tag:blogger.com,1999:blog-49702946855646320592024-02-07T15:52:31.460-08:00 Dr. Liverman/ Improving Metabolic Health Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.comBlogger146125tag:blogger.com,1999:blog-4970294685564632059.post-45682536122150771342019-03-25T08:01:00.000-07:002019-03-25T08:01:36.873-07:00Goldilocks, HRV, Resilience as a Function of Power and Protection<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 19px;">
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Acquired resilience effects every level of life from mitochondria, nucleus, cell, tissue, organ and organism.</div>
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The resilient organism has high HRV (relative to age and power)</div>
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The hormetically stressed (and resilient) organism has higher HRV for age.</div>
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This leads to an obvious paradox of organism resilience and organ damage coexisting.</div>
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In other words, high HRV AND immune stress disease aka aging.</div>
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Obviously resilience declines with aging.</div>
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Immune stress increases with age.</div>
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The paradox mentioned above is a phase equilibrium state like water and ice coexisting at 32° in the same body (of water/ice.) Safi Bahcall in Loonshots...</div>
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Protection is one side of resilience.</div>
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Power is the other side of resilience.</div>
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It is counterintuitive that adult dynamic equilibrium HRV is lower than the protection predominant state as in healthy youth but also higher than power deficit state of healthy aging.</div>
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HRV is relative and not absolute meaning that the savings rate does not imply absolute wealth but relative wealth to salary (power.). </div>
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Therefore absolute health is a function of power over (protection relative to power-HRV), and each is compounded to the apogee. How can one stay longer at the apogee level of absolute power and relative Resilience/HRV.</div>
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Who is dominant or optimum in performance, adolescents, young adults or geriatric adults?. This is the counterintuitive Goldilocks and HRV relationship. It also fits the paradigm of six sigma mean and upper and lower control limits as OUTLIERS.</div>
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One is an outlier of protection (youth) and one is an outlier of decreased power (aged.)</div>
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I have recently embarked on increasing power as an aging adult by taking niccotinamide riboside (NR.)to increase ATP production. Previously I was increasing protection by addition of Nrf2 activators to increase antioxidant enzyme capacity, and cell healing with methionine components. Both of these later components when deficient reduced further power in a negative feedback loop as measured by inflammatory biomarkers associated with aging as reported in unpublished trials.</div>
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Adding NAD precursor increased power and reduced aging inflammatory biomarkers transiently in human trials.</div>
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By addressing and restoring protection relative to power, 13 individuals have now continued to show steadily reducing inflammatory biomarkers or reversing aging.</div>
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Why was restoring protection necessary to increasing power in aged individuals?</div>
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One cannot increase power relative to the apogee of young adulthood without maintaining dynamic equilibrium with protection (and repair) forces.</div>
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HRV at peak physical, emotional and social age is the Goldilocks equilibrium of healthy adults. </div>
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In 50 year old humans NAD is 50% lower than apogee or peak.</div>
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In 50 year old humans Melatonin is likely 50% lower than apogee.</div>
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Age 50 has decreased power and protection relative to apogee or peak.</div>
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Picture the adolescent where protection is greater than power when rising to apogee or peak. HRV high.</div>
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Picture the aged where that protection is lesser than power when declining secondary to aging. HRV low.</div>
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Therefore the dynamic equilibrium state is peak power with adequate protection say age 25-35.</div>
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HRV is intermediate HRV 62 down from 68% at age 16-25.</div>
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HRV ultimately measures tone and capacity of sympathetic and vagal reserves in the locus ceruleus of the brain stem. The reserves are a function of stored fast acting chemicals and slow adding peptides.</div>
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Developmentally, the brain uses the most power as it develops and preserves a large and functioning network. Adult muscular peak lean body mass also adds power use. This is the apogee or peak mental, physical and emotional.</div>
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One might say that each system is peaking, but what about their tuning or alignment?</div>
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If our capacity to love is powerful, but the mind and bodily desires are driving without soulful controllers we are not adding both harmony and innovation.</div>
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It is this last dynamic equilibrium state that matters. Morality allows freedom, immorality ensures captivity. The rigidity of stability (homeostasis) must coexist with the flexibility of new strategies and products to drive productivity (power) safely (protection) to more and better for Mercy's and Goodness's sake. This results in more Wealth and Health as a function of time. A truly rich life requires a mission or raison d'etre.</div>
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<br /><a href="https://journals.sagepub.com/doi/full/10.1177/1559325818803428">https://journals.sagepub.com/doi/full/10.1177/1559325818803428</a><br /></div>
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Acquired Resilience: An Evolved System of Tissue Protection in Mammals</h1>
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Abstract</h2>
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This review brings together observations on the stress-induced regulation of resilience mechanisms in body tissues. It is argued that the <b>stresses that induce tissue resilience in mammals</b> arise from everyday sources: <b>sunlight, food, lack of food, hypoxia and physical stresses</b>. <b>At low levels, these stresses induce an organised protective response in probably all tissues;</b> and, at some higher level, cause tissue destruction. This pattern of response to stress is well known to toxicologists, who have termed it hormesis. The phenotypes of resilience are diverse and reports of stress-induced resilience are to be found in journals of neuroscience, sports medicine, cancer, healthy ageing, dementia, parkinsonism, ophthalmology and more. This diversity makes the proposing of a general concept of induced resilience a significant task, which this review attempts. We suggest that a system of stress-induced tissue resilience has evolved to enhance the survival of animals. By analogy with acquired immunity, <b>we term this system ‘acquired resilience’</b>. Evidence is reviewed that acquired resilience, like acquired immunity, fades with age. This fading is, we suggest, a major component of ageing. <b>Understanding of acquired resilience may, we argue, open pathways for the maintenance of good health in the later decades of human life.</b></div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-84358231434438151532019-03-23T07:25:00.000-07:002019-03-23T07:25:00.405-07:00Irrational Decision Making is Normal; Why and Can one Improve?<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 19px;">
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The mind body connection has a trinity of controllers (processors and activators).</div>
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Vagal, Sympathetic and Neuroenteric.</div>
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Heart, mind and gut decision making parallels these three decision making systems.</div>
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Recently nerve connections called synapses, previously thought of as plug like connections, are now known to be microprocessors with computer like processing and activation.</div>
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Auditory processing appears to have a subcortical buffer or memory of milliseconds that allows sound sampling in relation to words not letters.</div>
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Visual processing appears to have a similar subcortical working memory buffer such that word shapes allow rapid processing without every letter awareness.</div>
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Considering fractals (markov blankets) or distinguishable and scalable processors, processing is multilevel and pattern recognition comparators that predict or project. Therefore the Trinity of controllers is itself patterned at smaller and presumably larger (or corporate) scales.</div>
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Processors likely output as super imposed waves that are in phase or out of phase to change the wave form like recording "voice"as sound waves. Lean Six Sigma lingo compares the voice of the customer to the voice of the process.</div>
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The processors act like rheostats, voices in a choir, modulating decisions and processes into harmony or discordance in both individual and group (classroom) decision making.</div>
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Pedagogy and Preaching always target the brain, and less directly targets the intuition duo of feelings and gut. Decisions are derived from all three. A recent Nobel economics prize winner, Richard Thayer who wrote the book "Nudge" shows that <b>humans are predictably irrational. In effect they make decisions with gut, heart and mind, then rationalize the consensus</b>.</div>
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What if we taught, coached, evangelized and medically treated the TRINITY of DECISION MAKERS to align with the better aspects of each?</div>
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1. <b>Gut</b> palability. </div>
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You are neither hot nor cold but lukewarm and I will spit you out.</div>
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2. Autonomic nervous system/ vagal and sympathetic/(<b>heart</b>) - vagal compassion, connection and learning; sympathetic energy, focus and action. </div>
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Create in me a new heart.</div>
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3. <b>Mind </b>rationality (not rationalizations) derived from a connected human ensemble of language, theory of mind, inference, time travel and executive function/working memory. </div>
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Blessed is the man... Delight is in the law (learning what the right thing, at the right time for the right reason)...</div>
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We might leverage all three decision makers into an emergent biological property of improved complex decision makers who have tuned guts, hearts and minds. </div>
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De Tocqueville wrote in Democracy in America, "America is great because she is good. If America ceases to be good, America will cease to be great."</div>
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Great decision making individually and en mass collectively projects increasing goodness which compounds into greatness. Emergent property in which simple algorithms create complexity and if disturbed can be restored through simple algorithm.</div>
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<a href="https://journals.sagepub.com/doi/full/10.1177/2158244019837439">https://journals.sagepub.com/doi/full/10.1177/2158244019837439</a><br /></div>
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Head, Heart, and Gut in Decision Making: Development of a Multiple Brain Preference Questionnaire</h1>
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There is a growing body of literature that supports the idea that decision making involves not only cognition, but also emotion and intuition. However, following extant “<b>dual-process” decision theories, the emotional and intuitive aspects of decision making have predominantly been considered as one “experiential” entity</b>. The purpose of this article is to review the <b>neurological evidence for a three-factor model of head, heart, and gut aspects of embodied cognition in decision making </b>and to report on a study carried out to design and validate a psychometric instrument that measures decision-making preferences across <b>three separable interoceptive components</b>, representing the complex, <b>functional, and adaptive neural networks (or “brains”) of head (analytical/cognitive), heart (emotional/affective), and gut (intuition)</b>. Development and validation of the Multiple Brain Preference Questionnaire (MBPQ) instrument was carried out in three phases. Translational validity was assessed using content and face validity. Construct validity was undertaken via exploratory factor analysis of the results from the use of the instrument with 301 subjects from a global sampling, and reliability tests were performed using internal consistency and test–retest analysis. Results confirmed extraction of three factors (head, heart, and gut) was appropriate and reliability analysis showed the MBPQ to be both valid and reliable. Applications of the tool to coaching and leadership are suggested.</div>
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Introduction</h2>
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There is now a robust body of <b>research into the nature of decision making and in particular into the roles of cognition, emotion, and intuition in human decision making</b>. This research spans more than three decades (e.g., see <span class="converted-anchor" style="max-width: 100%;">Bohm & Brun, 2008</span>; <span class="converted-anchor" style="max-width: 100%;">Burke & Miller, 1999</span>; <span class="converted-anchor" style="max-width: 100%;">Lerner, Li, Valdesolo, & Kassam, 2015</span>; <span class="converted-anchor" style="max-width: 100%;">Schwarz, 2000</span>; <span class="converted-anchor" style="max-width: 100%;">Sinclair, 2014</span>). In earlier research, decision theorists suggested there were two dominant systems humans use in decision making: the “analytic system” and the “experiential system” (<span class="converted-anchor" style="max-width: 100%;">Gutnik, Forogh Hakimzada, Yoskowitz, & Patel, 2006</span>). <span class="converted-anchor" style="max-width: 100%;">Evans and Stanovich (2013)</span> discuss two major <b>channels for decision making </b>within the “dual-process/dual-system” decision theories. These two theories both assert that human information processing is accomplished in two different, but complementary ways (“<b>analytically” or “intuitively</b>”) through two substantially different and differently evolved types of thinking. System 1 is both fast and intuitive and System 2 is much slower and more deliberate in function. System 2, the analytic system, is slower and involves conscious, deliberate cognitive processes and logical, reason-oriented thinking. In contrast, System 1, the faster experiential system, uses emotion-related associations, intuitions, and “gut instincts” when making decisions (<span class="converted-anchor" style="max-width: 100%;">Bechara, Damasio, Tranel, & Damasio, 1997</span>).</div>
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This decision model also fits well with work emerging over the last decade from the fields of embodied cognition and interoceptive awareness. Most notably this includes Damasio’s somatic marker theory (<span class="converted-anchor" style="max-width: 100%;">Bechara & Damasio, 2005</span>; <span class="converted-anchor" style="max-width: 100%;">Damasio, Tranel, & Damasio, 1991</span>), Thayer’s neurovisceral integration model (<span class="converted-anchor" style="max-width: 100%;">Park & Thayer, 2014</span>; <span class="converted-anchor" style="max-width: 100%;">Thayer & Lane, 2000</span>, <span class="converted-anchor" style="max-width: 100%;">2009</span>), Craig’s findings on the neurobiological basis of interoceptive awareness (IA; <span class="converted-anchor" style="max-width: 100%;">Craig, 2002</span>, <span class="converted-anchor" style="max-width: 100%;">2009</span>, <span class="converted-anchor" style="max-width: 100%;">2014</span>), and Critchley’s work on heart-based viscerosensory signaling (<span class="converted-anchor" style="max-width: 100%;">Critchley, 2015</span>; <span class="converted-anchor" style="max-width: 100%;">Critchley, Wiens, Rotshtein, Ohman, & Dolan, 2004</span>). <b>These models and theories and the research supporting them all suggest that human cognition and decision making are strongly influenced by, or actively involved with, deep somatic and embodied re-representation and interoceptive processin</b>g. For example, Damasio’s “somatic marker” hypothesis (<span class="converted-anchor" style="max-width: 100%;">Damasio, 1994</span>, <span class="converted-anchor" style="max-width: 100%;">1999</span>) states that meta-representation of bodily states constitutes a set of emotional feelings, accessible to consciousness and providing the “gut-feeling” and “heart intelligence” that guides our decision processes.</div>
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According to <span class="converted-anchor" style="max-width: 100%;">Burr (2017)</span>, the older traditional cognitivist account of analytical decision-making “views choice behaviour as a serial process of deliberation and commitment, which is separate from perception and action” (p. 1). However, as Burr points out, recent work in embodied decision making has shown that this account is incompatible with emerging neurophysiological data. For example, current work on embodied decision making (<span class="converted-anchor" style="max-width: 100%;">Cisek & Pastor-Bernier, 2014</span>; <span class="converted-anchor" style="max-width: 100%;">Lepora & Pezzulo, 2015</span>) indicates that <b>decision making is inextricably intertwined with sensorimotor control such that there is a blurring of the boundaries between perception, action, and cognition, involving reciprocal communication between affective and sensorimotor neural regions.</b></div>
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Burr also highlights that <span class="converted-anchor" style="max-width: 100%;">Barrett and Bar (2009)</span> have convincingly argued that neural activity in perception is reflective of ongoing integration of sensory information from exteroceptive cues, with interoceptive information from the body and that this supports the view that when it comes to decisions, the involved <b>perceptual states are “intrinsically infused with affective value,”</b> such that the affective or emotional salience is deeply intertwined with its perception. This indicates that far from involving only head–brain based cognitive or logical (System 2) <b>processes, decision making is intrinsically and deeply entwined with emotional and interoceptive bodily sensorimotor </b>(System 1) experiences.</div>
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Interestingly, this notion that decision making involves deep aspects of somatic re-representation and <b>embodied “cognition” leads to an important insight</b>. Given our interoceptive processing and embodied cognition emerges up from embodied neural circuits into the deep limbic structures and eventually the frontal lobes of our cranial brain (<span class="converted-anchor" style="max-width: 100%;">Critchley, 2009</span>; <span class="converted-anchor" style="max-width: 100%;">Critchley & Harrison, 2013</span>), then this <b>neuroceptive processing must deeply involve our system of autonomic afferents</b> (<span class="converted-anchor" style="max-width: 100%;">Craig, 2014</span>; <span class="converted-anchor" style="max-width: 100%;">Critchley, 2009</span>; <span class="converted-anchor" style="max-width: 100%;">Porges, 2001</span>, <span class="converted-anchor" style="max-width: 100%;">2011</span>). And this <b>embodied autonomic and affective processing has two major key neural systems communicating to it and interacting with it within the body: the intrinsic cardiac neural plexus (<span class="converted-anchor" style="max-width: 100%;">Armour, 2007</span>) and the enteric neural plexus</b> (<span class="converted-anchor" style="max-width: 100%;">Gershon, 1999</span>).</div>
