your good bowel movement, sleep patterns, and weighing yourself as one way of monitoring your health
Keywords in clubalthea.com site: anti-parasitic, diet, inflammation, cancer, foods, parasites, whole foods

Check your bile acid production and stress level for fat metabolism

Bile acids are synthesized from cholesterol

Bile begins its life in the liver and spends a significant amount of time somewhere between the liver, gallbladder, and gastrointestinal tract, specifically the intestines. Liver cells manufacture bile before it undergoes modification in the bile duct epithelium, and then it is transported to the gallbladder for storage and, ultimately, use. Bile acids are synthesized from cholesterol with the aid of several different enzymes.

Soup of Sulfur rich bile acids will help balance bile production:

Mix these root crops to pinch of organic chicken broth powder: rutabaga, kale, carrot, parsnip, onion, garlic and a tsp of apple cider vinegar or lemon juice added in the last boiling.

bile

Short-chain fatty acids :  The gut microbiota can ferment complex dietary residues that are resistant to digestion by enteric enzymes.

This process provides energy for the microbiota but culminates in the release of short-chain fatty acids including butyrate, which are utilized for the metabolic needs of the colon and the body.

Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties:

  • It is the preferred energy source for colonocytes,
  • It maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation.

Note:  Protein residues and fat-stimulated bile acids are also metabolized by the microbiota to inflammatory and/or carcinogenic metabolites, which increase the risk of neoplastic progression.

The makeup of bile is largely water, at about 95%. The remaining five percent is made up of bile acids, bilirubin, amino acids, enzymes, steroid hormones including estrogen, glutathione, cholesterol, vitamins (especially vitamin D and some of the B vitamins), porphyrins, insulin, and other items, including toxins such as heavy metals, xenobiotics, medications and drugs, and environmental toxins targeted for excretion. There are also electrolytes, including sodium, potassium, chloride, calcium, magnesium, phosphate, sulfate, and bicarbonate. As you excrete more bile acid, bile flow is stimulated. There is also a circadian rhythm to the synthesis and circulation of bile acids.

In total, there are more than 50 species of bile acids in humans, but the main ones include cholic acid and chenodeoxycholic acid (CDCA). Although bile salts and bile acids are frequently used interchangeably, technically bile acids become bile salts upon conjugation with glycine or taurine. The gut bacteria metabolize bile acids to create secondary bile acids, of which there are more than 400 species. After the gut bacteria metabolize them, cholic acid becomes deoxycholic acid and CDCA becomes lithocholic acid. The amount of bile acids making their way into the colon affects the microbiome makeup. Bile acids are reabsorbed in the small intestine and colon to then come back into circulation as part of the enterohepatic circulation, which is a bidirectional pathway.

Bile acids, a key component of bile, are the main emulsifiers of fat. As such, bile ultimately finds its way into the small intestine for this function. When fat enters your small intestine, you secrete CCK (cholecystokinin), which signals your gallbladder to send bile into the small intestine to aid in digestion and absorption.

Functions of bile acid

Although this may be the function of bile most commonly known, there are actually many, many more. Some of the key functions of bile include:

  • Aids the immune system through excreting certain immune system signals, such as IgA and inflammatory cytokines
  • Elimination of certain hormones and pheromones
  • Endogenous ligand (binder to stimulate a signal) for several receptors, including nuclear receptor farnesoid X receptor (FXR), vitamin D receptor, and G protein-coupled receptor TGR5
  • Excretion of fat-soluble toxins and other waste, including endogenous substrates
  • Modulation of metabolic pathways, including lipid metabolism, glucose metabolism, and insulin sensitivity
  • Regulation of tight junction permeability
  • Removal of cholesterol
  • Signaling molecule and hormone

With so many different functions, it should come as no surprise that problems in the flow, metabolism, or synthesis of bile and/or bile acids could contribute to a variety of diseases.

Diseases such as colon and liver cancer

Problems with bile may stem from dysfunction in the synthesis of bile, an impairment in the secretion, or problems with the flow of bile. The metabolism of bile may become disturbed through problems stemming from the synthesis or conjugation with cholesterol, problems with the membrane transport, issues with the transport between the organs, or problems with the bacterial degradation of bile during the enterohepatic cycling. There may also be malabsorption of the bile acid, leading to higher concentrations in the colon, which may then negatively impact the function of the mucosal cells in the colon. Furthermore, when the concentration of bile acids is too high, it can be toxic and cause problems. Alterations to bile acids are also associated with disease.

The level of bile acids that reach the colon may contribute to functional bowel diseases. Elevated concentrations may contribute to diarrhea, while lower levels may play a role in constipation. In one study on children with functional constipation, the fecal bile acid profile was normal, but there were some who had the 3-sulfate version of CDCA as the dominant fecal bile acid, which could demonstrate a link for some cases.

Stress and Bile acids

Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress.

Vinegar helps increase bile production

Polyphenols such as chlorogenic acid which is present in high levels in apple cider vinegar could inhibit oxidation of LDLs and improve health by preventing cardiovascular diseases (Laranjinha and others 1994).

Avoid toxins that inflame the brain causing Alzheimer

. 2012 Jan; 9(1): 35–66.
Published online 2012 Jan. doi: 10.2174/156720512799015037
PMCID: PMC3349985
PMID: 22329651

Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimer’s Disease

Abstract

Alzheimer’s disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

Keywords: Alzheimer’s disease, dementia, neurofibrillary tangles, neurodegeneration cascade.