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In colloquial terms, humans often ascribe intuitive and informational roles to heart and gut regions of the body. We talk about “gut instincts,” “gut feelings,” “messages from the heart,” and “heart intuitions” (<span class="converted-anchor" style="max-width: 100%;">Soosalu & Oka, 2012a</span>). Given that we have two separable and complex neural plexuses in these regions, it may not be surprising then that the importance of the heart and gut in human processes such as decision making are being validated by a growing list of studies both in the lab and in real-world scenarios.</div>
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The Intrinsic Cardiac Network</h3>
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The heart contains a complex, functional and adaptive intrinsic neural network (<span class="converted-anchor" style="max-width: 100%;">Armour, 2007</span>). Intracardiac neurons are concentrated in multiple heart ganglia, and the structure of the interactions between neurons, both within intracardiac ganglia and also between individual ganglia, provide the basis for the <b>complex nervous network of the heart</b> (both anatomically and functionally) and has been <b>labeled by researchers in the new field of neurocardiology as a functional “brain</b>” (<span class="converted-anchor" style="max-width: 100%;">Ardell, 2004</span>; <span class="converted-anchor" style="max-width: 100%;">Brack, 2014</span>; <span class="converted-anchor" style="max-width: 100%;">Kukanova & Mravec, 2006</span>; <span class="converted-anchor" style="max-width: 100%;">D. Randall, 2000</span>; <span class="converted-anchor" style="max-width: 100%;">C. Randall, Wurster, Randall, & Xi-Moy, 1996</span>).</div>
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<span class="converted-anchor" style="max-width: 100%;">Dr. J. Andrew Armour (1991)</span>, a pioneer in this field, has undertaken extensive research and introduced the <b>concept of the intrinsic cardiac network as a functional “heart brain.”</b> His work demonstrated a complex intrinsic nervous system in the heart, that is deemed sufficiently sophisticated to qualify as a “little brain” in its own right (<span class="converted-anchor" style="max-width: 100%;">Armour, 2007</span>). The complexity of the neural circuitry in the heart allows independent action, separate from the cranial brain. <span class="converted-anchor" style="max-width: 100%;">Armour (1991)</span> has <b>demonstrated the ability of the heart to learn independently, it has its own memories, and it can feel and sense information.</b> This information from the heart is sent to the brain through a variety of different afferents, including autonomic afferents. These afferent nerves enter the brain at the medulla, and from there are dispersed to the higher centers of the brain, where they may have a variety of influences including in the context of perception, decision making, and other cognitive processes (<span class="converted-anchor" style="max-width: 100%;">Armour, 2004</span>; <span class="converted-anchor" style="max-width: 100%;">Thayer, 2007</span>). In <span class="converted-anchor" style="max-width: 100%;">Thayer’s (2007)</span> work on neurovisceral integration, he has shown how <b>the heart influences neural structures in the head–brain deeply involved in cognitive, affective, and autonomic regulation.</b></div>
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The Enteric Neural Plexus</h3>
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The <b>enteric neural plexus consists of approximately 500 million neurons</b> (<span class="converted-anchor" style="max-width: 100%;">Cognigni, Bailey, & Miguel-Aliaga, 2011</span>) and is said to be of a similar size and complexity to that of a cat’s head-brain (<span class="converted-anchor" style="max-width: 100%;">Mosley, 2012</span>; <span class="converted-anchor" style="max-width: 100%;">Watzke, 2010</span>). The network of enteric neural tissue is spread across the organs of the gastrointestinal tract, from oral cavity and esophagus to anus. <span class="converted-anchor" style="max-width: 100%;">Dr. Michael Gershon (1999)</span> in his groundbreaking work in the field of neurogastroenterology has described the <b>enteric nervous system as “the second brain.</b>” Gershon’s work, however, follows as a rediscovery, since Byron Robinson, MD, an American medical physician and anatomist working over 100 years ago, published in 1907 a book titled <i style="max-width: 100%;">The Abdominal and Pelvic Brain</i>, in which he described a complex nervous system or “brain” that he had discovered in the region of the gut (<span class="converted-anchor" style="max-width: 100%;">Robinson, 1907</span>).</div>
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The <b>enteric brain has been shown to be able to control the gut independently of the cranial brain</b> (<span class="converted-anchor" style="max-width: 100%;">Gershon, 1999</span>; <span class="converted-anchor" style="max-width: 100%;">Goldsteon, Hofstra, & Burns, 2013</span>). Virtually every aspect of gut activity is under the regulatory influence of this independent enteric nervous system (<span class="converted-anchor" style="max-width: 100%;">Holzer, 2017</span>; <span class="converted-anchor" style="max-width: 100%;">Holzer, Schicho, Holzer-Petsche, & Lippe, 2001</span>). There is also <b>growing evidence that the enteric brain deeply influences head-based affective information processing</b> (<span class="converted-anchor" style="max-width: 100%;">Berntson, Sarter, & Cacioppo, 2003</span>; <span class="converted-anchor" style="max-width: 100%;">Holzer, 2017</span>). As <span class="converted-anchor" style="max-width: 100%;">Mayer (2011)</span> points out in his paper titled “Gut Feelings: The Emerging Biology of Gut-Brain Communication,”</div>
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Recent <b>neurobiological insights into this gut–brain crosstalk have revealed a complex, bidirectional communication system</b> that not only ensures the proper maintenance of gastrointestinal homeostasis and digestion but is likely to <b>have multiple effects on affect, motivation and higher cognitive functions, including intuitive decision making.</b> (p. 453)</div>
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Head, Heart, and Gut in Decision Making</h3>
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Thus we see that <b>both of these gut and heart neural systems evince complex processing, learning and appear to be involved in higher order human functioning</b>. That these “brains” or complex, adaptive and functional neural systems are involved in decision making is being uncovered by a growing body of fascinating research. For example, a number of researchers have found that enhanced cardiac perception is associated with benefits in decision making (e.g., see: <span class="converted-anchor" style="max-width: 100%;">Dunn et al., 2010</span>; <span class="converted-anchor" style="max-width: 100%;">Werner, Jung, Duschek, & Schandry, 2009</span>).</div>
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As <span class="converted-anchor" style="max-width: 100%;">Dunn et al. (2010)</span> state,</div>
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These findings identify both the generation and the perception of bodily responses as pivotal sources of variability in emotion experience and intuition, and offer strong supporting evidence for bodily feedback theories, suggesting that <b>cognitive-affective processing does in significant part relate to “following the heart.”</b> (p. 1835)</div>
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In terms of gut-based functioning, <span class="converted-anchor" style="max-width: 100%;">Klarer et al. (2014)</span> examined anxiety and fear learning and decision behaviors in rats that had their gut vagal afferent nerves severed. They found that once the gut vagal neural pathways that subserve “gut feel” had been disconnected, the rats, as compared to sham controls, were no longer able to respond with normal innate anxiety decision-behaviors to fearful stimuli and that fear learning and conditioning was concomitantly affected. As they suggest, “The innate response to fear appears to be influenced significantly by signals sent from the stomach to the brain” (<span class="converted-anchor" style="max-width: 100%;">Meyer, 2014</span>, p. 1) and “These data add weight to theories emphasizing an important role of afferent visceral signals in the regulation of emotional behavior” (<span class="converted-anchor" style="max-width: 100%;">Klarer et al., 2014</span>, p. 7067).</div>
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That similar processes operate in humans is suggested by <span class="converted-anchor" style="max-width: 100%;">Mayer (2011)</span> in his examination of the emerging biology of gut–brain communication and the gut–brain interface. As Mayer points out, “ . . . the popular statement that somebody has made a decision based on their gut feelings may have an actual neurobiological basis related to brain–gut interactions, and to interoceptive memories related to such interactions” (p. 463).</div>
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Also supporting this notion that there are three separable domains in decision making of head (rational/logic), heart (emotions), and gut (intuitions) is the work of <span class="converted-anchor" style="max-width: 100%;">Sadler and Zeidler (2005)</span>, who examined patterns of informal reasoning and moral decision making and demonstrated evidence for individual patterns of rationalistic, emotive, and intuitive styles. They found that while some subjects employed all three decision styles, many subjects utilized individual patterns or combinations of these three styles of reasoning.</div>
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<b>In the field of leadership decision-making, there is also a growing awareness of the importance of the separable domains of head, heart, and gut </b>(<span class="converted-anchor" style="max-width: 100%;">Brack, 2011</span>; <span class="converted-anchor" style="max-width: 100%;">Genovese, 2016</span>). For example, <span class="converted-anchor" style="max-width: 100%;">Dotlich, Cairo, and Rhinesmith (2006)</span> found that <b>in complex business decision environments, the use of head, heart, and gut in decision styles lead to wiser and more effective decisions.</b> As they point out, “<b>Complex times require complete leaders . . . leaders capable of using their head, their heart, and their guts as situations demand”</b> (p. 1). And backing this up, <span class="converted-anchor" style="max-width: 100%;">Heifetz and Linsky (2004)</span> in their work on adaptive leadership claim that</div>
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Solutions to technical problems lie in the head and solving them requires intellect and logic. Solutions to adaptive problems lie in the stomach and the heart and rely on changing people’s beliefs, habits, ways of working or ways of life. (p. 35)</div>
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Finally, as <span class="converted-anchor" style="max-width: 100%;">Markic (2009)</span> points out in her examination of “Rationality and Emotions in Decision Making,”</div>
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Decision making is traditionally viewed as a rational process where reason calculates the best way to achieve the goal. Investigations from different areas of cognitive science have shown that human decisions and actions are much more influenced by intuition and emotional responses than it was previously thought. (p. 54)</div>
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Showing that there is a burgeoning awareness in the literature that logic, emotion, and intuition are all involved in the process of decision making.</div>
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Individual Differences</h3>
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Given that current research findings suggest that within the body there are <b>three key neural systems, or “brains,” involved in decision making, one in the head, one in the heart, and another in the gut</b>, it would not be surprising then that individual differences, competencies, and preferences might show up in how people use these neural systems in decision making. Indeed, emotions involving the heart and instincts/feelings involving the gut have evolved over time because of their adaptive functions in both genotypic and phenotypic survival (<span class="converted-anchor" style="max-width: 100%;">Haselton & Ketelaar, 2006</span>; <span class="converted-anchor" style="max-width: 100%;">Ketelaar, 2004</span>). We also know that the enteric nervous system evolved first before the intrinsic cardiac network and before the encephalization of the head-brain (<span class="converted-anchor" style="max-width: 100%;">Bishopric, 2005</span>; <span class="converted-anchor" style="max-width: 100%;">Mayer, 2011</span>; <span class="converted-anchor" style="max-width: 100%;">Porges, 2001</span>). So it would not be surprising therefore if head, heart, and gut neural intelligences have come to be used for differing aspects of decision making and that thereby different people might have differing propensities and preferences in their use of embodied cognitive functions.</div>
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Cardiovascular system research, looking at interoception (<span class="converted-anchor" style="max-width: 100%;">Critchley et al., 2004</span>; <span class="converted-anchor" style="max-width: 100%;">Katkin, 1985</span>; <span class="converted-anchor" style="max-width: 100%;">Pollatos, Herbert, Matthias, & Schandry, 2007</span>; <span class="converted-anchor" style="max-width: 100%;">Pollatos, Kirsch, & Schandry, 2005</span>) and the gastrointestinal system (<span class="converted-anchor" style="max-width: 100%;">Herbert & Pollatos., 2012</span>; <span class="converted-anchor" style="max-width: 100%;">Stephan et al., 2003</span>), demonstrates that there are a range of important interindividual differences in “interoceptive awareness” (IA) and interoceptive sensitivity. As <span class="converted-anchor" style="max-width: 100%;">Herbert and Pollatos (2012)</span> indicate, individual degrees of IA can be conceptualized as a trait-like sensitivity toward one’s visceral signals. With, for example, a greater sensitivity to how an individual emotionally responds being related to cardiac awareness, which can be developed through a range of embodied learning processes. In addition, <span class="converted-anchor" style="max-width: 100%;">Wiens, Mezzacappa, and Katkin (2000)</span> reported that individuals with heightened IA (as quantified objectively from performance in a heartbeat detection task) report more intense emotional experiences. So it would not be surprising then that such individuals might give more attention or salience to heart-based affective signals during decision making.</div>
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From a gut perspective, <span class="converted-anchor" style="max-width: 100%;">Riezzo, Porcelli, Guerra, and Giorgio (1996)</span> found that gastric electrical activity as measured by electrogastrography (EGG) was a useful indicator of psychophysiological stress created by activities such as arithmetic tasks and Stroop color–word tests, and that wide interindividual variability was observed during the stress period.</div>
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Thus people may have <b>marked individual differences in their awareness of and focus on head versus heart versus gut aspects of decision making. </b>Supporting this idea, <span class="converted-anchor" style="max-width: 100%;">Fetterman and Robinson (2013)</span> explored the different ways individuals metaphorically perceived or located the self in either head or heart. In a paper reporting seven studies, <span class="converted-anchor" style="max-width: 100%;">Fetterman and Robinson (2013)</span> demonstrated that those individuals described as head-locators perceived themselves to be rational, logical, and interpersonally cold, whereas heart-locators described themselves as emotional, feminine, and interpersonally warm. Head-locators showed more accuracy in general knowledge assessments and obtained higher grade results. Conversely, heart-locators favored emotional rather than rational considerations within the context of moral decision making. <span class="converted-anchor" style="max-width: 100%;">Adam, Obodaru, and Galinsky (2015)</span> also examined head versus heart-locators and found strong individual differences among men versus women and in American versus Indian cohorts. These findings show strong support for individual differences in head versus heart preference in decision-making style.</div>
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<span class="converted-anchor" style="max-width: 100%;">Epstein, Pacini, Denes-Raj, and Heier (1996)</span> and <span class="converted-anchor" style="max-width: 100%;">Epstein (1990)</span> in their work on cognitive-experiential self-theory (CEST) and the associated Rational-Experiential Inventory (REI) also showed that people differ in their reliance on the experiential/intuitive system versus the rational/cognitive system. CEST is a dual-process model of perception and cognition that posits that people operate using two separate systems for information processing: analytical-rational and intuitive-experiential. <span class="converted-anchor" style="max-width: 100%;">Norris and Epstein (2011)</span>, more recently, identified intuitive-experiential system: intuition, emotionality, and imagination as three reliable subfactors, and we can see that these three facets nicely mirror the aspects of head (imagination), heart (emotion), and gut (intuition) that <span class="converted-anchor" style="max-width: 100%;">Soosalu and Oka (2012a</span>, <span class="converted-anchor" style="max-width: 100%;">2012b</span>) have highlighted as key functions in decision making of the three brains. The research using the REI has also found strong individual differences in preference for these particular decision styles and that this preference is often associated with a number of meaningful life outcomes (<span class="converted-anchor" style="max-width: 100%;">Shiloh, Salton, & Sharabi, 2002</span>; <span class="converted-anchor" style="max-width: 100%;">Sladek, Bond, & Phillips, 2010</span>).</div>
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Intuition and the Conflation of Heart and Gut</h3>
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One of the key challenges in the existing decision-making research literature is the conflation or mixing of heart and gut into the “intuitive” domain. Researchers often appear to lump heart, gut, and (general) intuitive labels into their questionnaire instruments. This is not surprising given the focus in decision-making research on the dual-factor theory of System 1 (intuitive/experiential) and System 2 (cognitive/rational).</div>
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However, if it is true that embodied cognition utilized in decision making involves separable interoceptive components from the key neural plexuses of the cardiac and enteric regions, then it would be useful for greater theoretical and empirical specificity for the field of decision-making research to begin examining head, heart, AND gut preferences in decision-making mode or style.</div>
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To show that heart and gut are often conflated together in studies on intuitive versus cognitive decision making, let us examine some representative research. For example, in a series of studies examining differences in decision modes (intuitive vs. analytical), <span class="converted-anchor" style="max-width: 100%;">Weber and Lindemann (2008)</span> used questions such as,</div>
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How likely would you be to make this decision based on your immediate <i style="max-width: 100%;">feelings</i> or <i style="max-width: 100%;">gut reaction</i> to the situation? (p. 199)</div>
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Thus showing that (heart-based) feelings and gut reactions have been conflated or mixed into the one question. Interestingly from an individual differences perspective, the results of their research showed that while many respondents could be influenced into using either the intuitive or analytical modes based on domain and situational compatibility, nevertheless nearly one third of subjects exhibited a chronic disposition to operate in an affect-based (intuitive) or a calculation-based (analytic) mode, showing that individual differences in decision mode preference can be strong and enduring.</div>
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<span class="converted-anchor" style="max-width: 100%;">Betsch (2008)</span> also examined chronic preferences for intuition and deliberation in decision making. In her study she developed what she called the “Preference for Intuition and Deliberation Scale (PID).” This scale grouped questions such as the following:</div>
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My <i style="max-width: 100%;">feelings</i> play an important role in my decisions.</div>
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When it comes to trusting people, I can usually rely on my <i style="max-width: 100%;">gut feelings</i>. (p. 246)</div>
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And grouped such questions into the single “intuition” (or affective-decision) category, once again mixing and conflating emotional/affective (heart) with gut (visceral) signals. Importantly, however, she found, “People differ in the way they rely on their heads or their hearts. Even though virtually everybody is able to feel and to think, people follow their strategy preferences if they have the chance to” (p. 243). In an earlier series of studies, <span class="converted-anchor" style="max-width: 100%;">Betsch (2004)</span> asked people directly which strategy they would rely on in different situations (those requiring intuition or deliberation to different degrees). She found that, beyond the situational requirement, a subject’s preferred strategy significantly explained variance in strategy selection (<span class="converted-anchor" style="max-width: 100%;">Betsch, 2004</span>, Study 3), which led people who favored intuition to choose intuition more frequently than deliberation across all scenarios.</div>