ALZHEIMER’S DISEASE AND BRAIN GLUCOSE METABOLISM

Alzheimer’s disease [AD] is the most common cause of dementia in North America, and over the past several decades, the prevalence rates of sporadic AD have become epidemic []. Although the clinical diagnosis of AD is based on criteria set by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS/ ADRDA) and DSM-IV criteria [], embracement of additional tools such as neuroimaging and standardized biomarker panels could facilitate early detection of disease []. Characteristic neuropathological hallmarks of AD include: neuronal loss, abundant accumulations of abnormal, hyperphosphorylated cytoskeletal proteins in neuronal perikarya and dystrophic fibers, and increased expression and abnormal processing of amyloid-beta precursor protein (AβPP), leading to AβPP-Aβ peptide deposition in neurons, plaques, and vessels. For nearly three decades, the dominant trends have been to interpret selected AD-associated abnormalities, namely the hyper-phosphorylation of tau and deposition of AβPP-Aβ as causal rather than consequential to the neurodegeneration cascade. This approach posed significant limitations on the scope of investigation and the goals with respect to designing new treatments; ergo, success has been either modest or disappointing. On the other hand, due to collected contributions of a number of researchers, the field has recently become more receptive to alternative concepts, opening the doors to exciting new avenues of investigation and therapeutic strategies.

Growing evidence supports the concept that AD fundamentally represents a metabolic disease in which brain glucose utilization and energy production are impaired []. Metabolic abnormalities have been linked to brain insulin and insulin-like growth factor (IGF) resistance with disruption of signaling pathways that regulate neuronal survival, energy production, gene expression, and plasticity []. On a cellular basis, inhibition of insulin/IGF signaling contributes to AD-type neurodegeneration by increasing: 1) the activity of kinases that aberrantly phosphorylate tau; 2) expression of AβPP and accumulation of AβPP-Aβ; 3) levels of oxidative and endoplasmic reticulum (ER) stress; 4) the generation of reactive oxygen and reactive nitrogen species that damage proteins, RNA, DNA, and lipids; 5) mitochondrial dysfunction; and 6) activation of pro-inflammatory and pro-death cascades. On a functional basis, insulin/IGF resistance causes down-regulation of target genes that are needed for cholinergic homeostasis, and it compromises systems that mediate neuronal plasticity, memory, and cognition.

The gold standard for definitively diagnosing AD is to perform a postmortem examination of the brain, with the objective of demonstrating beyond-normal aging associated densities of neurofibrillary tangles, neuritic plaques, and AβPP-Aβ deposits in corticolimbic structures, bearing in mind that neurodegeneration frequently involves multiple other cortical regions as well. The common thread among these characteristic lesions is that they harbor insoluble aggregates of abnormally phosphorylated and ubiquitinated tau, and neurotoxic AβPP-Aβ in the form of oligomers, fibrillar aggregates, or extracellular plaques. Secreted AβPP-Aβ oligomers have been demonstrated to be neurotoxic and to inhibit hippocampal long-term potentiation, i.e. synaptic plasticity [].

Ultimately, to improve our capacity for diagnosis and treatment, we should be able to connect the development and progression of neuropathological lesions with the molecular, biochemical, physiological, neuro-imaging, and clinical abnormalities that correlate with AD. Therefore, gaining a better understanding of the pathophysiology of these lesions could improve our current diagnostic and treatment approaches to AD. One way to begin the process in earnest is to acknowledge that the rigid employment of standardized criteria for diagnosing AD, in fact, restricts our ability to fully comprehend the underlying disease process. For example, in addition to the characteristic lesions noted above, AD is associated with loss of neurons, fibers, and synapses, disruption of the cortical-laminar architecture, gliosis, proliferation of dystrophic neurites, and neuro-inflammatory responses, including microglial cell activation. For unclear reasons, these abnormalities are not systematically quantified, and consequently, they are not routinely incorporated into the AD diagnostic equation. At the same time, many basic cellular, molecular, biochemical, and structural abnormalities in AD overlap with those in other neurodegenerative diseases such as dementia with Lewy bodies, fronto-temporal dementias, and multiple systems atrophy, indicating that one or two biomarkers might not be sufficient to consistently and accurately diagnose AD.

Hints that AD could represent a metabolic disease emerged from studies showing that the early stages of AD were marked by deficits cerebral glucose utilization [], and that as the disease progressed, metabolic and physiological abnormalities worsened [,]. Subsequently, AD was shown to be associated with brain insulin resistance and insulin deficiency, with significant abnormalities in the expression of genes and activation of kinases that are regulated by insulin and insulin-like growth factor (IGF) signaling []. Moreover, it was shown that in AD, progressive declines in cerebral glucose utilization, and deficits in insulin signaling and insulin-responsive gene expression worsen with severity of disease. In particular, insulin/IGF regulated genes, including choline acetyltransferase, tau, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which mediate cholinergic/cognitive, neuronal cytoskeletal, and metabolic functions, are suppressed in AD []. Insulin resistance mediated impairments in energy metabolism lead to oxidative stress, generation of reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction, all of which drive pro-apoptosis, pro-inflammatory, and pro-AβPP-Aβ cascades. Experimental animals in which brain insulin receptor expression and function were suppressed exhibited cognitive impairment and neurodegeneration with features that overlap with AD [].

In AD brains, deficits in insulin/IGF signaling are due to the combined effects of insulin/IGF resistance and deficiency. Insulin/IGF resistance is manifested by reduced levels of insulin/IGF receptor binding and decreased responsiveness to insulin/IGF stimulation, while the trophic factor deficiency is associated with reduced levels of insulin polypeptide and gene expression in brain and cerebrospinal fluid [,]. In essence, AD can be regarded as a form of brain diabetes that has elements of both insulin resistance and insulin deficiency. To consolidate this concept, we proposed that AD be referred to as, “Type 3 diabetes” [,].

INSULIN AND INSULIN-LIKE GROWTH FACTOR ACTIONS IN THE BRAIN

In the central nervous system (CNS), insulin and IGF signaling play critical roles in regulating and maintaining cognitive function. Insulin, IGF-1 and IGF-2 polypeptide and receptor genes are expressed in neurons [] and glial cells [] throughout the brain, and their highest levels of expression are in structures typically targeted by neurodegenerative diseases [,]. Insulin and IGFs regulate a broad range of neuronal functions throughout life, from embryonic and fetal development to adulthood. The corresponding signaling pathways are activated by insulin and IGF binding to their own receptors, resulting in phosphorylation and activation of intrinsic receptor tyrosine kinases. Subsequent interactions between the phosphorylated receptors and insulin receptor substrate (IRS) molecules promote transmission of downstream signals that inhibit apoptosis, and stimulate growth, survival, metabolism, and plasticity. Anti-apoptotic mechanisms inhibited by insulin/IGF stimulation include BAD (inhibitor of Bcl-2), Forkhead Box O (FoxO), glycogen synthase kinase 3β (GSK-3β), and nuclear factor kappa B (NF-κB). GSK-3β regulates Wnt signaling by phosphorylating β-catenin and thereby targeting it for ubiquitin/proteosome-mediated degradation. Wnt signaling mediates synaptic plasticity in the CNS. Therefore, major functions supported by the insulin/IGF signaling axis include, neuronal growth, survival, differentiation, migration, energy metabolism, gene expression, protein synthesis, cytoskeletal assembly, synapse formation, neurotransmitter function, and plasticity [,]. Correspondingly, impaired signaling through insulin and IGF receptors has dire consequences with respect to the structural and functional integrity of the CNS.

IMPAIRED INSULIN/IGF SIGNALING AND TAU PATHOLOGY IN AD

The major neuronal cytoskeletal lesions that correlate with severity of dementia in AD, including neurofibrillary tangles and dystrophic neurites, contain aggregated and ubiquitinated insoluble fibrillar tau. In other words, tau accumulation and pathology are the most significant structural correlates of dementia in AD [,]. In AD, tau, a microtubule-associated protein, gets hyperphosphorylated due to inappropriate activation of several proline-directed kinases, including GSK-3β. As a result, tau protein misfolds and self-aggregates into insoluble fibrillar structures [paired helical filaments and straight filaments] that form neurofibrillary tangles, dystrophic neurites, and neuropil threads []. Intra-neuronal accumulations of fibrillar tau disrupt neuronal cytoskeletal networks and axonal transport, leading to synaptic disconnection and progressive neurodegeneration []. Besides fibrillar tau, pre-fibrillar tau can aggregate, forming soluble tau oligomers or insoluble granular tau, which contribute to neurodegeneration by causing synaptic disconnection and neuronal death []. The eventual ubiquitination of hyper-phosphorylated tau [], combined with dysfunction of the ubiquitin-proteasome system [], cause further accumulation of insoluble fibrillar tau, oxidative stress, and ROS generation, which together promote neuronal apoptosis, mitochondrial dysfunction, and necrosis in AD [].

Growing evidence suggests that many of the aforementioned cellular aspects of AD neurodegeneration may be caused by brain insulin/IGF resistance [,] which, as in other brain insulin-resistance states, results in inhibition of downstream pro-growth and pro-survival signaling pathways (Fig. 11) []. Tau gene expression and phosphorylation are regulated by insulin and IGF stimulation [,]. In AD, brain insulin and IGF resistance result in decreased signaling through phosphoinositol-3-kinase (PI3K), Akt [,], and Wnt/β-catenin [], and increased activation of glycogen synthase kinase 3β (GSK-3β) []. GSK-3β over-activation is partly responsible for the hyper-phosphorylation of tau, which leads to tau misfolding and fibril aggregation []. In addition, tau hyper-phosphorylation in AD is mediated by increased activation of cyclin-dependent kinase 5 (cdk-5) and c-Abl kinases [,], and inhibition of protein phosphatases 1 and 2A [,,]. Besides hyper-phosphorylation, tau pathology in AD is mediated by impaired tau gene expression due to reduced insulin and IGF signaling []. Consequences include, failure to generate sufficient quantities of normal soluble tau protein, vis-a-vis accumulation of hyper-phosphorylated insoluble fibillar tau, and attendant exacerbation of cytoskeletal collapse, neurite retraction, and synaptic disconnection.

An external file that holds a picture, illustration, etc.
Object name is CAR-9-35_F1.jpg

Roles of brain insulin deficiency and brain insulin resistance in Tau pathology. Tau protein is normally regulated by insulin and IGF signalling. Insulin deficiency [effective trophic factor withdrawal] and insulin resistance lead to the over-activation of kinases and inhibition of phosphatases, which result in hyper-phosphorylation of tau. Attendant increased oxidative stress leads to ROS generation and ubiquitination, followed by misfolding of Tau. Misfolded tau aggregates and forms insoluble twisted fibrils that are neurotoxic and mediate dementia-associated neuropathological processes, i.e. neurofibrillary tangle formation, proliferation of dystrophic neuritis and neuropil threads, and synaptic disconnection.