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A further example of the conflation of heart and gut interoception in decision research is that of the work of <span class="converted-anchor" style="max-width: 100%;">Katkin, Wiens, and Ohman (2001)</span>. They examined the development of “gut feelings” in subjects presented with fear inducing stimuli through behavioral conditioning; however, they used heartbeat detection as a measure of visceral or gut feeling sensitivity.</div>
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In examining decision making in nursing practice, <span class="converted-anchor" style="max-width: 100%;">Hams (2000)</span> also looked at intuition as “gut feeling.” However, she then conflated gut instinct with heart-based intuiting, stating that</div>
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For me [the nurse] it’s a physical sensation. I have two kinds of knowing. I have the knowing that comes from my head that is subject to conscious awareness. And I have the knowing that, for me, comes out of my heart which is where I feel it. (p. 311)</div>
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Unfortunately, this mixed focus on head, heart, and gut and the undifferentiated lumping of heart and gut into the appellation “intuition” has lead to a number of challenges in the study of individual difference in decision making. Indeed, <span class="converted-anchor" style="max-width: 100%;">Appelt, Milch, Handgraaf, and Weber (2011)</span>, in their development of a Decision-Making Individual Differences Inventory lamented that “Individual differences in decision making are a topic of long-standing interest, but often yield inconsistent and contradictory results” (p. 252). One possible reason for such inconsistency in the examination of individual differences is that researchers have tended to contrast decision-making style as either cognitive or intuitive, and have conflated intuitive style with differing focus on heart interoceptive–based intuitions versus gut-feel intuitions. Indeed in numerous studies we see that authors talk about studying intuitive decision making by examining “gut feel” and then use heart interoception monitoring as the experimental measure, thus conflating heart and gut embodiment aspects of interoceptive intuition. In contrast, intuition can be divided into at least three domains of head (based on conscious reasoning or unconscious cognitive heuristics, for example, <span class="converted-anchor" style="max-width: 100%;">Gigerenzer & Gaissmaier, 2011</span>; <span class="converted-anchor" style="max-width: 100%;">Kahneman, 2011</span>), heart (cardiac interoception), and gut (enteric/visceral interoception).</div>
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That the field of decision-making research is only now beginning to become aware of the difference in types of intuitive signaling is shown by a very recent study. <span class="converted-anchor" style="max-width: 100%;">Sadler-Smith (2016)</span> examined the linguistic structure of human resource practitioners’ experience of intuition. He found that intuitions emerge into consciousness as “bodily awareness” and “cognitive awareness” and that bodily awareness comprised two first-order concepts of “gut reactions” and “feelings.” <b>Such a categorization of intuition specifically into differing elements of cognitive, feeling, and gut reaction is currently relatively rare and a commendable addition to the field of decision-making research</b>. For as <span class="converted-anchor" style="max-width: 100%;">Pollatos (2015)</span> in examining cardiac versus gut-based IA and sensitivity points out, these bodily signals represent distinct and separate processes and should therefore not be conflated.</div>
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Head, Heart, and Gut Preference in Decision Making</h3>
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To support the examination of and research focus on head, heart, and gut domains in decision making, in the present study, we developed and validated a psychometric instrument that explores multiple brain (head, heart, and gut) preferences in decision making. While it is expected that people will exhibit individual differences in their preference for head, heart, and gut decision-making patterns, existing research suggests that these neural systems are interconnected and interdependent (<span class="converted-anchor" style="max-width: 100%;">Mayer, 2011</span>; <span class="converted-anchor" style="max-width: 100%;">Thayer & Lane, 2009</span>). The Multiple Brain Preference Questionnaire (MBPQ) instrument explores individual patterns or preferences for head (analytical/cognitive), heart (emotional/affective), and gut (intuition) based decision-making styles, which accumulatively create an individuals’ holistic and integrated response in decision making.</div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-54483117241488129732019-03-12T04:47:00.000-07:002019-03-12T04:47:29.752-07:00ANS the Autonomic Nervous System and Compassion for Self and Others; Golden Rule(r)<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Why my 8 minutes can change your life blog post is relevant.</div>
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Why the podcast, though primitive in understanding physiology, was sent to my colleagues yesterday.</div>
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Because it represents two important legs or foundations of neuroimmune regulation.</div>
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Cardiac autonomic dysfunction (30-70% in chronic diabetes) has a 5x mortality rate with dysfunction rather than function!</div>
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Function requires feedback and positive and negative controls.</div>
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The controls are focused in brain stem,the locus ceruleus,where fast neurotransmitters/neuromodulators and slow neuropeptides (bdnf and gdnf) affect structure (imaging and pathology) and function (imaging and nerve function testing.)</div>
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Also hidden in the article is the word antidromic which means backwards nerve transmission. This implies that nerve communication, though directional, actually goes both ways.</div>
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What does this have to do with daily hormetic doses of high intensity rest (vagal biofeedback breathing) and Tabata (high intensity interval feedback?</div>
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It strengthens and increases these chemical reserves and their responsiveness!</div>
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Consider shoulder pain secondary to tendinopathy.</div>
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Therapy stimulates a hormetic response that includes rest with progressive doses of exercise; isometric and passive motion, eccentric and passive and active motion, concentric and active followed by return to normal activities. Brief hormetic doses to stimulate nerves and growth factors for healing.</div>
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It takes a minimum of six minutes to stimulate a healing response.</div>
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Therefore, promoting healing and recovery forces is medicine's mandate. </div>
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The ANS is the systemic driver of healing for shoulders, brains and other organs.</div>
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In fact, the wandering vagus nerve, is the internet for compassion and healing both within and without.</div>
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Why not follow sage advice and exercise rest and therapeutic acute (not chronic) stress systems for enduring health, recovery and resilience?</div>
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<a href="https://n.neurology.org/content/92/8/377.abstract">https://n.neurology.org/content/92/8/377.abstract</a><br /></div>
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Autonomic nervous system and neuroimmune interactions</h1>
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New insights and clinical implications</h2>
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<b>Normal organ function, homeostasis, and adaptation through change (allostasis) require close reciprocal interactions between the autonomic and the immune system</b>s. The 3 subdivisions of the autonomic nervous system—<b>sympathetic, parasympathetic, and enteric nervous system (ENS)</b>—as well as primary sensory afferents, receive signals from <b>immune cells</b> and release <b>neurochemical transmitters that regulate the functions of these cell</b>s. These neuroimmune interactions occur at multiple levels, including the gut, the CNS, and lymphoid organs. For example, enteric neurons and glial cells interact with enteroendocrine cells and local macrophages and can sense signals from the gut lumen, including those from the microbiota; these signals elicit local immune responses and reach the CNS via humoral and neural pathways. Interleukins (ILs) and other signals from immune cells can access the hypothalamus via the neurovascular unit or circumventricular organs; these signals can also activate receptors in nerve terminals, such as vagal afferents, and thereby <b>reach the brainstem</b>. In response to these signals, the <b>CNS initiates immunomodulatory autonomic and endocrine responses</b>. For example, sympathetic output to lymphoid organs, including the spleen, elicits potent anti-inflammatory responses via β2 adrenergic receptors (adrenoceptors) expressed in multiple cells of the innate and adaptive immune systems. Vagal efferents affect immune responses in the gut via the ENS, and both <b>vagal and dorsal root ganglion afferents trigger immunomodulatory responses via antidromic release of neuropeptides and other signals</b> at the target organs. Since the last review on autonomic control of immune function in this series,<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">1</sup> studies performed primarily on mice have provided new insight into the role of the microbiota, enteric neurons and glial cells, and autonomic immunomodulatory pathways in these neuroimmune interactions. These studies have elucidated some mechanisms by which these interactions may contribute to the pathophysiology of neurologic disorders including multiple sclerosis (MS) and spinal cord injury (SCI). These findings thus have potential therapeutic implications. There are several recent reviews on these topics.<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">2–12</sup></div>
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Go to <a href="http://n.neurology.org/lookup/doi/10.1212/WNL.0000000000006942" style="color: #416ed2; max-width: 100%;">Neurology.org/N</a> for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the article.</div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-27535697178538050402019-03-08T04:38:00.000-08:002019-03-10T15:22:00.674-07:00 Somatic and Stem Cells Health is Binomial and Reciprocal for Health and Longevity<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Fasting mimicking diet reverses inflammatory bowel disease.</div>
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Note that this was superior to water only fasting.</div>
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Why?</div>
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Clean diet (fat burning) with Mediterranean supplementation with young cells containing Nrf2 drivers increased antioxidant enzyme status reversing disease in SOMATIC CELLS. </div>
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Fasting improved regeneration and stemness in STEM CELLS.</div>
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I recommend a ketodiet, low carb high fat diet with Mediterranean supplements (wheat germ, nuts, olives, fruits and vegetables).</div>
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I recommend twelve or more hours of daily fasting.</div>
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Valter Longo endorses interval fasting mimicking diet in cancer treatment and cancer prevention. This is another way of age (inflamaging) reversal which also improves "stemness". This should be added at intervals on the above regimen.</div>
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Loss of "stemness" and accumulation of senescent cells is the proximate cause of decline and death"</div>
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Mi<span style="font-family: "helvetica"; font-size: 12pt;">Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal Regeneration to Reduce Inflammatory Bowel Disease Pathology: Cell Reports</span><span style="font-size: 1.5rem;">micking Diet Modulates Microbiota and Promote</span><span style="font-family: "helvetica"; font-size: 12pt;">Fastin</span><span style="background-color: rgba(255 , 255 , 255 , 0); font-family: "uictfonttextstyletallbody"; font-size: small;">Summary</span></h1>
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<span style="background-color: rgba(255, 255, 255, 0);">Dietary interventions are potentially effective therapies for inflammatory bowel diseases (IBDs). We tested the effect of 4-day fasting-mimicking diet (FMD) cycles on a chronic dextran sodium sulfate (DSS)-induced murine model resulting in symptoms and pathology associated with IBD. These <b>FMD cycles reduced intestinal inflammation, increased stem cell number, stimulated protective gut microbiota, and reversed intestinal pathology</b> caused by DSS, whereas <b>water-only fasting increased regenerative and reduced inflammatory markers <u>without reversing pathology</u></b>. Transplants of <em style="box-sizing: border-box;">Lactobacillus</em>or fecal microbiota from DSS- and FMD-treated mice reversed DSS-induced colon shortening, reduced inflammation, and increased colonic stem cells. In a clinical trial, three FMD cycles reduced markers associated with systemic inflammation. The effect of FMD cycles on microbiota composition, immune cell profile, intestinal stem cell levels and the reversal of pathology associated with IBD in mice, and the anti-inflammatory effects demonstrated in a clinical trial show promise for FMD cycles to ameliorate IBD-associated inflammation in humans."</span></div>
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https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30181-0</div>
<br class="Apple-interchange-newline" style="-webkit-text-size-adjust: auto;" />Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-8913172489707770052019-03-04T13:21:00.000-08:002019-03-04T13:21:05.795-08:00LDL Cholesterol is not the correct target for treating heart disease?<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
This is heresy in medicine but the evidence appears sound to me.</div>
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A single exception questions a rule. Multiple exceptions disprove the validity of a rule. The evidence is cited here based on that rule of logic.</div>
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My take away is that LDL is not the cause or appropriate target for treatment or prediction of heart disease.</div>
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Endothelial dysfunction treatment or increased resilience is the appropriate treatment target.</div>
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Endothelial function is measured by plethysmography or increased compliance (from NO and H2S) flow mediated dilation and increased HRV heart rate variability. Erectile dysfunction indicates decreased flow mediated dilation of the cavernosa. ED is a predictor of premature cardiovascular events. Similarly migraine is decreased flow mediated dilation or decreased autoregulatoon of cerebral blood flow as a function of dysautonomia.</div>
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HRV is lowered by dysautonomia and increased by hormesis induced by both high intensity interval exercise (Tabata) and high intensity interval rest (Biofeedback breathing two minutes twice daily.)</div>
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Highly sensitive balanced autonomic tone or high HRV index indicates atherosclerosis resilience.</div>
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What are your thoughts on this matter?</div>
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blob:https://www.tandfonline.com/862f1599-be5e-4b7d-bb4a-006242be5749</div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-35288164281359131412019-02-23T06:44:00.000-08:002019-02-23T06:44:02.065-08:00How are Love AND Learning Related?<div style="color: #454545; font-family: ".SF UI Text"; font-size: 17px; font-stretch: normal; line-height: normal;">
<span style="font-family: ".SFUIText"; font-size: 17pt;">Resilience determines locus of control, success and happiness.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Consider that learning and loving are predominantly physiological and natural pursuits. How well one learns and loves is therefore increased or decreased by the drivers of executive control/working memory, language, theory of mind, inference and mental time travel. Consider first a romantic "spark" or scene from Pride and Prejudice, starting Keira Kneightly.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">The camera highlights a discreet touch between Darcy and Elizabeth, flashes their facial awareness or fighting awareness and then shows Darcy clench his fist. Body language 101 reads his taciturn face and clenched fist as struggle. This touch or caress to fist as Darcy gives a hand to Lizzie as he helped her into the carriage after her visit is a "spark."</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Aren't students a continuum of active learners and reluctant taciturn learners?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Why?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Consider a student as needing to find the "spark" and love of lifetime learning required for happiness and success. How can we best fan this physiological spark into a flame?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">We all know students who love learning or have a passion for learning. </span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">I posit that every one of them has resilience.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">I posit that society believes that wealth and social capital is the source of resilience.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">I also posit that they are wrong!</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">The driver of resilience is the locus ceruleus and is a function of strong sympathetic and vagal tone. </span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">It is physiological not sociological. </span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">It is plastic, malleable and can be strengthened.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Can one tune attraction and attachment in love and learning?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">I posit one strengthens physiological resilience with physiological tools based on excitement/exercise AND relaxation breathing.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">These can be paced just as concretely as a pacemaker produces a steady heart rate.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Jolt of noradrenaline, increases focus with awareness of effort, joined by jolt of acetylcholine, effort floats away with the strong impression of feeling safe and content within the bubble of communion/classroom.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">No longer biased, no longer judging and aware of too much or too little. All that remains is just right.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Righteousness with self, other and the world.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">The perfect physiological state for learning and love of self and others.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Isn't this recapitulated in every intimate encounter physiologically with vagal arousal and sympathetic climax between attached couples. The strength of the attachment is a function of strong vagal and sympathetic tone. Resilient individuals and teams have strong accelerators and brakes, high HRV. (The marriage study showing success was greater with physiology than communication/teaching) I am paralleling learning with love because orthodoxy states that love is predominantly physiological and learning is predominantly pedagogical.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">I have previously reframed RESILIENCE as the relative strength of sympathetic and vagal capacity in the locus ceruleus and its projections into both brain and body. One can stratify students and their educational attainment on the resilience to vulnerable continuum. One can also stratify their relative vulnerability to "mind altering" substance and behavioral addictions. A secondary benefit of resilience.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Does the resilient vulnerable continuum vary with HRV?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Does educational attainment vary directly with HRV.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">The resilient are vibrant learners and high on life.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">The vulnerable are searching for external drivers of vitality and are willing to JOLT their bodies with stimulants and depressants.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Unfortunately, external drivers are uncontrolled and use up precious physiologic capital needed to strengthen resilience by strengthening rest AND stress. The vulnerable who raise HRV or strengthen autonomic tone build the physiologic capital to feel confident, try and succeed. (Amy Cuddy Body Language study showing two minutes of posing/breathing reduced or increased cortisol, affected confidence, trying, and succeeding.)</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Twelve step programs have no scientific validity and a poor track record for resilience building.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Does public education have scientific validity?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">What track record for building resilience do average schools have?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">Even if it correlates with socioeconomic status of students, aren't there exceptions?</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">A single exception should make one question the correlation and not mistake socioeconomic drivers as the cause. One can certainly point to myriad examples of failure to launch from success predicted launch pads. And vice versa.</span></div>