INSULIN/IGF RESISTANCE AND AMYLOID-BETA (AΒ) NEUROTOXICITY

AD is associated with dysregulated expression and processing of amyloid precursor protein (AβPP), resulting in the accumulation of AβPP-Aβ (Aβ) oligomeric fibrils or insoluble larger aggregated fibrils (plaques) that are neurotoxic (Fig. 22). Pathophysiologically, increased AβPP gene expression, together with altered proteolysis, result in accumulation of 40 or 42 amino acid length Aβ peptides that can aggregate. In familial forms of AD, mutations in the AβPP, presenilin 1 (PS1), and PS2 genes, or inheritance of the Apoliprotein E ε4 (ApoE- ε4) allele, are responsible for increased synthesis and deposition of Aβ peptides in the brain. However, in sporadic AD, which accounts for 90% or more of the cases, the causes of Aβ accumulation and toxicity are still under intense investigation. Over the past few years, interest in the role of impaired insulin/IGF signaling as either the cause or consequence of dysregulated AβPP-Aβ expression and protein processing has grown.

An external file that holds a picture, illustration, etc.
Object name is CAR-9-35_F2.jpg

Brain insulin resistance and AβPP-Aβ deposition and toxicity. Brain insulin resistance caused by peripheral insulin resistance diseases or primary toxic and neurodegenerative processes in the brain promote neuroinflammation and increased expression of AβPP. Throught the action of Beta and Gamma secretases, AbPP is cleaved to generate excessive 40-42 kD AβPP-Aβ peptides that aggregate and form insoluble fibrils and plaques, or oligomers and AβPP-Aβ-derived diffusible ligands (ADDLs), which are neurotoxic. AβPP-Aβ oligomers and ADDLs promote oxidative stress and increased activation of kinases that lead to Tau hyperphosphorylation, and its eventual ubiquitination, misfolding, and aggregation. AβPP-Aβ oligomers and ADDLs may also block insulin receptor function and contribute to insulin resistance. Carriers of the ApoE e4 allele or Presenilin mutations are predisposed to excessive and abnormal AβPP cleavage, and AβPP-Aβ accumulation, aggregation, and fibril formation, correlating with increased rates and familial occurrences of AD.

The concept that Aβ toxicity causes insulin resistance, and the opposing argument that brain insulin resistance with attendant oxidative stress and neuro-inflammation promotes Aβ accumulation and toxicity are both supported by experimental data. For example, studies have established that insulin stimulation accelerates trafficking of Aβ from the trans-Golgi network, where it is generated, to the plasma membrane, and that insulin stimulates Aβ extracellular secretion [] and inhibits its intracellular accumulation and degradation by insulin-degrading enzyme [,]. Although it remains uncertain as to whether these physiological actions of insulin on AβPP processing contribute to Aβ burden, what is apparent is that impaired insulin signaling can disrupt both the processing of AβPP and clearance of Aβ []. The accumulation of Aβ exacerbates the problem because Aβ disrupts insulin signaling by competing with insulin, or reducing the affinity of insulin binding to its own receptor [,]. In addition, AβPP oligomers inhibit neuronal transmission of insulin-stimulated signals by desensitizing and reducing the surface expression of insulin receptors. Furthermore, intracellular AβPP-Aβ directly interferes with PI3 kinase activation of Akt, which leads to impaired survival signaling, increased activation of GSK-3β, and hyper-phosphorylation of tau. Hyper-phosphorylated tau is prone to misfold, aggregate, and become ubiquitinated, leading to the formation of dementia-associated paired-helical filament-containing neuronal cytoskeletal lesions. Since IGF-1 or IGF-2 suppression of GSK-3β activity [] reduces the neurotoxic effects of AβPP [], the neuro-protective properties of these and related trophic factors could be exploited for therapeutic purposes in AD.

INSULIN/IGF RESISTANCE, OXIDATIVE STRESS, AND METABOLIC DYSFUNCTION IN AD

Insulin and IGF signaling pathways regulate glucose utilization, metabolism, and ATP synthesis needed for cellular homeostasis and dynamic modulation of a broad range of functions (Tables 1,1,22). Deficits in cerebral glucose utilization and energy metabolism occur very early in the course of AD, such that they are detectable either prior to, or coincident with the initial stages of cognitive dysfunction [,,]. These findings lend strong support the concept that impairments in insulin signaling have important roles in the pathogenesis of AD []. Glucose uptake and utilization in brain are dependent upon glucose transport. Glucose transporter 4 (GLUT4) is abundantly expressed along with insulin receptors, in medial temporal lobe structures, which notably are major targets of AD neurodegeneration. Insulin stimulates GLUT4 gene expression and protein trafficking from the cytosol to the plasma membrane to modulate glucose uptake and utilization. Therefore, insulin stimulation of GLUT4 is critical to the regulation of neuronal metabolism and the generation of energy needed for memory and cognition. Although postmortem brain studies have not detected significant reductions in GLUT4 expression in AD [], the well-documented deficits in brain glucose utilization and energy metabolism vis-a-vis brain insulin/IGF resistance could instead be mediated by impairments in GLUT4 trafficking between the cytosol and plasma membrane.

Table 1.

Metabolic Hypothesis of Alzheimer’s Disease-Consequences of Brain Insulin Resistance

Impairment Adverse Effect Role in Alzheimer’s Disease
GLUT4 function Reduced glucose uptake and utilization Energy deficits; compromised homeostatic functions, disruption of neuronal cytoskeleton, synaptic disconnection
Insulin receptor function Decreased signaling through IRS, PI3K-Akt Reduced neuronal and oligodendroglial survival, neuronal plasticity, myelin maintenance
Increased activation of GSK-3β and phosphatases that negatively regulate insulin signaling Increased tau phosphorylation, oxidative stress, neuro-inflammation, pro-apoptosis signaling
Decreased Wnt signaling
Reduced insulin-responsive gene expression Reduced choline acetyltransferase expression –> deficits in acetylcholine
Decreased GAPDH expression, further impairment of glucose metabolism
Insulin receptor function or hyper-insulinemia Endothelial cell injury, intimal thickening, and vessel wall fibrosis Microvascular disease and cerebral hypoperfusion
Mitochondrial function Increased oxidative stress, ROS, RNS DNA damage, lipid peroxidation, energy deficits, cell death, increased AβPP expression, Aβ42 deposition and fibrillarization
Myelin maintenance Myelin breakdown, increased generation of ceramides and other toxic sphingolipids; lipid peroxidation; ROS Increased neuro-inflammation, oxidative stress, pro-apoptosis signaling, further insulin resistance
White matter atrophy due to fiber and myelin loss
Insulin/IGF availability Trophic factor withdrawal Death or impaired function of insulin/IGF dependent neurons and glial cells
Hyperglycemia Accumulation of advanced glycation end-products Disrupts removal of Aβ42

Abbreviations: GLUT4=glucose transporter 4; IRS= insulin receptor substrate; PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; GAPDH=glyceraldehyde-3-phosphate dehydrogenase; ROS=reactive oxygen species; RNS=reactive nitrogen species; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product; IGF=insulin-like growth factor.

Table 2.

Neuropathologic Processes Contributing to Brain Insulin Resistance in Alzheimer’s Disease

Neurodegenerative Disease Process Mechanism of impairing brain insulin signaling Consequences in relation to brain insulin signaling
Aβ42 toxicity Competes with insulin and reduces affinity of insulin binding to its receptor
AβPP oligomers desensitize and reduce surface expression of insulin receptors
Interferes with PI3K activation of Akt
Disrupts insulin signaling
Impairs insulin stimulated neuronal survival and plasticity
Increases GSK-3β activation and tau hyperphosphorylation
Microvascular disease Cerebral hypoperfusion, hypoxic-ischemic injury Exacerbates insulin resistance;
Oxidative stress DNA damage, lipid peroxidation, fibrillarization of oligomeric tau and Aβ42 Increases neuro-inflammation and pro-inflammatory cytokine inhibition of insulin signaling
Toxic lipids impair signaling through PI3K-Akt
Transition metal ion accumulations Mitochondrial dysfunction, oxidative stress, tau and AβPP oligomer fibrillarization Impairs glucose uptake and utilization, inhibits insulin signaling
Hyperphosphorylated-ubiquitinated tau Increases oxidative stress, promotes neuro-inflammation Enhances insulin resistance

Abbreviations: PI3K= phosphoinositol-3- kinase; GSK-3β = glycogen synthase kinase 3β; AβPP= amyloid-β – precursor protein; Aβ 42=amyloid beta peptide-42 amino acids 1-42 cleavage product

Deficiencies in energy metabolism tipped by inhibition of insulin/IGF signaling increase oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokine activation [,,]. Oxidative stress leads to increased generation and accumulation of reactive oxygen (ROS) and reactive nitrogen species (RNS) that attack subcellular components and organelles. The resulting chemical modifications, including adducts formed with DNA, RNA, lipids, and proteins, compromise the structural and functional integrity of neurons. Consequences include, loss of cell membrane functions, disruption of the neuronal cytoskeleton with dystrophy and synaptic disconnection, deficits in neurotransmitter function and neuronal plasticity, and perturbation of signal transduction and enzymatic pathways required for energy metabolism, homeostasis, and neuronal survival.

Mitochondrial dysfunction exacerbates electron transport chain function, reducing ATP generation and increasing ROS production. Pro-inflammatory cytokine activation is mediated by neuro-inflammatory responses in microglia and astrocytes. Neuro-inflammation increases oxidative stress, organelle dysfunction, and pro-apoptosis signaling. Moreover, stresses caused by inhibition of insulin/IGF signaling stimulate AβPP gene expression [] and aberrant AβPP cleavage, with attendant increased AβPP-Aβ deposition and toxic fibril formation in the brain [,]. Persistence of oxidative stress leads to constitutive activation of kinases e.g. GSK-3β, that promote aberrant hyper-phosphorylation of tau. Therefore, in AD, oxidative stress and impairments in energy metabolism stemming from brain insulin/IGF resistance quite likely contribute to neuronal loss, AβPP toxicity, tau cytoskeletal pathology, and neuro-inflammation [,,]. The degree to which these abnormalities can be effectively targeted for therapy in AD is actively under investigation.

MECHANISMS OF BRAIN INSULIN/IGF RESISTANCE IN NEURODEGENERATION [FIG. [FIG.33]

An external file that holds a picture, illustration, etc.
Object name is CAR-9-35_F3.jpg

High caloric intake and/or chronic low-level nitrosamine exposures [through diet, smoking, agriculture], promote fatty liver disease (steatohepatitis) that progresses due to injury and inflammation, eventually leading to hepatic insulin resistance. The same poor physiological states also promote obesity, diabetes mellitus, and other peripheral insulin resistance diseases. Toxic lipids, including ceramides, made in the liver, get released into the circulation, cross the blood-brain barrier, and cause brain insulin resistance, inflammation, energy failure, toxicity, and local production of toxic ceramides. The end result is progressive neurodegeneration, including Alzheimer’s disease.