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<span style="font-family: ".SFUIText"; font-size: 17pt;">I suspect tuning our ANS physiology will have effects on both fluid and crystallized intelligence, educational attainment, life success and happiness.</span></div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-16144581857442704842019-02-16T06:12:00.000-08:002019-02-16T06:12:57.772-08:00Biological Anti-Aging Biomarkers<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Inflamaging and inflammation biomarkers are predictive of performance and cognition in elders.</div>
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Telomere length is a derivative of low inflammation; not vice versa.</div>
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If renal function improves, biologic age goes down and function goes up.</div>
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If inflammatory markers go down, biologic age goes down and function goes up.</div>
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If cortisol, insulin and IGf goes down, and FOXO3 and bdnf goes up, biologic age goes down and function goes up.</div>
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Conjecture from senescence markers: when senescent cells go down, and stem cell markers go up, biologic age goes exponentially down and enduring function goes up.</div>
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Why?</div>
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The fate of stem cell health determines destiny and fate. Our bodies have two progenies; offspring and replacement somatic cells. Therefore biologically young offspring (children, grandchildren and great grandchildren) and biologically young somatic cells PROFIT US MUCH.</div>
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<br /><a href="https://www.ncbi.nlm.nih.gov/pubmed/26629551">https://www.ncbi.nlm.nih.gov/pubmed/26629551</a><br /></div>
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Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.</h1>
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<span role="menubar" style="max-width: 100%;"></span>2015 Jul 29;2(10):1549-58. doi: 10.1016/j.ebiom.2015.07.029. eCollection 2015 Oct.</div>
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To <b>determine the most important drivers of successful ageing</b> at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We <b>combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains</b>. In Cox proportional hazard models, <b>inflammation predicted all-cause mortality with hazard ratios</b> (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, <b>inflammation predicted capability (10.8% variance explained) and cognition (8(.)6% variance explained) in (semi-)supercentenarians better than chronologic age or gender.</b> The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = - 0.795 (- 1.436 to - 0.154). Centenarians and their offspring were <b>able to maintain long telomeres, but telomere length was not a predictor of successful ageing</b> in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.</div>
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ALT, alanine aminotransferase or alanine transaminase; ANOVA, analysis of variance; AST, aspartate aminotransferase or aspartate transaminase; Ageing; CD, cluster of differentiation; CMV, cytomegalovirus; CRP, C-reactive protein; CVD, cardiovascular disease; Centenarian; ELISA, enzyme-linked immunosorbent assay; GGTP, gamma-glutamyl-transpeptidase; IL-6, interleukin 6; IQR, inter-quartile range; Inflammation; JSS, Japanese Semi-Supercentenarians Study; LTL, leukocyte telomere length; MMSE, Mini-Mental State Examination; NK cells, natural killer cells; PCR, polymerase chain reaction; SD, standard deviation; TCS, Tokyo Centenarians Study; TNF-alpha, tumour necrosis factor-alpha (TNF-alpha); TOOTH, Tokyo Oldest Old Survey on Total Health; Telomere; eGFR, estimated glomerular filtration rate</div>
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<span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;">Publication type, MeSH terms, Substance, Grant support</span><span style="max-width: 100%;"></span></span></h3>
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Joseph Thomas (Tony) Liverma</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-52828928965577143902019-02-13T04:36:00.000-08:002019-02-13T04:36:16.570-08:008 Minutes of No Cost Activities Daily Will Change Your Life and Health<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Biofeedback vagal nerve stimulating breathing reduced HOSTILITY and reduced hospitalizations by 50% and ER visits by 65%.</div>
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Two minutes of slow 0.1cps breathing twice daily improves costs, mood and outcome in CAD patients. Actually this is useful for everyone with metabolic syndrome, provides a free smoking cessation benefit from acetylcholine blocking of the alpha 7 Nicotinic acetylcholine receptor, the same receptor that chantix occupies. </div>
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This is a free treatment with infinite return on investment. </div>
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Combined with Tabata four minutes of daily high intensity interval exercise it promotes healthy functional ANS autonomic tone in 8 minutes daily. Autonomic dysfunction, either too much sympathetic or too much vagal tone results in damaging dysautonomia.</div>
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This is practical low hanging fruit to improve our outcomes. Vagal tone activates the cholinergic anti inflammatory pathway and likely protects all organs and not just the heart.</div>
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Exercise and mindfulness, improved autonomic tone and function, improves anxiety and depression by 42% or results in RESILIENCE.</div>
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Shouldn't this be part of CCM? Shouldn't this be part of wellness for the 62% of our insulin resistance patients at increased risk for cardiovascular morbidity?</div>
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Couldn't this reduce health insurance costs for state teachers and employees?. Small no cost change in big populations produces large benefits and savings which compound year over year.</div>
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<br /><a href="https://link.springer.com/article/10.1007/s12529-017-9707-7">https://link.springer.com/article/10.1007/s12529-017-9707-7</a><br /></div>
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<h1 class="title" style="font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
One-Year Cardiovascular Prognosis of the Randomized, Controlled, Short-Term Heart Rate Variability Biofeedback Among Patients with Coronary Artery Disease</h1>
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<time class="date" datetime="2018-01-02" style="display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;">02 January 2018</time></div>
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Abstract</h2>
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Purpose</h3>
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<b>Heart rate variability biofeedback (HRV-BF) is an effective </b>psychophysiological <b>intervention</b>, with short-term effects of <b>increased autonomic nervous system homeostasis, strengthened baroreflex sensitivity, and decreased hostility in patients with coronary artery disease (CAD)</b>. The study examined the 1-year HRV-BF effect on cardiovascular prognosis of these patients.</div>
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Methods</h3>
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Of 222 patients with CAD referred by cardiologists, 210 were screened and randomly assigned to the HRV-BF and control groups. All patients received psychophysiological assessment and completed psychological questionnaires at pre- and post-interventions and 1-year follow-up. The <b>cardiovascular prognosis primary endpoints included hospital readmission, emergency revisits, and mortality.</b></div>
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Results</h3>
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The <b>HRV-BF group had fewer all-cause readmissions (12.00 vs. 25.42%) and all-cause emergency visits (13.33 vs. 35.59%) than the control group. </b>The low-frequency HRV in the HRV-BF group increased at post-intervention and 1-year follow-up compared with that at pre-intervention. Although no significant interaction effect was found in the standard deviation of the normal-to-normal intervals (<em style="max-width: 100%;">F</em> = 2.96, <em style="max-width: 100%;">p</em> = 0.055), it increased by 26.68% from pre- to post-intervention and 15.77% from pre-intervention to follow-up in the HRV-BF group. However, it decreased by 3.60% from pre- to post-intervention and increased by 1.99% from pre-intervention to follow-up in the control group. <b>Depression and hostility scores decreased significantly at post-intervention and 1-year follow-up only in the HRV-BF group</b>.</div>
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Conclusions</h3>
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The <b>long-term HRV-BF effect was confirmed by improved cardiovascular prognosis, increased cardiac autonomic homeostasis and baroreflex sensitivity, and decreased depression and hostility.</b> HRV-BF is an effective psychophysiological intervention with short- and long-term effects in cardiac rehabilitation programs.</div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-65200414143907494092019-02-07T04:33:00.001-08:002019-02-07T04:33:26.331-08:00Anti-aging or Optimum Metabolic Health in 3 Steps<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Why age related decline in...</div>
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Melatonin is one axis leading to aging.</div>
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NAD age related decline in NAD is a second axis leading to aging.</div>
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Loss of protein quality control or proteostasis is a third axis of aging.</div>
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Therefore, the 1,2,3 of anti aging is the following:</div>
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Melatonin.</div>
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NR niccotinamide riboside.</div>
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Spermidine, wheat germ.</div>
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Death and frailty result from stem cell exhaustion. This regimen is central to both somatic and stem cells survival and quality control.</div>
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<br /><a href="https://www.sciencedirect.com/science/article/pii/S1043276018302261">https://www.sciencedirect.com/science/article/pii/S1043276018302261</a><br /></div>
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Sirtuins in Metabolic and Epigenetic Regulation of Stem Cells</h1>
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Highlights</h2>
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As <b>cellular metabolic and stress sensors, sirtuin family of NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>-dependent deacylases are pivotal regulators of stem cell biology in addition to their well-known roles in metabolic diseases and aging.</b></div>
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Despite their common dependence on cellular NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>, different sirtuins display cell type-specific and/or stage-dependent <b>impacts on stem cell biology </b>in response to various environmental cues.</div>
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Nuclear and cytosolic <b>sirtuins modulate pluripotent stem cells and embryogenesis through regulation of pluripotency factors, metabolism, epigenetics, redox homeostasis, and cellular stress response.</b></div>
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<b>Sirtuins maintain self-renewal, quiescence, and regenerative capacity of adult stem cells and protect against adult stem cell depletion in response to stress and aging.</b></div>
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<span style="max-width: 100%;"><a href="https://www.blogger.com/topics/biochemistry-genetics-and-molecular-biology/sirtuin" style="color: #416ed2; max-width: 100%;" title="Learn more about Sirtuin">Sirtuins</a> are highly conserved NAD</span><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>-dependent enzymes that are capable of removing a wide range of lipid lysine acyl-groups from protein substrates in a NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>-dependent manner. These NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup><span style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">-dependent activities enable sirtuins to monitor <a href="https://www.blogger.com/topics/medicine-and-dentistry/cell-energy" style="color: #416ed2; max-width: 100%;" title="Learn more about Cell Energy">cellular energy</a> status and modulate </span><a href="https://www.blogger.com/topics/medicine-and-dentistry/genetic-transcription" style="color: #416ed2; max-width: 100%;" title="Learn more about Genetic Transcription">gene transcription</a><span style="max-width: 100%;"><span style="max-width: 100%;">, <a href="https://www.blogger.com/topics/medicine-and-dentistry/genomic-instability" style="color: #416ed2; max-width: 100%;" title="Learn more about Genomic Instability">genome stability</a>, and </span><a href="https://www.blogger.com/topics/medicine-and-dentistry/energy-metabolism" style="color: #416ed2; max-width: 100%;" title="Learn more about Energy Metabolism">energy metabolism</a> in response to environmental signals. Consequently, sirtuins are important for </span></span><a href="https://www.blogger.com/topics/medicine-and-dentistry/cell-survival" style="color: #416ed2; max-width: 100%;" title="Learn more about Cell Survival">cell survival</a><span style="max-width: 100%;">, stress resistance, proliferation, and differentiation. In recent years, sirtuins are increasingly recognized as crucial regulators of stem <a href="https://www.blogger.com/topics/medicine-and-dentistry/cytotechnology" style="color: #416ed2; max-width: 100%;" title="Learn more about Cytotechnology">cell biology</a> in addition to their well-known roles in metabolism and aging. This review article highlights our current knowledge on sirtuins in stem cells, including their functions in </span></span><a href="https://www.blogger.com/topics/medicine-and-dentistry/pluripotent-stem-cell" style="color: #416ed2; max-width: 100%;" title="Learn more about Pluripotent Stem Cell">pluripotent stem cells</a>, </span><a href="https://www.blogger.com/topics/biochemistry-genetics-and-molecular-biology/embryogenesis" style="color: #416ed2; max-width: 100%;" title="Learn more about Embryogenesis">embryogenesis</a><span style="max-width: 100%;">, and development as well as their roles in <a href="https://www.blogger.com/topics/medicine-and-dentistry/adult-stem-cell" style="color: #416ed2; max-width: 100%;" title="Learn more about Adult Stem Cell">adult stem cell</a><span style="max-width: 100%;"> maintenance, <a href="https://www.blogger.com/topics/medicine-and-dentistry/regeneration" style="color: #416ed2; max-width: 100%;" title="Learn more about Regeneration">regeneration</a>, and aging.</span></span></span></div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-43459350387632535402019-01-30T04:55:00.000-08:002019-01-30T10:54:36.517-08:00Daytime and Nighttime Circadian Rhythm Hormones Reverse Aging Effectors<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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The kyureine pathway is important to generate NAD+ that recovers oxidative phosphorylation in aging cells. See below.</div>
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This abstract demonstrates recovery of aging (stressed) macrophages.</div>
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The transition of M2 to M1 anti inflammatory to pro inflammatory macrophages is oxidative, nitrosative and immune stress.</div>
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High M1 macrophagesdamages cartilage in arthritis, bone is osteoporosis and neurons in neurodegenerative diseases.</div>
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Ditto neuropathy, retinopathy, atherosclerosis, congestive heart failure, Steatohepatitis.</div>
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<br /></div>
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Note how relevant Vitamin D and Melatonin (effector of kyureine pathway) are to aging or degenerative decline.</div>
<div class="original-url">
Ditto spermidine (wheat germ), sulforaphane (broccoli sprout extract) which promotes proteostasis and Nrf2 respectfully.</div>
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<a href="https://www.nature.com/articles/s41590-018-0255-3">https://www.nature.com/articles/s41590-018-0255-3</a></div>
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<h1 class="title" style="font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation</h1>
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<li class="byline" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person" style="-webkit-padding-start: 0px; display: inline !important; font-size: 1em !important; list-style-type: none; margin: 0px; max-width: 100%;"><span itemprop="name" style="display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;"></span>,</li>
<span class="delimiter" style="display: inline !important; font-size: 1em !important; margin: 0.07em 0.45em 0px; max-width: 100%; padding: 0px;"></span><time class="date" datetime="2018-11-26" itemprop="datePublished" style="display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;">26 November 2018</time></div>
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<span style="max-width: 100%;">Abstract</span></h2>
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Recent advances highlight a pivotal role for <b>cellular metabolism in programming immune responses</b>. Here, we demonstrate that <b>cell-autonomous generation of nicotinamide adenine dinucleotide (NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>) via the kynurenine pathway (KP) regulates macrophage immune function in aging and inflammation</b>. Isotope tracer studies revealed that macrophage NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> derives substantially from <b>KP metabolism of tryptophan</b>. Genetic or pharmacological blockade of de novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> synthesis depleted NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>, suppressed mitochondrial NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>-dependent signaling and respiration, and impaired phagocytosis and resolution of inflammation. Innate immune challenge triggered upstream KP activation but paradoxically suppressed cell-autonomous NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> synthesis by limiting the conversion of downstream quinolinate to NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>, a profile recapitulated in aging macrophages. <b>Increasing de novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> generation in immune-challenged or aged macrophages restored oxidative phosphorylation and homeostatic immune responses.</b> Thus, <b>KP-derived NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> operates as a metabolic switch to specify macrophage effector responses</b>. Breakdown of de novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> synthesis may underlie declining NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> levels and rising innate immune dysfunction in aging and age-associated diseases.</div>
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<span style="max-width: 100%;">References</span></h2>
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<div data-container-section="references" style="max-width: 100%;">
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<li data-test="citation" itemprop="citation" itemscope="itemscope" itemtype="http://schema.org/Article" style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;"><span style="max-width: 100%;">1.</span><div style="max-width: 100%;">
Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. <i style="max-width: 100%;">Immunity</i> <b style="max-width: 100%;">38</b>, 633–643 (2013).</div>
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<li data-test="ref_link" style="max-width: 100%;"><a aria-label="View reference 1 on CAS" data-track-action="outbound reference" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/cas-redirect/1%3ACAS%3A528%3ADC%252BC3sXmt1SltL8%253D" style="color: #416ed2; max-width: 100%;">CAS</a></li>