Although aging is clearly the dominant risk factor for AD, growing evidence suggests that peripheral insulin resistance with obesity, T2DM, metabolic syndrome (dyslipidemic states), and non-alcoholic steatohepatitis (NASH) mediate brain insulin/IGF resistance, and thereby contribute to the pathogenesis of mild cognitive impairment (MCI), dementia, and AD [,,,,,,]. However, only within the past several years has this field greatly expanded due to input from both human and experimental animal studies that produced new information about the causes and consequences of brain insulin resistance and deficiency in relation to cognitive impairment [,,,,]. Concerns over the role of peripheral insulin resistance as a mediator of cognitive impairment and sporadic AD have been ratcheted up by globalization of the obesity epidemic [,]. In order to develop logical and novel approaches for treating and preventing neurodegeneration based on the brain insulin resistance hypothesis, three main questions must be addressed: 1) Do T2DM and other peripheral insulin resistance states cause neurodegeneration, including AD? 2) Do T2DM and other peripheral insulin resistance disease states principally serve as co-factors in the pathogenesis of cognitive impairment and neurodegeneration? or 3) Do T2DM and AD fundamentally represent the same disease processes occurring in different target organs and tissues? These questions are addressed below.

Contributions of Obesity and T2DM to Cognitive Impairment and Neurodegeneration

Epidemiologic studies demonstrated that individuals with glucose intolerance, deficits in insulin secretion, or T2DM have a significantly increased risk for developing mild cognitive impairment (MCI) or AD-type dementia. Longitudinal studies provided further evidence that T2DM [,] and obesity/dyslipidemic disorders [] were correlated with later development of MCI, dementia, or AD [,]. However, one study showed that obesity itself, with or without superimposed T2DM, increased the risk for MCI, AD, or other forms of neurodegeneration [], suggesting that systemic factors related to obesity, other than T2DM, can promote neurodegeneration. On the other hand, although a relatively high percentage of individuals with MCI or dementia have T2DM, peripheral insulin resistance, or obesity, the vast majority of patients with AD do not have these diseases. To gain a better understanding of the contributions of T2DM and obesity to neurodegeneration, attention must be given to postmortem human and experimental animal studies.

In general, the arguments made in favor of the concept that T2DM or obesity causes AD are not founded; however, the concept that peripheral insulin resistance disease states contribute to cognitive impairment and AD pathogenesis or progression does have a sound basis. Against a causal role are the findings that, postmortem human brain studies demonstrated no significant increase in AD diagnosis among diabetics [], and similarly abundant densities of senile plaques and rates of neurofibrillary tangle pathology were observed in subjects with T2DM compared with normal aged controls, although peripheral insulin resistance was more common in AD than with normal aging []. Since neurofibrillary tangles and dystrophic neurites are hallmarks of AD and correlate with severity of dementia, the abovementioned findings in human postmortem studies indicate that T2DM alone is not sufficient to cause AD. On the other hand, in experimental mouse and rat models, chronic high fat diet (HFD) feeding and diet induced obesity (DIO) with associated T2DM, do cause cognitive impairment with deficits in spatial learning and memory [,]. Moreover, experimental obesity with T2DM causes mild brain atrophy with brain insulin resistance, neuro-inflammation, oxidative stress, and deficits in cholinergic function [,]. An important qualifier about these studies is that the associated brain abnormalities were typically modest in severity, and they were devoid of the most important structural lesions that characterize AD, i.e. neurofibrillary tangles. Therefore, observations both in humans and experimental models suggest that while obesity or T2DM can be associated with cognitive impairment, mild brain atrophy, and a number of AD-type biochemical and molecular abnormalities in brain, including insulin resistance and oxidative stress, they do not cause significant AD pathology. Instead, the findings suggest that T2DM, obesity, and probably other peripheral/systemic insulin resistance states serve as co-factors contributing to the pathogenesis or progression of neurodegeneration. The significance of these results is that therapeutic strategies designed to treat T2DM, obesity, and systemic insulin resistance could help slow the progress or reduce the severity of AD, but they will not likely prevent it altogether. Correspondingly, a number of studies have already demonstrated that treatment with hypoglycemic or insulin sensitizer agents can be protective in reducing the incidence and severity of AD brain pathology [].

How to heal a weak liver

Years of hard work and introduction of other environmental toxins from medications, parasites, bacteria , alcohol , lack of sleep and stress strain our liver and can cause an irreversible damage. Although, our liver can still function even when only 10% of the liver cells are healthy, our heart will be severely affected.

Many whole foods can help heal the liver from bitter greens and sour fruits. Reducing stress, sunshine, adequate sleep and clean water and air will be major factors in living longer.

As a health blogger and a senior home care professional, I am most affected when one of my family members has weak liver cells due to aging and over worked body.

Life Extension has the 4th edition book that helped me weave thru the many alternative ways to heal the liver using supplements and whole foods. The biggest holistic healing way that can impact the health of the liver are loving care from family and friends.

Caregivers play an important role in preparing healthy foods and giving massage. I told her to expose her body in the early morning sun and continue on boiling fresh turmeric and ginger and she is feeling well each day. It takes a little longer for the aging body to heal.