<li data-test="ref_link" style="max-width: 100%;"><a aria-label="View reference 1" data-track-action="outbound reference" data-track-category="article body" data-track-label="link" data-track="click" href="https://doi.org/10.1016%2Fj.immuni.2013.04.005" style="color: #416ed2; max-width: 100%;">Article</a></li>
<li style="max-width: 100%;"><a aria-label="Search for reference 1 on Google Scholar" data-track-action="outbound reference" data-track-category="article body" data-track-label="link" data-track="click" href="http://scholar.google.com/scholar_lookup?&title=Metabolic%20pathways%20in%20immune%20cell%20activation%20and%20quiescence&journal=Immunity&volume=38&pages=633-643&publication_year=2013&author=Pearce%2CEL&author=Pearce%2CEJ" style="color: #416ed2; max-width: 100%;">Google Scholar</a></li>
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Mills, E. L., Kelly, B. & O’Neill, L. A. J. Mitochondria are the powerhouses of immunity. <i style="max-width: 100%;">Nat. Immunol.</i> <b style="max-width: 100%;">18</b>, 488–498 (2017).</div>
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<li data-test="ref_link" style="max-width: 100%;"><a aria-label="View reference 2 on CAS" data-track-action="outbound reference" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/cas-redirect/1%3ACAS%3A528%3ADC%252BC2sXmtFKiu74%253D" style="color: #416ed2; max-width: 100%;">CAS</a></li>
<li data-test="ref_link" style="max-width: 100%;"><a aria-label="View reference 2" data-track-action="outbound reference" data-track-category="article body" data-track-label="link" data-track="click" href="https://doi.org/10.1038%2Fni.3704" style="color: #416ed2; max-width: 100%;">Article</a></li>
<li style="max-width: 100%;"><a aria-label="Search for reference 2 on Google Scholar" data-track-action="outbound reference" data-track-category="article body" data-track-label="link" data-track="click" href="http://scholar.google.com/scholar_lookup?&title=Mitochondria%20are%20the%20powerhouses%20of%20immunity&journal=Nat.%20Immunol.&volume=18&pages=488-498&publication_year=2017&author=Mills%2CEL&author=Kelly%2CB&author=O%E2%80%99Neill%2CLAJ" style="color: #416ed2; max-width: 100%;">Google Scholar</a></li>
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<li data-test="citation" itemprop="citation" itemscope="itemscope" itemtype="http://schema.org/Article" style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;"><span style="max-width: 100%;">3.</span><div style="max-width: 100%;">
Verdin, E. NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> in aging, metabolism, and neurodegeneration. <i style="max-width: 100%;">Science</i> <b style="max-width: 100%;">350</b>, 1208–1213 (2015).</div>
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<span style="max-width: 100%;">Acknowledgements</span></h2>
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This work was supported by grant no. RO1AG048232 (K.I.A.), grant no. RF1AG058047 (K.I.A.), grant no. 1P50 AG047366 (K.I.A.), Bright Focus (K.I.A.), The Paul and Daisy Soros Fellowship for New Americans (P.S.M.), the Gerald J. Lieberman Fellowship (P.S.M.), grant no. DP1DK113643 (L.L. and J.D.R.), grant no. 5U54DK10255603 (K.C., B.A.L., and M.P.S.), grant no. 5R01CA188055 (C.D. and R.M.), R37 AA11147 MERIT (A.J. and D.M.R.), the Takeda Pharmaceuticals’ Science Frontier Fund (D.M.R.), and grant no. 5T32HL094274 (M.C. and D.B.). The authors would like to thank L. Alexandrova at the Stanford University Mass Spectrometry Core, J. Perrino at the Stanford Microscopy Facility (supported by NIH grant no. 1S10RR02678001), and the Stanford Human Immune Monitoring Center. </div>
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Affiliations</h3>
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Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA</h4>
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<li style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;"> & Katrin I. Andreasson</li>
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Neurosciences Graduate Program, Stanford University, Stanford, CA, USA</h4>
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Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA</h4>
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Department of Chemistry, Princeton University, Princeton, NJ, USA</h4>
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Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA</h4>
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Department of Hematology, Stanford School of Medicine, Stanford, CA, USA</h4>
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Department of Genetics, Stanford School of Medicine, Stanford, CA, USA</h4>
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Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA</h4>
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Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA</h4>
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Stanford Neuroscience Institute, Stanford University, Stanford, CA, USA</h4>
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Stanford Immunology Program, Stanford University, Stanford, CA, USA</h4>
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Contributions</h3>
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P.S.M., L.L., P.K.M., A.U.J., C.D., S.M., Q.W., M.C., D.B., D.M.R., and R.M. designed and performed the experiments and analyzed the data and M.M. provided advice. K.C., B.A.L., and M.P.S. performed untargeted metabolomics and analyzed the data. L.L. and J.D.R. performed targeted metabolomics and quantification of isotope labeling. P.S.M. and K.I.A. conceived and supervised the project, designed the experiments, interpreted the data, and wrote the manuscript.</div>
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Competing interests</h3>
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The authors declare no competing interests.</div>
<h3 style="font-size: 1.25em; max-width: 100%;">
Corresponding author</h3>
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Correspondence to <a href="https://www.blogger.com/articles/s41590-018-0255-3/email/correspondent/c1/new" rel="nofollow" style="color: #416ed2; max-width: 100%;">Katrin I. Andreasson</a>.</div>
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<h2 style="font-size: 1.43em; max-width: 100%;">
<span style="max-width: 100%;">Integrated supplementary information</span></h2>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/9" style="color: #416ed2; max-width: 100%;">Supplementary Figure 1 Effects of the NAMPT inhibitor FK866 and KYN supplementation.</a></h3>
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HuMDMs were treated with either vehicle or FK866 (10 μM, 20 h) and were supplemented with either vehicle or KYN (25 μM, 20 h). <b style="max-width: 100%;">a</b>, Representative western blot of NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> synthetic enzymes NMNAT1 and NADS and NAMPT; <i style="max-width: 100%;">n</i> = 3 per group, shown as mean ± S.E. with protein levels normalized to β-actin; non-significance determined by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">b</b>, Administration of NMN to FK866-treated huMDMs restores NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> levels, as measured by LC/MS; <i style="max-width: 100%;">n</i> = 6 per group, represented as mean ± S.E., two-way ANOVA: effects of NMN and FK866, <i style="max-width: 100%;">P</i> < 0.0001 with Tukey post hoc test: ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">c</b>, LC/MS measurements of QA, NaMN, NaAD; <i style="max-width: 100%;">n</i> = 6 per group, represented as mean ± S.E.; two-way ANOVA, for QA effect of KYN, <i style="max-width: 100%;">P</i> < 0.0001; for NaMN, effects of KYN and FK866, <i style="max-width: 100%;">P</i> < 0.0001; for NaAD, effects of KYN and FK866, <i style="max-width: 100%;">P</i> < 0.001; Tukey post hoc tests: ***<i style="max-width: 100%;">P</i> = 0.0001 QA: veh-veh versus KYN-veh; ***<i style="max-width: 100%;">P</i> = 0.0002 QA: veh-FK866 versus KYB-FK866; ****<i style="max-width: 100%;">P</i> < 0.0001 NaMN: veh-veh versus KYN-veh; <sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">####</sup><i style="max-width: 100%;">P</i> < 0.0001 KYN-veh versus KYN-FK866; ***<i style="max-width: 100%;">P</i> = 0.0002 NaAD: veh-veh versus KYN-veh; <sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">###</sup><i style="max-width: 100%;">P</i> = 0.0002 NaAD: KYN-veh versus KYN-FK866. <b style="max-width: 100%;">d</b>, Reaction mechanism for isotope labeling of KYN to generate <i style="max-width: 100%;">M</i>+2 de novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>.</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/10" style="color: #416ed2; max-width: 100%;">Supplementary Figure 2 Effects of the NAMPT inhibitor FK866 and KYN supplementation.</a></h3>
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<b style="max-width: 100%;">a</b>, Diagram of the site of action of 1MT and phthalic acid (PTH), selective inhibitors of IDO1 and QPRT, respectively. <b style="max-width: 100%;">b</b>, Representative flow cytometry plot from three independent experiments of cells treated for 20 h with either vehicle, 1MT (200 μM), or pthalic acid (PTH, 500 μM) stained with propidium iodide (<i style="max-width: 100%;">n</i> = 25,000–30,000 cells per group). <b style="max-width: 100%;">c</b>, Gating strategy for huMDMs. <b style="max-width: 100%;">d</b>–<b style="max-width: 100%;">h</b>, HuMDMs were treated with the IDO1 inhibitor 1MT (200 μM, 20 h). <b style="max-width: 100%;">d</b>, LC/MS measurement of NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, shown as mean ± S.E.; *<i style="max-width: 100%;">P</i> = 0.0233 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">e</b>, Representative trace from three independent experiments for effect of 1MT on OCR, <i style="max-width: 100%;">n</i> = 10 biologically independent samples/group, shown mean ± S.E. <b style="max-width: 100%;">f</b>, Effects of 1MT on basal respiration, maximal respiration, and spare respiratory capacity; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, shown as mean ± S.E.; ***<i style="max-width: 100%;">P</i> = 0.0004 for basal respiration, ***<i style="max-width: 100%;">P</i> = 0.0006 for maximal respiration, and **<i style="max-width: 100%;">P =</i> 0.0087 for spare respiratory capacity by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">g</b>, Effect of 1MT on ECAR; <i style="max-width: 100%;">n</i> = 3 biologically independent samples/group, mean ± S.E.; *<i style="max-width: 100%;">P</i> = 0.0411 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">h</b>, Peritoneal macrophages from WT and <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> mice were supplemented with either vehicle or 25 μM KYN for 20 h and assayed for spare respiratory capacity and maximal respiration; <i style="max-width: 100%;">n</i> = 6 biologically independent samples per WT group and <i style="max-width: 100%;">n</i> = 9 biologically independent samples per <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> group, represented as mean ± S.E.; two-way ANOVA, effect of genotype <i style="max-width: 100%;">P</i> < 0.0001 for both, effect of KYN <i style="max-width: 100%;">P</i> < 0.05 and <i style="max-width: 100%;">P</i> < 0.0001 for spare respiratory capacity and max respiration, respectively; Tukey post hoc ***<i style="max-width: 100%;">P</i> = 0.0001, *<i style="max-width: 100%;">P</i> = 0.0200, and ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">i</b>, Permeabilized macrophages from WT and <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> mice were stimulated with complex-specific substrates, including pyruvate + malate for assessing complex I, succinate + rotenone for complex II, duroquinol for complex III, and TMPD + ascorbate for complex IV. Data are represented as mean ± S.E.; <i style="max-width: 100%;">n</i> = 8 biologically independent samples per group; ****<i style="max-width: 100%;">P</i> < 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test.</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/11" style="color: #416ed2; max-width: 100%;">Supplementary Figure 3 Untargeted metabolomic profiling of WT and <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> macrophages.</a></h3>
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<b style="max-width: 100%;">a</b>, Hierarchical clustering of validated and significantly altered metabolites (<i style="max-width: 100%;">q</i> < 0.05) are represented. <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> macrophages show disrupted amino acid metabolism and lipid metabolism and increased glycolysis (<i style="max-width: 100%;">n</i> = 8 mice per group, two-tailed parametric Welch’s <i style="max-width: 100%;">T</i>-test with multiple-hypothesis <i style="max-width: 100%;">q</i>-value correction. FDR < 0.05 was considered significant). <b style="max-width: 100%;">b</b>, MBROLE enrichment analysis of untargeted metabolomics from comparison of <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> versus WT macrophages (<i style="max-width: 100%;">n</i> = 8 per genotype).</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/12" style="color: #416ed2; max-width: 100%;">Supplementary Figure 4 Inhibition of QPRT disrupts oxidative phosphorylation and cellular metabolism.</a></h3>
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<b style="max-width: 100%;">a</b>–<b style="max-width: 100%;">e</b>, HuMDMs were treated with vehicle or the QPRT inhibitor phthalic acid (PTH; 500 μM, 20 h). <b style="max-width: 100%;">a</b>, LC/MS of NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> with PTH treatment; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, shown as mean ± S.E.; **<i style="max-width: 100%;">P</i> = 0.0048 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">b</b>, Representative trace of PTH-treated huMDMs. <b style="max-width: 100%;">c</b>, Basal respiration, maximal respiration, and spare respiratory capacity in PTH-treated huMDMs; <i style="max-width: 100%;">n</i> = 4 biologically independent samples per group, shown as mean ± S.E; Basal respiration: **<i style="max-width: 100%;">P</i> = 0.0023; maximal respiration **<i style="max-width: 100%;">P</i> = 0.0019; spare respiratory capacity: **<i style="max-width: 100%;">P</i> = 0.0089; all by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">d</b>, ECAR in PTH-treated huMDMs; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, *<i style="max-width: 100%;">P</i> < 0.05. <b style="max-width: 100%;">e</b>, Hierarchical clustering of targeted metabolomics for glycolysis, pentose phosphate pathway, and citric acid cycle metabolites of huMDMs treated with PTH (500 μM, 20 h; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group). <b style="max-width: 100%;">f</b>, Targeted metabolomics from <b style="max-width: 100%;">e</b> with PTH-treated huMDMs reveals an upregulation of lactate, the pentose phosphate pathway and proinflammatory TCA intermediates (in red), similar to changes seen in <i style="max-width: 100%;">Qprt</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> macrophages. <b style="max-width: 100%;">g</b>, Metabolism of <sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">13</sup>C[TRP] to NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> yields M+6–labeled NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>.</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/13" style="color: #416ed2; max-width: 100%;">Supplementary Figure 5 Effects of de novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> synthesis on macrophage polarization.</a></h3>
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<b style="max-width: 100%;">a</b>, Representative histograms of three independent experiments for surface markers in huMDMs stimulated with LPS and phthalic acid (PTH). <b style="max-width: 100%;">b</b>, Complex I inhibitors rotenone and piericidin A (500 nM, 20 h) in huMDMs mimic the effect of QPRT inhibition (<i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, three independent flow experiments, represented as mean ± S.E.; **<i style="max-width: 100%;">P</i> < 0.01, ***<i style="max-width: 100%;">P</i> < 0.001. ****<i style="max-width: 100%;">P</i> < 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">c</b>, Hierarchical clustering of immune factors in huMDMs treated with either vehicle or piericidin A (500 nM, 20 h). <b style="max-width: 100%;">d</b>, Quantification of <b style="max-width: 100%;">c</b>. Significantly regulated immune factors in huMDMs stimulated with PTH and/or LPS, <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, represented as mean ± S.E.</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/14" style="color: #416ed2; max-width: 100%;">Supplementary Figure 6 Effect of LPS on OXPHOS, the KP, and complex activities.</a></h3>
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<b style="max-width: 100%;">a</b>, Macrophages from WT and <i style="max-width: 100%;">Ido1</i><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">–/–</sup> mice supplemented ± NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> (2 mM) and assayed for Sirt3 steady-state kinetics (<i style="max-width: 100%;">n</i> = 4 biologically independent samples/group, mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001 by linear regression analysis; curved thin lines denote 95% CI). <b style="max-width: 100%;">b</b>, Macrophages from huMDMs treated ± phthalic acid (PTH) (500 μM, 20 h) were supplemented ± NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> (2 mM) and assayed for Sirt3 steady-state kinetics (<i style="max-width: 100%;">n</i> = 4 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001 by linear regression analysis; curved thin lines denote 95% CI). <b style="max-width: 100%;">c</b>, Quantitative immunoblot of Sirt3 levels in huMDMs ± PTH (500 μM, 20 h), normalized to actin (<i style="max-width: 100%;">n</i> = 6 biologically independent samples per group, represented as mean ± S.E.; non-significance determined by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">d</b>, OCR trace for huMDMs treated with either LPS (100 ng/mL) or vehicle for 20 h. <b style="max-width: 100%;">e</b>, Basal respiration in huMDMs following LPS (<i style="max-width: 100%;">n</i> = 5 biologically independent samples per veh group, <i style="max-width: 100%;">n</i> = 6 biologically independent samples per LPS group, represented as mean ± S.E.; **<i style="max-width: 100%;">P</i> < 0.01 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">f</b>, ECAR in huMDMs (<i style="max-width: 100%;">n =</i> 9 biologically independent samples/group, mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">g</b>, Changes in KP enzyme levels by quantitative western analysis are observed by 4 h after LPS challenge in huMDMs (<i style="max-width: 100%;">n</i> = 8 biologically independent samples per veh group, <i style="max-width: 100%;">n</i> = 9 biologically independent samples per LPS group, represented as mean ± S.E.; **<i style="max-width: 100%;">P</i> < 0.01 and *<i style="max-width: 100%;">P</i> < 0.05 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">h</b>, Increases in KP metabolites are observed by 4 h after LPS challenge in huMDMs (<i style="max-width: 100%;">n</i> = 5 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001, ***<i style="max-width: 100%;">P</i> < 0.001, **<i style="max-width: 100%;">P</i> < 0.01, and *<i style="max-width: 100%;">P</i> < 0.05 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">i</b>, Permeabilized huMDMs ± LPS (100 ng/mL) were stimulated with complex-specific substrates, including pyruvate + malate for assessing complex I, succinate + rotenone for complex II, duroquinol for complex III, and TMPD + ascorbate for complex IV (<i style="max-width: 100%;">n</i> = 8 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">j</b>, OCR trace for huMDMs transfected with either GFP control vector or QPRT vector, stimulated with LPS (100 ng/mL) and assayed at 20 h (<i style="max-width: 100%;">n</i> = 6 biologically independent samples per group, represented as mean ± S.E.). <b style="max-width: 100%;">k</b>, Maximal respiration and spare respiratory capacity of control- and QPRT-transfected huMDMs ± LPS (<i style="max-width: 100%;">n</i> = 6 biologically independent samples per group, represented as mean ± S.E.; two-way ANOVA, effect of QPRT <i style="max-width: 100%;">P</i> < 0.0001 and <i style="max-width: 100%;">P</i> < 0.01 for maximal respiration and spare respiratory capacity, respectively; effect of LPS <i style="max-width: 100%;">P</i> < 0.01 for maximal respiration; Tukey post hoc test: <i style="max-width: 100%;">*P</i> < 0.05, **<i style="max-width: 100%;">P</i> < 0.01, ****<i style="max-width: 100%;">P</i> < 0.0001).</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/15" style="color: #416ed2; max-width: 100%;">Supplementary Figure 7 Overexpression of QPRT rescues metabolic changes induced by LPS in huMDMs.</a></h3>
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Untargeted metabolomics analysis was carried out on huMDMs ± LPS transfected with either GFP control vector or QPRT vector. <b style="max-width: 100%;">a</b>, Hierarchical clustering of significant validated metabolites is shown (<i style="max-width: 100%;">q</i> < 0.05 by Student’s two-tailed t test with FDR correction for multiple hypotheses; see <a data-track-action="section anchor" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3#Sec12" style="color: #416ed2; max-width: 100%;">Methods</a>). Hierarchical clustering reveals rescue of altered amino acid, fatty acid, nucleotide, and glucose metabolism with QPRT overexpression in LPS-stimulated huMDMs (<i style="max-width: 100%;">n</i> = 6 biologically independent samples per the con + LPS and con + veh groups, <i style="max-width: 100%;">n</i> = 4 biologically independent samples per group for all others). <b style="max-width: 100%;">b</b>, Principal-component analysis of <b style="max-width: 100%;">a;</b> untargeted metabolomics shows separation of LPS-treated control huMDMs from the QPRT + veh, QPRT + LPS, and con + veh groups (<i style="max-width: 100%;">n</i> = 6 biologically independent samples per the con + LPS and con + veh groups, <i style="max-width: 100%;">n</i> = 4 biologically independent samples per group for all others). <b style="max-width: 100%;">c</b>, Enrichment of KEGG pathways (<i style="max-width: 100%;">n</i> = 6 biologically independent samples per the con + LPS and con + veh groups, <i style="max-width: 100%;">n</i> = 4 biologically independent samples per group for all others).</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/16" style="color: #416ed2; max-width: 100%;">Supplementary Figure 8 Effect of increased de novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> on immune factor generation in LPS-stimulated macrophages.</a></h3>