In the bay area, we help seniors live in the comfort of their homes providing home aid assistance and nursing care, in non medical way and more on holistic, ensuring healthy living using healthy soups and massage.

card mother

Health and wellness by Dr Corey Kirshner

Finding the Cause of Your Peripheral Neuropathy

September 28, 2016 / Conditions / By Corey Kirshner
Trying to explain what peripheral neuropathy is, and how finding the cause of your peripheral neuropathy is essential to your successful treatment, may seem daunting in the space of a blog post. At times it can be a very easy condition to address and fix, but more frequently it is very complex.

Peripheral neuropathy means the nerves outside of your spinal cord are damaged. Although often related to diseases like diabetes, the nerve damage ultimately comes from one of five things.

Five common causes of Peripheral Neuropathy:

1. Nerves are not getting enough nutrients (fuel) to stay healthy.

2. Nerves are not being activated, or used enough to stay healthy.

3. Nerves are being deprived of oxygen.

4. Nerves are being compressed, and from the point of compression on down, they are dying because of a lack of fuel, oxygen or activation.

5. Or, you are suffering from a combination of all of the above.

Depending upon the cause of your peripheral neuropathy, and which nerves are affected, you will eventually have symptoms like pain, tingling and numbness predominately in your feet, but it may spread to your hands as well. As nerves continue to die these symptoms will worsen and start to affect other tissue. The most commonly affected is the cerebellum, the part of your brain that controls eye movement, balance, and coordination of movement, so it is not coincidental that along with your peripheral neuropathy you may also have trouble balancing.

Try this test: stand in a relaxed manner, putting more weight on your left foot, then try to place your right foot on the floor directly in front of the left, touching the right heal to the left toe. Were you able to keep your balance? Now switch sides and try again? You should not wobble.

Pain is a normal, natural and essential sensation for your body to experience. It tells you something is wrong. Medications may truly give you relief from your pain symptoms, but relief only occurs while taking the medication; it masks symptoms for as long as you continue taking it. When you stop, you are still left with the underlying condition – your peripheral neuropathy. It has not been cured. And what’s worse, the entire time your symptoms and pain were being masked there is a good chance your nerves degenerated further. The purpose of medication is to change your brain chemistry NOT find the root cause of your symptoms. How will you ever regain healthy nerves if you don’t find which of the 5 causes of peripheral neuropathy you are suffering from?

Patient A and Patient B both suffered from peripheral neuropathy. Both had symptoms that were continuing to worsen. Patient A was 57 and Patient B was 62. Both were on Lyrica to minimize pain yet, their pain was slowly increasing, especially the burning foot pain at night.

Patient A suffered from diabetes and blood tests also revealed macrocytic anemia. Both conditions can deprive nerves of adequate fuel and oxygen. Knowing 2 of the causes of peripheral neuropathy are a lack of fuel (nutrients) and a lack of oxygen to the nerves, a fairly simple treatment plan was developed for Patient A. One which got his blood sugar under control and supported the efficient transport of oxygen rich blood. Within 4 months Patient A related that his peripheral neuropathy pain was gone, his use of Lyrica eliminated, and his blood sugar which was 160-180 with meds before treatment was reduced to 85-110 after treatment enabling him to decrease is diabetes medication by 75%.

Patient B, also diabetic, presented a more complex case. In addition to his diabetes, his initial examination showed he was suffering from loss of “wide diameter afferent neurons.” These nerves, when healthy, block pain. With this information treatment was directed to stabilize blood sugar and improve activation of these “wide diameter afferent nerves.” It was explained to Patient B that this treatment would take longer to see results. Five months into the care he related an 80% reduction of pain intensity and he was able to sleep at night with no pain.

Even though their peripheral neuropathy symptoms seemed the same, it took a careful individual assessment to find the underlying cause or causes in each case. Finding the cause of your peripheral neuropathy is the first step in a successful, drug free plan to improve nerve health and live a pain free life.

Why Are My Hands and Feet Always Cold?
September 28, 2016 / Conditions / By Corey Kirshner

Why Are My Hands and Feet Always Cold?

It’s a warm and slightly humid 82 degree end of summer kind of day. Bright sun, kids heading back to school, thoughts of reorganizing and cleaning out the house are pervasive as we move from one season to the next. If you look carefully the outer tips of leaves are starting to change, some have even begun to fall bringing with them thoughts of apple picking, football and pumpkins. A wonderful stirring of emotions until you remember this seasonal change brings with it a drop in temperature and the longing for spring when your hands and feet will be warm again. Unfortunately, some of us don’t even enjoy the reprieve of summer; we spend our days wondering “why are my hands and feet always cold?”

Contrary to popular belief cold hands and feet don’t just happen, they are a symptom of something not working optimally in your body that the warmest of mittens won’t fix. Although there can be a number of CAUSES for your cold hands and feet, it’s important not to fall too quickly into the trap of focusing on one single thing as the culprit.

Possible causes of cold hands and feet:

Anemia and other nutritional deficiencies

Autoimmune diseases like Raynaud’s and Hashimoto’s
Over active sympathetic nerves
Hormonal imbalances
Thyroid Dysfunction
Chances are you have been researching your condition and understand my caution when reading the above list. For those new to this information let me explain. All of the conditions listed have the ability to cause cold hands and feet on their own BUT they are most often intertwined with one another. We refer to this as a “web of physiologic dysfunction.” For instance, thyroid dysfunction occurs in approximately 30% of women, some will have anemia and cold hands and feet, or the autoimmune condition known as Raynaud’s and an inability to lose weight, others may be experiencing digestive disorders and depression along with their cold hands and feet. So, again it is essential to consider all the possible culprits.