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HuMDMs transfected with either GFP control vector or QPRT vector were stimulated with LPS for 20 h. <b style="max-width: 100%;">a</b>, Representative BN-PAGE from three independent experiments. <b style="max-width: 100%;">b</b>, Permeabilized huMDMs ± LPS were stimulated with complex-specific substrates (<i style="max-width: 100%;">n</i> = 8 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test). <b style="max-width: 100%;">c</b>, Representative immunoblot from two independent experiments of SOD2, Ac-SOD2, and COXIV loading control. <b style="max-width: 100%;">d</b>, Comparison of proinflammatory (in red) and anti-inflammatory (in green) factors that are upregulated and downregulated by QPRT inhibition with phthalic acid (PTH) versus QPRT overexpression under basal conditions (left) and LPS-stimulated conditions (right). Note the similarity of subsets of the pro- and anti-inflammatory factors and reciprocal regulation in control versus experimental conditions. <b style="max-width: 100%;">e</b>, Representative immune factors regulated by QPRT overexpression in huMDMs ± LPS (<i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, represented as mean ± S.E.).</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/17" style="color: #416ed2; max-width: 100%;">Supplementary Figure 9 De novo NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> synthesis regulates mitochondrial respiration and polarization state in aged macrophages.</a></h3>
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Young and aged huMDMs were derived from human subjects ≤35 and ≥65 years old, respectively. <b style="max-width: 100%;">a</b>, qPCR of the telomere length of young versus aged macrophages (<i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, mean ± S.E.; **<i style="max-width: 100%;">P</i> = 0.0046 by Student’s two-tailed <i style="max-width: 100%;">t</i> test)<b style="max-width: 100%;">. b</b>, Representative immunoblots from three independent experiments for all KP enzymes demonstrates loss of QPRT expression in aged macrophages as compared to young macrophages<b style="max-width: 100%;">. c</b>, Mean fluorescence intensities (MFI) increase for proinflammatory markers CD86 and CD64 and decrease for anti-inflammatory markers CD206 and CD23 in aged versus young huMDMs ± LPS; <i style="max-width: 100%;">n</i> = 3 biologically independents samples per group, represented as mean ± S.E.; two-way ANOVA: effects of age and LPS, <i style="max-width: 100%;">P</i> < 0.0001 for all four surface markers; Tukey post hoc test ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">d</b>–<b style="max-width: 100%;">i</b>, Young and aged huMDMs were transfected with either control vector (con) or QPRT vector (QPRT). <b style="max-width: 100%;">d</b>, Top, representative immunoblot from two independent experiments of huMDMs derived from young and aged subjects transfected with control or QPRT vectors. Bottom, quantification of changes in QPRT protein levels; <i style="max-width: 100%;">n</i> = 3 biologically independent samples/group, mean ± S.E.; two-way ANOVA, effects of age and QPRT <i style="max-width: 100%;">P</i> < 0.0001; Tukey post hoc test ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">e</b>, QPRT overexpression increases metabolism of QA to NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> and restores NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup> levels in aged macrophages to those of young huMDMs; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, represented as mean ± S.E.; two-way ANOVA, effect of age and QPRT for QA, <i style="max-width: 100%;">P</i> < 0.0001; two-way ANOVA, effect of age and QPRT for NAD<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">+</sup>, <i style="max-width: 100%;">P</i> < 0.01; Tukey post hoc test ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">f</b>, OCR trace for young and aged control or QPRT-expressing huMDMs; <i style="max-width: 100%;">n</i> = 3 biologically independent samples per group, mean ± s.d. <b style="max-width: 100%;">g</b>, Basal respiration and ECAR in aged control and QPRT-expressing huMDMs; <i style="max-width: 100%;">n</i> = 2 biologically independent samples per con group, <i style="max-width: 100%;">n</i> = 3 biologically independent samples per QPRT-OE group, mean ± s.d.; *<i style="max-width: 100%;">P</i> = 0.034 and ***<i style="max-width: 100%;">P</i> = 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">h</b>, Top, representative BN-PAGE of complex II activity in young and aged huMDMs transfected with either control or QPRT vectors. Bottom, quantification of complex II activity; <i style="max-width: 100%;">n</i> = 6 biologically independent samples per group, mean ± S.E.; two-way ANOVA, effect of age and QPRT, <i style="max-width: 100%;">P</i> < 0.0001; Tukey post-hoc test, ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">i</b>, Left, representative 2D SDS immunoblot from two independent experiments of complex II in young and aged huMDMs ±, assayed for acetyl-lysine immunoreactivity. Right, quantification of acyl-lysines in complex II; <i style="max-width: 100%;">n</i> = 6 biologically independent samples/group, mean ± S.E.; two-way ANOVA, effects of age and QPRT, <i style="max-width: 100%;">P</i> < 0.0001; Tukey post hoc test ****<i style="max-width: 100%;">P</i> < 0.0001. <b style="max-width: 100%;">j</b>, MFI of huMDMs treated with the complex II inhibitor dimethyl malonate (DMM, 1 mM, 20 h); <i style="max-width: 100%;">n</i> = 3 biologically independent samples/group, mean ± S.E.; CD86 **<i style="max-width: 100%;">P</i> = 0.0083, CD64 ***<i style="max-width: 100%;">P</i> = 0.0003, CD206 ***P = 0.0005, CD23 **<i style="max-width: 100%;">P</i> = 0.0022 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">k</b>, Cytokine/chemokine profiles of culture medium from huMDMs stimulated with DMM (1 mM, 20 h). <b style="max-width: 100%;">l</b>, Representative histograms from three independent experiments of young and aged huMDMs supplemented with NMN (10 μM, 20 h).</div>
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<a data-track-action="view supplementary info" data-track-category="article body" data-track-label="link" data-track="click" href="https://www.blogger.com/articles/s41590-018-0255-3/figures/18" style="color: #416ed2; max-width: 100%;">Supplementary Figure 10 Mitochondrial respiration decreases in aged mouse macrophages.</a></h3>
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Primary peritoneal macrophages from young (3 month) and aged (16–20 month) mice were examined for mitochondrial respiration, complex activity, and mitochondrial sirtuin steady-state kinetics. <b style="max-width: 100%;">a</b>, Real-time changes in OCR in young versus aged primary macrophages (<i style="max-width: 100%;">n</i> = 10 biologically independent samples per group). <b style="max-width: 100%;">b</b>, Quantification of basal respiration and extracellular acidification rate (ECAR); <i style="max-width: 100%;">n</i> = 10 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P</i> < 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">c</b>, Left, representative BN-PAGE from three independent experiments of complex activities in young versus aged mouse primary macrophages. Right, quantification demonstrates reduced complex I and complex II activities, <i style="max-width: 100%;">n</i> = 6 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P <</i> 0.0001 by Student’s two-tailed <i style="max-width: 100%;">t</i> test. <b style="max-width: 100%;">d</b>, Young and aged mouse macrophages were assayed for mitochondrial Sirt3 steady-state kinetics; <i style="max-width: 100%;">n</i> = 4 biologically independent samples per group, represented as mean ± S.E.; ****<i style="max-width: 100%;">P <</i> 0.0001 by linear regression analysis; curved thin lines denote 95% CI.</div>
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<div dir="ltr" id="AppleMailSignature" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-75678192650252011732019-01-30T04:52:00.000-08:002019-01-30T04:52:55.328-08:00Insulin Resistance Syndrome Drives Osteoarthritis and All Degenerative Diseases of Aging<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Epigenetic change promotes osteoarthritis. (And all degenerative diseases of aging)</div>
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Drivers?</div>
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Leaky gut.</div>
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Methylation.</div>
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Histone acetylation.</div>
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Decreased Nrf2 (<b>lack of BHB</b>)</div>
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BHB beta hydroxybutyrate is a Nrf2 activator and histone deacetylase inhibitor.</div>
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Obesity, diabetes skewed toward osteoarthritis.</div>
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<b>IRS is an OBESITY PROXY.</b></div>
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<b>Healthy gut, keto diet, Mediterranean Nrf2 supplements should reduce osteoarthritis.</b></div>
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<br /></div>
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Atherosclerosis is promoted by inflammation.</div>
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Osteoarthritis is promoted by inflammation.</div>
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<a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28020">https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28020</a></div>
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Epigenetics in osteoarthritis: Novel spotlight - Fathollahi - - Journal of Cellular Physiology - Wiley Online Library</h1>
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Osteoarthritis (OA) is the most common type of arthritis and no longer is considered as an absolute consequence of joint mechanical use (wear and tear); rather recent data demonstrate the <b>pivotal role of inflammatory mediators in the development and progression of this disease</b>. This multifactorial disease results from several environmental and inherited factors. Genetic cannot solely explain all the contribution share of inheritance and, this way, it is speculated that <b>epigenetics can play a role</b>, too. Moreover, environmental factors can induce local epigenetic changes. The epigenetic contribution to OA pathogenesis occurs at all of its levels, <b>DNA methylation, histone modification</b>, microRNA, and long noncoding RNA. In fact, during early phases of OA pathogenesis, environmental factors employ <b>epigenetic mechanisms to provide a positive feedback for the OA</b>‐related pathogenic mechanisms and pathways with an ultimate outcome of a well‐established clinical OA. These epigenetic changes stay during clinical disease and <b>prevent the body natural healing and regenerative processes to work properly</b>, resulting in an incurable disease condition. In this review article, we aimed to have an overview on the studies performed with regard to understanding the role of epigenetics in the etiopathogenesis of OA and highlighted the importance of such kind of regulatory mechanisms within this context.</div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-35270174714605931512019-01-26T05:09:00.000-08:002019-01-26T05:09:34.076-08:00How Anti-aging of Ovaries (and Testes) Informs Longevity and Health<div dir="ltr" style="-webkit-text-size-adjust: auto; font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Melatonin reduces oxidative stress that crosstalks with the other factors of ovarian aging.</div>
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Ovaries (and testes) age in advance of the organism.</div>
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Therefore, what slows gonadal aging SLOWS ALL AGING.</div>
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Interestingly, PCOS polycystic ovarian system (4% of women) is associated with both premature ovarian aging and insulin resistance syndrome.</div>
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INSULIN RESISTANCE SYNDROME is the root cause of DEGENERATIVE OXIDATIVE AUTOIMMUNE DISEASES.</div>
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Insulin resistance is the root cause of oxidative stress and premature aging.</div>
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Calorie restriction (fat consumption for energy) reverses many of the listed factors of ovarian (organisms) aging.</div>
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Why?</div>
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Clean burning triglyceride reduces oxidative stress and improves the other listed aging factors below.</div>
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Fasting is cleaner than ketodiet.</div>
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Ketodiet is cleaner than western diet.</div>
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Western diet with (nrf2 activators, molecular hydrogen, magnesium and spermidine-wheat germ) is cleaner than western diet sans supplement.</div>
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Sulforaphane (nrf2 driver) and Spermidine in yeast, C elegans worms, fruit flies, mice and human cell cultures prolong healthspan and lifespan (slow aging).</div>
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The lean athletic individual on ketodiet, melatonin, <span style="background-color: rgba(255, 255, 255, 0);">nrf2 activators, molecular hydrogen, magnesium and spermidine-wheat germ MAY SLOW AGING.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">A proxy test for this hypothesis is delayed menopause and delayed andropause in the intermediate term.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">A short term proof might be restoring fertility in PCOS.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Ketodiet in PCOS associated infertility reverses insulin resistance syndrome and improves fertility rates.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Melatonin also reverses insulin resistance syndrome effects and improves fertility rates.</span></div>
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<span style="font-size: 12pt;">Melatonin as Potential Targets for Delaying Ovarian Aging: Ingenta Connect</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">In previous studies, oxidative stress damage has been solely considered to be the mechanism of ovarian aging, and several antioxidants have been used to delay ovarian aging. But recently, more <b>reports have found that endoplasmic reticulum stress, autophagy, sirtuins, mitochondrial dysfunction, telomeres, gene mutation, premature ovarian failure, and polycystic ovary syndrome are all closely related to ovarian agin</b>g, and these factors <b>all interact with oxidative stress</b>. These novel insights on ovarian aging are summarized in this review. Furthermore, as a <b>pleiotropic molecule, melatonin is an important antioxidant</b> and used as drugs for several diseases treatment. Melatonin regulates not only oxidative stress, but also the various molecules, and normal and pathological processes interact with ovarian functions and aging. Hence, the mechanism of ovarian aging and the extensive role of melatonin in the ovarian aging process are described herein. This systematic review supply <b>new insights into ovarian aging and the use of melatonin to delay its onset</b>, further supply a novel drug of melatonin for ovarian aging treatment.</span></div>
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<br /><a href="https://www.ingentaconnect.com/contentone/ben/cdt/2019/00000020/00000001/art00003">https://www.ingentaconnect.com/contentone/ben/cdt/2019/00000020/00000001/art00003</a></div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-78646381946878337992019-01-24T04:49:00.000-08:002019-01-24T04:49:59.270-08:00Autophagy for cells, kidneys and personal health and longevity<div class="original-url" style="-webkit-text-size-adjust: auto;">
Renal protection and renal recovery depends on the Trinity following:</div>
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1. Reduced oxidative stress or increased antioxidant enzyme capacity. (Nrf2 2 activators.)</div>
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2. Reduced neuroimmune stress, (vagal activation of cholinergic anti inflammatory pathway, repair of leaky gut with homemade yogurt.)</div>
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3. Autophagy.</div>
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Autophagy promoters include the following:</div>
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1. Fat burning producing beta hydroxybutyrate ( ketodiet, fasting, lactate producing exercise.)</div>
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2. Spermidine (2 tablespoons of wheat germ daily.)</div>
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3. Sulforaphane (Broccoli sprouts or other Nrf2 activation, H2, melatonin, Mediterranean diet.)</div>
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I was impressed by Wu and Wang in this review on autophagy and chronic kidney disease. The renal protective and recovery factors listed for acute and chronic kidney disease is congruent with renal recovery which depends on,at least, the Trinity of factors above. All three factors should be synergistic and protective. </div>
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Every aging kidney would benefit. So would every aging cell.</div>
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<br /><a href="https://www.mdpi.com/2073-4409/8/1/61/htm">https://www.mdpi.com/2073-4409/8/1/61/htm</a><br /></div>
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<h1 class="title" style="font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
Autophagy in Chronic Kidney Diseases</h1>
<div class="metadata singleline" style="margin-bottom: 1.45em; margin-top: -0.75em; max-width: 100%;">
<a class="byline" href="https://www.blogger.com/search?authors=Tien-An%20Lin&orcid=0000-0001-6036-6635" itemprop="author" style="color: #416ed2; display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;">Tien-An Lin</a></div>
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<i style="max-width: 100%;">Cells</i> <b style="max-width: 100%;">2019</b>, <i style="max-width: 100%;">8</i>(1), 61; doi:</div>
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Review</div>
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<span style="max-width: 100%;"><a href="https://www.blogger.com/search?authors=Victor%20%20Chien-Chia%20Wu&orcid=0000-0002-9918-4369" itemprop="author" style="color: #416ed2; max-width: 100%;">Victor Chien-Chia Wu</a><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;"> 2</sup><a data-author-id="1593407" href="mailto:please_login" style="color: #416ed2; max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;"><i style="max-width: 100%;"></i></sup></a><a href="https://orcid.org/0000-0002-9918-4369" style="color: #416ed2; max-width: 100%;" target="_blank"><img class="reader-image-tiny" data-cfsrc="https://www.mdpi.com/img/design/orcid.png?1b5ed457ed71c59e" data-cfstyle="position: relative; width: 13px; margin-left: 3px; max-width: 13px !important; height: auto; top: -5px;" src="https://www.mdpi.com/img/design/orcid.png?1b5ed457ed71c59e" style="display: inline; height: auto; margin: 0px; max-width: 100%;" title="OrcID" /></a> and </span><span style="max-width: 100%;"><a href="https://www.blogger.com/search?authors=Chao-Yung%20Wang&orcid=" itemprop="author" style="color: #416ed2; max-width: 100%;">Chao-Yung Wang</a><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;"> 2,3,</sup>*<a data-author-id="1593408" href="mailto:please_login" style="color: #416ed2; max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;"><i style="max-width: 100%;"></i></sup></a></span></div>
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<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">1</sup></div>
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Department of General Surgery, Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan</div>
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<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sup></div>
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Department of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan City 333, Taiwan</div>
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<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">3</sup></div>
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Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan</div>
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<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">*</sup></div>
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Author to whom correspondence should be addressed. </div>
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Received: 8 December 2018 / Accepted: 9 January 2019 / Published: 16 January 2019</div>
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Abstract</h2>
<b style="max-width: 100%;">:</b><div style="max-width: 100%;">
Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins. Current evidence suggests that autophagy is critical in kidney physiology and homeostasis. In clinical studies, autophagy activations and inhibitions are linked to acute kidney injuries, chronic kidney diseases, diabetic nephropathies, and polycystic kidney diseases. Oxidative stress, inflammation, and mitochondrial dysfunction, which are implicated as important mechanisms underlying many kidney diseases, modulate the autophagy activation and inhibition and lead to cellular recycling dysfunction. Abnormal autophagy function can induce loss of podocytes, damage proximal tubular cells, and glomerulosclerosis. After acute kidney injuries, activated autophagy protects tubular cells from apoptosis and enhances cellular regeneration. Patients with chronic kidney diseases have impaired autophagy that cannot be reversed by hemodialysis. Multiple nephrotoxic medications also alter the autophagy signaling, by which the mechanistic insights of the drugs are revealed, thus providing the unique opportunity to manage the nephrotoxicity of these drugs. In this review, we summarize the current concepts of autophagy and its molecular aspects in different kidney cells pathophysiology. We also discuss the current evidence of autophagy in acute kidney injury, chronic kidney disease, toxic effects of drugs, and aging kidneys. In addition, we examine therapeutic possibilities targeting the autophagy system in kidney diseases.</div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-42697636846892919192019-01-19T07:34:00.000-08:002019-01-19T07:34:53.392-08:00Healthspan and Lifespan is Determined by Redox Chemistry Cellular Homeostasis<div class="original-url" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
<h2 style="max-width: 100%;">
<span style="font-size: small;">Thioredoxin/TXNIP ratio may be the servocontrol or lynchpin of redox homeostasis. Intermittent fasting, Nrf2 activation, keto diet and molecular hydrogen H2 allow restoration of Thioredoxin CAPACITY to signal rapid transcription and post translation modification changes that prevent oxidative damage and senescent or apoptotic changes.</span></h2>
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<span style="font-size: small;">Diabetes or insulin resistance results from lowered ratio of Thioredoxin/TXNIP.</span></div>
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<span style="font-size: small;">Insulin resistance syndrome is the root cause of virtually all degenerative diseases.</span></div>
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<span style="font-size: small;">Because of the lower respiratory quotient of triglyceride versus carbohydrate (0.7 versus 0.95), ketogenic diets restore health and resilience for 2/3 of adult patients in early adulthood and speculative every aged person.</span></div>
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<span style="font-size: small;"><br /></span></div>
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<span style="font-size: small;">Aging reduces proteostasis which reduces redox signaling which causes degenerative changes. Spermidine (wheat germ) uniquely improves proteostasis by virtue of its spermidine content.</span></div>
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);"><br /></span></span></h2>
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);">4. Conclusions and Future Directions</span></span></h2>
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<span style="background-color: rgba(255, 255, 255, 0);">Binding to target DNA and triggering the expression of gene transcription involved in essential biological pathways, transcription factors are integral players in the proper cellular and organismal function and survival. Any <b>dysregulation or dysfunction in a transcription factor can lead to a broad range of diseases including cancer, autoimmune disease, cardiovascular disease, neurological disease, and diabetes </b><span class="converted-anchor" style="max-width: 100%;">[108]</span>. <b>Maintenance of ROS levels is essential for organismal well-being and are controlled by enzymatic and non-enzymatic antioxidant defenses that scavenge oxidative aggression. </b>ROS induce PTMs on protein thiols which in turn calibrate protein activities towards an adequate cellular response. Here we discussed the role of PTMs in regulating oxidative stress-responsive TFs. We described TFs that are participating in rapid redox reaction such as inter-disulfide exchange, that way titrating a response to changing redox level. As depicted in <span class="converted-anchor" style="max-width: 100%;">Fig. 5</span>, PRDX1, as well as PRDX2, perform such relay function with FOXO3 and STAT3, respectively. Given the requirement of reducible disulfide bridges in the relay partners, it is <b>conceivable to assume that with a rise in H<sub style="line-height: 1; max-width: 100%;">2</sub>O<sub style="line-height: 1; max-width: 100%;">2</sub> levels, the relay is shut off due to non-reducible thiol modifications that prohibit further regulation of TFs by redoxins</b>. The high-affinity redoxins have for ROS may be the key to this mechanism. For example, the rate constant for reactions between H<sub style="line-height: 1; max-width: 100%;">2</sub>O<sub style="line-height: 1; max-width: 100%;">2</sub> and PRDXs ranges between 3.0 x 10<sup style="line-height: 1; max-width: 100%;">5</sup> – 1.0 x 10<sup style="line-height: 1; max-width: 100%;">8</sup> (M<sup style="line-height: 1; max-width: 100%;">-1</sup>s<sup style="line-height: 1; max-width: 100%;">-1</sup>) <span class="converted-anchor" style="max-width: 100%;">[109]</span>, <span class="converted-anchor" style="max-width: 100%;">[110]</span>, in times of stress when H<sub style="line-height: 1; max-width: 100%;">2</sub>O<sub style="line-height: 1; max-width: 100%;">2</sub> levels are high, a PRDX can quickly scavenge the H<sub style="line-height: 1; max-width: 100%;">2</sub>O<sub style="line-height: 1; max-width: 100%;">2</sub>, becoming oxidized, and in turn can promptly oxidize a target transcription factor. Depending on the manner in which the transcription factor is regulated that is activation or inactivation, this fast action can result in the fact up-regulation or down-regulation of target genes that may be key in to the stress response or reestablishing redox homeostasis. The <b>redoxin-driven regulatory pathways may be critical sensors able to differentiate systems operating in a healthy state from systems affected by oxidative stress</b>. By gaining a deeper understanding of the various mechanisms by which signaling during oxidative stress affects TF activity will provide a better understanding of disease pathologies related to disturbed redox homeostasis, such as cancer and neurodegenerative condition</span></div>
<a href="https://www.sciencedirect.com/science/article/pii/S2213231718307055">https://www.sciencedirect.com/science/article/pii/S2213231718307055</a><br /></div>
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<h1 class="title" style="font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
Redoxins as gatekeepers of the transcriptional oxidative stress response</h1>
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<span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Barbara L.</span><span style="max-width: 100%;">Hopkins</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">a</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">c</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">d</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Carola A.</span><span style="max-width: 100%;">Neumann</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">b</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">c</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">d</sup></span></span></span></div>
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<h2 style="font-size: 1.43em; max-width: 100%;">
Abstract</h2>
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Transcription factors control the rate of transcription of genetic information from DNA to messenger RNA, by binding specific DNA sequences in promoter regions. Transcriptional gene control is a rate-limiting process that is tightly regulated and based on transient environmental signals which are translated into long-term changes in gene transcription. Post-translational modifications (PTMs) on transcription factors by phosphorylation or acetylation have profound effects not only on sub-cellular localization but also on substrate specificity through changes in DNA binding capacity. During times of cellular stress, specific transcription factors are in place to help protect the cell from damage by initiating the transcription of antioxidant response genes. Here we discuss PTMs caused by reactive oxygen species (ROS), such as H<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>O<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>, that can expeditiously regulate the activation of transcription factors involved in the oxidative stress response. Part of this rapid regulation are proteins involved in H<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>O<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>-related reduction and oxidation (redox) reactions such as redoxins, H<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>O<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub> scavengers described to interact with transcription factors. Redoxins have highly reactive cysteines of rate constants around 6-10<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">-1</sup>s<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">-1</sup> that engage in nucleophilic substitution of a thiol-disulfide with another thiol in inter-disulfide exchange reactions. We propose here that H<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>O<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub> signal transduction induced inter-disulfide exchange reactions between redoxin cysteines and cysteine thiols of transcription factors to allow for rapid and precise on and off switching of transcription factor activity. Thus, redoxins are essential modulators of stress response pathways beyond H<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>O<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub> scavenging capacity.</div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-89875315687658864512019-01-12T07:02:00.000-08:002019-01-12T07:02:18.794-08:00Mindfulness and Exercise Prevents or Delays Aging Consequences<div class="original-url" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Aging is associated with organ dysfunctions.</div>
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Atherosclerosis, cognitive decline, chronic kidney disease, sarcopenia, thinning of skin, osteopenia to name an obvious set.</div>
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This study below relates the first two diseases to resting heart rate over twenty years of follow up.</div>
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Higher heart rates show greater declines!</div>
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Why?</div>
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Heart rate resting is a function of ANS tone precisely measured by HRV which declines with aging. </div>
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HRV is related inversely to mortality. High HRV equals low mortality risk and vice versa.</div>
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Heart rate increases due to vagal tone decline.</div>
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Heart failure has a greater mean mortality than mean cancer mortality.</div>
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Heart failure has vagal exhaustion as a hallmark.</div>
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Preserving vagal tone and ANS balance increases healthspan and lifespan.</div>
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Strong brakes AND strong accelerators, together, constitute high metabolic function.</div>
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Daily mindfulness and exercise promotes higher HRV.</div>
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I promote vagal nerve stimulating biofeedback breathing as illustrated by Gervitz HRV on YouTube for 2 minutes twice daily AND Tabata four minutes of high intensity interval exercise daily.</div>
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<br /><a href="https://www.sciencedirect.com/science/article/pii/S0002914918319684">https://www.sciencedirect.com/science/article/pii/S0002914918319684</a><br /></div>
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Relation of Elevated Resting Heart Rate in Mid-Life to Cognitive Decline Over 20 Years (from the Atherosclerosis Risk in Communities [ARIC] Study)</h1>
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<span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Stephanie</span><span style="max-width: 100%;">Wang</span><span style="max-width: 100%;">MD</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">a</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">1</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Oluwaseun E.</span><span style="max-width: 100%;">Fashanu</span><span style="max-width: 100%;">MD, MPH</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">b</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">1</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Di</span><span style="max-width: 100%;">Zhao</span><span style="max-width: 100%;">PhD</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">b</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">c</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Eliseo</span><span style="max-width: 100%;">Guallar</span><span style="max-width: 100%;">MD, DrPH</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">b</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">c</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Rebecca F.</span><span style="max-width: 100%;">Gottesman</span><span style="max-width: 100%;">MD, PhD</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">c</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">d</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Andrea L.C.</span><span style="max-width: 100%;">Schneider</span><span style="max-width: 100%;">MD, PhD</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">d</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">John W.</span><span style="max-width: 100%;">McEvoy</span><span style="max-width: 100%;">MBBCh, MHS</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">b</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Faye L.</span><span style="max-width: 100%;">Norby</span><span style="max-width: 100%;">MS, MPH</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">e</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Amer I.</span><span style="max-width: 100%;">Aladin</span><span style="max-width: 100%;">MD</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">f</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Alvaro</span><span style="max-width: 100%;">Alonso</span><span style="max-width: 100%;">MD, PhD</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">g</sup></span></span></span><span class="converted-anchor" style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;">Erin D.</span><span style="max-width: 100%;">Michos</span><span style="max-width: 100%;">MD, MHS</span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">a</sup></span><span style="max-width: 100%;"><sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">b</sup></span></span></span></div>
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<span style="max-width: 100%;"><a href="https://www.blogger.com/topics/medicine-and-dentistry/resting-heart-rate" style="color: #416ed2; max-width: 100%;" title="Learn more about Resting Heart Rate">Resting heart rate</a> (RHR) is independently associated with </span><a href="https://www.blogger.com/topics/medicine-and-dentistry/cardiovascular-disease" style="color: #416ed2; max-width: 100%;" title="Learn more about Cardiovascular Disease">cardiovascular disease</a><span style="max-width: 100%;"><span style="max-width: 100%;"> (CVD) risk. We determined whether RHR, measured in mid-life, is also associated with cognitive decline. We studied 13,720 middle-aged white and black ARIC participants without a history of <a href="https://www.blogger.com/topics/medicine-and-dentistry/apoplexy" style="color: #416ed2; max-width: 100%;" title="Learn more about Apoplexy">stroke</a><span style="max-width: 100%;"> or atrial fibrillation. RHR was obtained from a 12-lead resting <a href="https://www.blogger.com/topics/medicine-and-dentistry/electrocardiogram" style="color: #416ed2; max-width: 100%;" title="Learn more about Electrocardiogram">electrocardiogram</a> at the baseline visit (1990 to 1992) and categorized into groups as <60 (reference), 60 to 69, 70 to 79 and ≥80 beats/min. Cognitive scores were obtained at baseline and at up to 2 additional visits (1996 to 1998 and 2011 to 2013). The primary outcome was a global composite cognitive score (Z-score) derived from 3 tests: delayed </span></span><a href="https://www.blogger.com/topics/medicine-and-dentistry/word-recognition" style="color: #416ed2; max-width: 100%;" title="Learn more about Word Recognition">word recall</a><span style="max-width: 100%;">, digit symbol substitution, and word fluency. The associations of RHR with cognitive decline and incident <a href="https://www.blogger.com/topics/medicine-and-dentistry/dementia" style="color: #416ed2; max-width: 100%;" title="Learn more about Dementia">dementia</a> were examined using linear mixed-effects and Cox hazard models, respectively, adjusting for sociodemographics, CVD risk factors, and AV-nodal blockade use. Multiple imputation methods were used to account for attrition over follow-up. Participants had mean ± SD age of 58 ± 6 years; 56% were women, 24% black. Average RHR was 66 ± 10 beats/min. Over a mean follow-up of 20 years, those with RHR ≥80 beats/min had greater global cognitive decline (average adjusted Z-score difference −0.12 [95% confidence interval −0.21, −0.03]) and increased risk for incident dementia (hazard ratio 1.28 (1.04, 1.57), compared with those with RHR <60 beats/min. In conclusion, elevated RHR is independently associated with greater cognitive decline and incident dementia over 20 years. Further studies are needed to determine whether the associations are causal or secondary to another underlying process, and whether modification of RHR can affect cognitive decline.</span></span></div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-5953154761786320252018-12-29T08:12:00.000-08:002018-12-29T08:12:55.841-08:00Protect Your Brain with Real Food<div class="original-url" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Energy consumption raises GIP and GLP1 in the proximal and distal intestine respectfully. </div>
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Processed foods that are nearly completely absorbed in proximal intestine raise GIP and reduce GLP1.</div>
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Unprocessed foods and low glycemic foods raise both GIP and GLP1.</div>
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Fruit juice (processed) raises GIP but fruit with peel and fiber raises first GIP and later raises GLP1.</div>
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GLP1 is neuroprotective. GIP added to GLP1 is even more protective.</div>
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They have developed dual agonist for disease state protection.</div>
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A smart strategy is to eat real food that has low glycemic index and fiber to feed gut bacteria primarily and secondarily via fermentation products to raise GLP1 in the distal ileum.</div>
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<br /><a href="https://www.sciencedirect.com/science/article/pii/S0028390818300406">https://www.sciencedirect.com/science/article/pii/S0028390818300406</a><br /></div>
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abstract</h1>
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In animal models of neurodegenerative disorders, they show superior neuroprotective effects.</div>