Let’s look at some of the possibilities more closely starting with thyroid conditions.

As mentioned, 30% of women in the US suffer from thyroid related issues. Your thyroid gland controls your metabolism. Metabolism is your body’s process for turning food into energy. If your thyroid is sluggish your metabolism slows down and so do all of the systems of your body that depend upon it. Cold hands and feet can easily be attributed to poor blood flow to peripheral nerves as a result of faulty metabolism. Other metabolic break downs may appear as hair loss, weight gain, depression, fatigue and digestive disorders.

80% of thyroid related issues actually stem from an autoimmune condition call Hashimoto’s. What does that mean for you? Your thyroid symptoms, fatigue, depression, hair loss, dry skin, digestive disorders and yes, cold hands and feet are secondary to an autoimmune condition. Meaning you generally won’t have one without the other. The web of physiologic dysfunction is in play here. If your thyroid condition is treated without considering the autoimmune component or vice versa there is a high probability you will continue to suffer and allow the underlying cause to wreak havoc on your body.

Anemia, hormonal imbalances and nerve issues, all of which may be related to metabolic breakdown, are also listed above as possible culprits of your cold hands and feet. But as you are learning, these may be the primary problem causing your symptoms OR the secondary problem; remember the role the web of physiologic dysfunction plays in your health. The relationship of anemia in thyroid sufferers is well documented, with some studies claiming as many as 43% of hypothyroid patients having some type of anemia.

In reality you are suffering from two things: the SYMPTOMS – cold hands and feet, and the underlying CAUSES of your condition.

The biggest pitfalls in your care will be treating the symptoms as the problem, and focusing only on one possible cause. Avoid these pitfalls and stop asking “Why are my hands and feet always cold?” Get proper testing, including a complete thyroid panel (not just TSH) with thyroid antibodies, check Vitamin D levels, as low Vitamin D is a precursor for many diseases including autoimmune conditions, and when indicated, test for intestinal permeability, a condition that will cause significant nutritional deficits.

Wouldn’t it be a nice change to enjoy a mug of warm apple cider because of the sweet, spicy dance it performs on your tongue instead of holding onto it for dear life as your hand warmer?

Why Can’t I Eat Anything Without Feeling Sick?
September 28, 2016 / Conditions / By Corey Kirshner
One of the most commonly asked questions among IBS, Crohn’s & Colitis patients is “Why can’t I eat anything without feeling sick?” Typically when people are intolerant to may foods they will direct their attention to the “what” question. “What can I eat? What will calm down the reaction? What do I take to settle my stomach?” Answering the “what” question will lead to many “solutions” but will not uncover the underlying cause. “What” solutions are many: restrict your diet, take pills and acid blockers, get tested for food allergies. Or, you can start asking Why you can’t eat anything without feeling sick.

By asking why you can’t eat anything without feeling sick , you are seeking the root cause of your condition, not just a resolution to the effects or symptoms from your condition. Although there are other possible reasons you may be reacting to everything you eat, one of the most common causes is a condition called Intestinal Permeability, or Leaky Gut. Your digestive tract begins with your mouth and ends with, well, your other end. Each part of the system has a specific job, from ingesting food to excreting it, the system is finely tuned to keep your body functioning properly. The job of the small intestine, where Leaky Gut can occur is to breakdown the proteins, fats and carbohydrates from the foods you eat before they enter your blood stream to nourish all the cells of your body. A healthy small intestine is lined with densely packed cells that act as a filter for the broken down particles. The space between these cells are referred to as junctions. A healthy intestine will have tight junctions or a very fine filter. Like the screens in your house, the junctions create a barrier that are meant to let the good stuff in while keeping the bad stuff out. Large undigested particles of food, parasites, and bacteria are all able to pass through the weakened junctions of a leaky gut which alerts the body to a foreign invader causing an inflammatory reaction.

Systemic inflammatory reactions related to Intestinal Permeability:

Nonspecific joint pain
Brain fog
Fatigue
Skin issues
Bloating
Constipation
Diarrhea
Without fixing this barrier, you will develop more food intolerances and more systemic inflammatory reactions.

Going back to the most important question-Why? Why would you have Intestinal Permeability? This question has many answers. Foods sensitivities, low Vitamin D, intestinal parasites, medications, stress, and hyperthyroid or hypothyroid are all known culprits. From these culprits your barrier system will be affected in stages, starting with localized inflammation of the intestinal lining. As the lining continues to degrade your whole immune system will join the battle and, even though the damage is confined to the gut, the whole body immune/inflammatory reaction may cause symptoms anywhere in the body. Brain fog, skin conditions like acne or eczema, headaches, joint pain, and of course food sensitivities are all inflammatory reactions to Leaky Gut. As leaky gut progresses even further you will develop an accumulation of lipopolysaccharides locally in the gut, which is basically an overgrowth of bad bacteria or sludge on the intestinal wall which further affects the inflammatory process and inhibits digestion, creating a state of malnutrition.

By allowing the condition to persist you are seriously hindering any chance of regaining health. There are tests available to determine if you have Intestinal Permeability and what type you may have. Uncovering this roadblock will help to answer the question “Why can’t I eat anything without feeling sick?”

Dr. Kirshner holds Free Workshops where you can learn more about your condition and how to control it without medication.