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<span style="max-width: 100%;"><span style="max-width: 100%;"><span style="max-width: 100%;"><a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/non-insulin-dependent-diabetes-mellitus" style="color: #416ed2; max-width: 100%;" title="Learn more about Non Insulin Dependent Diabetes Mellitus">Type 2 diabetes</a><span style="max-width: 100%;"> is a risk factor for several chronic neurodegenerative disorders such as Alzheimer's or <a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/parkinson-disease" style="color: #416ed2; max-width: 100%;" title="Learn more about Parkinson Disease">Parkinson's disease</a>. The link appears to be insulin </span></span><a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/desensitization" style="color: #416ed2; max-width: 100%;" title="Learn more about Desensitization">de-sensitisation</a><span style="max-width: 100%;"> in the brain. Insulin is an important <a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/neuroprotective-agent" style="color: #416ed2; max-width: 100%;" title="Learn more about Neuroprotective Agent">neuroprotective</a><span style="max-width: 100%;"><span style="max-width: 100%;"> <a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/growth-factor" style="color: #416ed2; max-width: 100%;" title="Learn more about Growth Factor">growth factor</a>. GLP-1 and </span><a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/gastric-inhibitory-polypeptide" style="color: #416ed2; max-width: 100%;" title="Learn more about Gastric Inhibitory Polypeptide">GIP</a><span style="max-width: 100%;"> are growth factors that re-sensitise insulin and GLP-1 mimetics are used in the clinic to treat diabetes. GLP-1 and GIP mimetics initially designed to treat diabetes show good protective effects in animal models of Alzheimer's and Parkinson's disease. Based on these results, several clinical trials have shown first encouraging effects in patients with Alzheimer's or Parkinson’ disease. Novel dual GLP-1/GIP <a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/receptor-agonist" style="color: #416ed2; max-width: 100%;" title="Learn more about Receptor Agonist">receptor agonists</a> have been developed to treat diabetes, and they also show good neuroprotective effects that are superior to single GLP-1 analogues. Several newer dual analogues have been tested that have been engineered to cross the </span></span></span></span><a href="https://www.blogger.com/topics/neuroscience/blood-brain-barrier" style="color: #416ed2; max-width: 100%;" title="Learn more about Blood Brain Barrier">blood –brain barrier</a>. They show clear neuroprotective effects by reducing inflammation and </span><a href="https://www.blogger.com/topics/neuroscience/oxidative-stress" style="color: #416ed2; max-width: 100%;" title="Learn more about Oxidative Stress">oxidative stress</a><span style="max-width: 100%;"> and apoptotic signalling and protecting memory formation, synaptic numbers and synaptic activity, motor activity, <a href="https://www.blogger.com/topics/pharmacology-toxicology-and-pharmaceutical-science/dopamine-receptor-stimulating-agent" style="color: #416ed2; max-width: 100%;" title="Learn more about Dopamine Receptor Stimulating Agent">dopaminergic</a> neurons, cortical activity and energy utilisation in the brain. These results demonstrate the potential of developing disease-modifying treatments for Alzheimer's and Parkinson's disease that are superior to current single GLP-1 mimetics.</span></div>
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This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’</div>
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<br class="Apple-interchange-newline" style="-webkit-text-size-adjust: auto;" />Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-78288454480304268842018-12-29T07:56:00.000-08:002018-12-29T07:56:17.451-08:00Hormones Make Us Lean or Stout- You Can Manage Your Hormonal Portfolio<div class="original-url" style="-webkit-text-size-adjust: auto; font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Everyday physicians treat metabolic syndrome and their resulting diseases. 2 of every 3 patients are insulin resistant.</div>
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This blog post by Amy Berger in the link below states an uncommon truth. I highly recommend her blog, books and YouTube talks and especially appreciate her ease of expression and simplicity of approach to better metabolic health. Hyperinsulinemia or insulin resistance syndrome can only be reversed by lowering chronic insulin levels (and modifying other hormones.) How?</div>
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Low carb diet.</div>
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12 hours or more of daily fasting.</div>
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Tabata daily exercise to improve insulin resistance by 39%.</div>
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Mediterranean diet.</div>
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1. Wheat germ.</div>
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2. Nuts and olives.</div>
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3. Fruit (skins) and broccoli family vegetables.</div>
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(The above are young seeds and sprouts that have chemicals that increase Nrf2 activation that raise antioxidant enzymes. Antioxidant enzymes are directly proportional to mitochondria mass and basal metabolic rate.)</div>
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Amendment to Mediterranean diet.</div>
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4. Eggs. (Animal seeds or sprouts) See above remark about young cells effect on older cells metabolism.</div>
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Reduce leaky bowel, bacterial translocation, inflammation that increases CORTISOL with homemade yogurt loaded with probiotics, omega 3 fatty acids, butyrate and lactate.</div>
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Reduce stress increased CORTISOL with vagal nerve stimulation to stimulate the CAP cholinergic anti inflammatory pathway. Two minutes of biofeedback cardiopulmonary resonant breathing at rate of 0.1 cps or one breath every six seconds. One could also use a transcutaneous vagal nerve stimulator 4 minutes daily.</div>
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Restorative sleep and optimized circadian rhythm increases intermittent MELATONIN the restorative and neuroprotective hormone. (Also a great supplement)</div>
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Adequate sunlight during the day increases intermittent production of VITAMIN D, the sunshine hormone. (Also Vitamin D3 is a great supplement especially during the winter months without sunshine)</div>
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Magnesium rich foods or magnesium chloride. (Magnesium is required by every ATP energy molecule in addition to other enzymes.)</div>
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Avoid processed foods which raise GIP/GLP1 ratios and drive appetite hormone. GIP is in the proximal small intestine and GLP1 is in the stomach and distal small intestine. Over processing allows absorption and GIP stimulation and decreased distal carbohydrates for GLP1 stimulation.</div>
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I speculate that controlling "chronic" elevation of both CORTISOL and INSULIN is required for optimum health. Bacterial translocation increases with aging or inflamaging of gut and may be responsible for insulin resistance syndrome and chronic cortisol elevation because of LPS or endotoxin stimulation of neuroimmune system sensors. </div>
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A single exception disproves a rule. 1 of 3 adults (and most children) are metabolically healthy despite the western diet which makes them resilient. I speculate that strong exterior barrier function of healthy gut, skin and respiratory linings, and healthy internal barrier linings including the blood brain barrier accounts for their resilience to simulators of inflammation.</div>
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In other words, leaky gut allows bacterial translocation and causes chronic inflammation that manifest as chronic hormonal drivers of insulin resistance syndrome. I suspect this is the core or root cause of dysbiosis, a driver of leaky bowel, chronic hormonal dysregulation and insulin resistance syndrome. Therefore vagal nerve simulation and homemade yogurt and other fermented foods are essential to climb out of the metabolic insulin resistance hole to become whole and resilient.</div>
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<br /><a href="http://www.tuitnutrition.com/2016/11/obesity-is-hormonal.html#more">http://www.tuitnutrition.com/2016/11/obesity-is-hormonal.html#more</a><br /></div>
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Obesity is (mostly) a Hormonal Issue: Let's Stop Pretending it's Solely About Calories</h1>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-78086676135359493812018-12-22T06:51:00.000-08:002018-12-22T06:51:57.804-08:00Cortical Nerve Network Plasticity; Build Out then Maintain.<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
<span style="background-color: rgba(255, 255, 255, 0);">Developing children have basal nerve stem cell formation and therefore basal neurogenesis and repair. In short, basal cortical plasticity.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Not so the mature adult. Once the brain is well formed or built, neurogenesis becomes a function of autophagy and stemness maintenance. </span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Daily twelve hour or more fasting promotes autophagy and stemness.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Other stemness maintenance agents are spermidine for proteostasis and autophagy, melatonin, hydrogen rich water and Nrf2 activators such as sulforaphane which also increases autophagy.</span></div>
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Separately, both spermidine (wheat germ) and Sulforaphane (broccoli sprout extract) have increased healthspan and lifespan 30% in yeast, c. Elegans worms, fruit flies, mice and human cell cultures.</div>
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<span style="background-color: rgba(255, 255, 255, 0);">Except from: </span><span style="font-family: Helvetica; font-size: 12pt;">On the Role of Basal Autophagy in Adult Neural Stem Cells and Neurogenesis</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">Adult neurogenesis persists in the adult mammalian brain due to the existence of neural stem cell (NSC) reservoirs in defined niches, where they give rise to new neurons throughout life. Recent research has begun to address the implication of constitutive (basal) autophagy in the regulation of neurogenesis in the mature brain. This review summarizes the current knowledge on the <b>role of autophagy-related genes in modulating adult NSCs, progenitor cells and their differentiation into neuron</b>s. The general function of autophagy in neurogenesis in several areas of the embryonic forebrain is also revisited. <b>During development, basal autophagy regulates</b> Wnt and Notch signaling and is mainly required for <b>adequate neuronal differentiation</b>.</span></div>
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<span style="background-color: rgba(255, 255, 255, 0);">The available <b>data in the adult indicate that the autophagy-lysosomal pathway regulates adult NSC maintenance, the activation of quiescent NSCs, the survival of the newly born neurons and the timing of their maturation.</b> </span></div>
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<br />https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187079/</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-40027687552618896672018-12-19T04:56:00.000-08:002018-12-19T04:56:27.573-08:00Vagal cardiorespiratory breathing improves fluid intelligence and other organ function<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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This article is interesting relative to cardiorespiratory resonant breathing.</div>
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<span style="background-color: rgba(255, 255, 255, 0);">Buteyko breathing improves asthma because of breathing retaining?</span></div>
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Prayama yoga breathing also improves asthma similarly.</div>
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In India diabetes is mitigated by this breathing technique.</div>
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<br /></div>
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In the case below asthma measurably improves.</div>
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Stress symptoms are lowered.</div>
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Why?</div>
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Cardiorespiratory resonant breathing activates a vagal reflex that improves the brain by lowering cortisol and increasing BDNF; it improves organ function by activating the CAP cholinergic anti-inflammatory pathway by releasing acetylcholine into circulation to phenotypicaly shift angry M1 macrophages into M2 status macrophages. That shift reduces immune stress that degrades cells, tissues and organs.</div>
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Vagal nerve stimulation also tunes the ensemble of 5 unique human abilities.</div>
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I infer that this "tunes"or connects the human "hive" mind in every individual to improve their fluid intelligence which allows novel problem solving.</div>
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<br /><a href="https://www.tandfonline.com/doi/abs/10.1080/09593985.2017.1400139">https://www.tandfonline.com/doi/abs/10.1080/09593985.2017.1400139</a><br /></div>
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Breathing pattern recordings using respiratory inductive plethysmography, before and after a physiotherapy breathing retraining program for asthma: A case report</h1>
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<b>Breathing retraining (BR) improves symptoms, psychological well-being and quality of life in adults with asthma; but there remains uncertainty as to mechanism of effect</b>. One of the intuitively logical theories is that BR works through altering breathing pattern. There is currently no evidence, however, that BR does result in measurable changes in breathing pattern. In this case report we describe the effects of physiotherapy BR on a 57-year-old female with a 10-year history of asthma. Data were collected before and after a physiotherapy BR program comprising three sessions over 18 weeks: breathing pattern (respiratory inductive plethysmography (RIP); physiology (end tidal carbon dioxide (ETCO<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">2</sub>), heart rate, oxygen saturations, spirometric lung function); questionnaires (Asthma Control Questionnaire (ACQ), Hospital Anxiety and Depression Score, Nijmegen Questionnaire); and medication usage. <b>After BR, the patient’s symptoms improved. Her physiology was largely unchanged, although her FEV<sub style="font-size: 0.75em; line-height: 1; max-width: 100%;">1</sub> increased by 0.12L, peak flow by 21L/min.</b> The patient reported <b>using less Salbutamol</b>, yet her asthma control improved (ACQ down 1.5). Her Nijmegen score dropped from positive to negative for hyperventilation (from 39 to 7). Her <b>anxiety-depression levels both reduced into ‘normal’ ranges</b>. The patient’s expiratory time increased, with longer respiratory cycles and slower respiratory rate. No changes were seen in relative contributions of ribcage and abdomen. Controlled trials are now needed to determine the generalizability of these findings.</div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-64840382426642164162018-11-01T04:34:00.000-07:002018-11-01T04:34:53.856-07:00Health and Disease is a NONLINEAR FUNCTION<div class="original-url" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
TG/HDL ratio is the strongest predictor of insulin resistance syndrome which is the root cause or strongest cause of atherosclerotic morbidity and mortality. Not LDL!</div>
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Endothelial dysfunction increases as arteries become stiff and microvascular vessels become less able to normally promote flow mediated dilation to increase metabolism and function of cells, tissues and organs, like the heart, brain and kidneys.</div>
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Study table 1. As ratio increases every parameter of metabolic syndrome increases.</div>
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Blood pressure, fatty liver, diabetes, etc correlates.</div>
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I suspect sleep apnea also correlates and the ratio improves with cpap.</div>
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Mediterranean diet, exercise, vagal nerve stimulation, 12 hours of fasting REDUCE RISK EXPONENTIALLY. This means that small changes in ratio produces greater rewards for atherosclerosis prevention.</div>
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Compare ACE/ARB to metoprolol. The former reduces diabetes (insulin resistance syndrome) 9% and the latter increases diabetes risk 9%. It follows that endothelial dysfunction, arterial stiffness, heart failure, stroke, dementia and acute coronary syndrome mean occurrence is therefore shifted toward or away from disease. </div>
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The Mediterranean diet studies show an 8 fold reduction in coronary artery disease </div>
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( 2% vs 16%.) Does a 9% downward shift in diabetes risk (18% from metoprolol) result in. fold or 800% reduction in coronary artery disease, a non linear result that costs the same. Lifestyle changes cost next to nothing and therefore is priceless.</div>
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This study also informs about the non linear relationship or exponential increase (or decrease) in risk. Small changes and small costs are exponentially beneficial. TG/HDL ratio is a useful biomarker of right track wrong track.</div>
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401 K is exponentially increased at retirement from strongest to weakest by time (start early), interest rate (aggressive but safe asset allocation model) and capital ( invest all lose money up to maximum.)</div>
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Knowing where the leverage in any system allows minimum effort to achieve Herculean outcomes.</div>
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<br /><a href="https://lipidworld.biomedcentral.com/articles/10.1186/s12944-018-0776-7">https://lipidworld.biomedcentral.com/articles/10.1186/s12944-018-0776-7</a><br /></div>
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<h1 class="title" style="font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
Triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio and arterial stiffness in Japanese population: a secondary analysis based on a cross-sectional study</h1>
<div class="metadata singleline" style="margin-bottom: 1.45em; margin-top: -0.75em; max-width: 100%;">
<span class="byline" itemprop="author" itemscope="" itemtype="http://schema.org/Person" style="display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">Jia-Lin Dai</span></div>
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<div style="max-width: 100%;" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:meta="http://www.springer.com/app/meta" xmlns="">
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<span style="max-width: 100%;"><span itemid="#periodical" itemscope="" itemtype="http://schema.org/Periodical" style="max-width: 100%;"><span style="font-style: italic; max-width: 100%;" xmlns="http://www.w3.org/1999/xhtml">Lipids in Health and Disease</span></span><span style="max-width: 100%;">2018</span><span style="max-width: 100%;"><strong itemprop="isPartOf" itemtype="http://schema.org/PublicationVolume" style="max-width: 100%;">17</strong>:130</span></span></div>
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<a href="https://doi.org/10.1186/s12944-018-0776-7" itemprop="sameAs" style="color: #416ed2; max-width: 100%;">https://doi.org/10.1186/s12944-018-0776-7</a></div>
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© The Author(s). 2018</div>
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<ul class="list-style-type-none" style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;">
<li style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;"><strong style="max-width: 100%;">Received: </strong><span style="max-width: 100%;">20 November 2017</span></li>
<li style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;"><strong style="max-width: 100%;">Accepted: </strong><span style="max-width: 100%;">14 May 2018</span></li>
<li style="-webkit-padding-start: 0px; list-style-type: none; max-width: 100%;"><strong style="max-width: 100%;">Published: </strong><span itemprop="datePublished" style="max-width: 100%;">29 May 2018</span></li>
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<section lang="en" style="max-width: 100%;" xmlns:fn="http://www.w3.org/2005/xpath-functions" xmlns:meta="http://www.springer.com/app/meta" xmlns=""><h2 style="font-size: 1.43em; max-width: 100%;">
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<h3 style="font-size: 1.25em; max-width: 100%;" xmlns="">
Background</h3>
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Previous studies have revealed that triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio (henceforth TG/HDL-C) is one of major risk factors of cardiovascular diseases, insulin resistance and metabolism syndrome. However, there are fewer scientific dissertations about the correlation between TG/HDL-C and bapWV. This study was undertaken to investigate the relationship between Triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio and brachial-ankle pulse wave velocity (baPWV) in Japanese.</div>
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Methods</h3>
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The present study was a cross-sectional study. 912 Japanese men and women, aging 24−84 years old, received a health medical a health check-up program including the results from baPWV inspection and various standardized questionnaire in a health examination Center in Japan. Main outcome measures included TG/HDL-C ratio, baPWV, fatty liver, postmenopausal status. Abdominal ultrasonography was used to diagnose fatty liver. Postmenopausal state was defined as beginning 1 year after the cessation of menses. It was noted that the entire study was completed by Fukuda et al., and uploaded the data to the DATADRYAD website. The author only used this data for secondary analysis.</div>
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Results</h3>
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After adjusting potential confounders (age, sex, BMI, SBP, DBP, AST, ALT, GGT, uric acid, fasting glucose, TC, LDL, eGFR, smoking and exercise status, fatty liver, alcohol consumption and ABI), non-linear relationship was detected between TG/HDL-C and baPWV, whose point was 5.6. The effect sizes and the confidence intervals on the left and right sides of inflection point were 12.7 (1.9 to 23.5) and − 16.7 (− 36.8 to 3.3), respectively. Subgroup analysis showed, in participants with excessive alcohol consumption (more than 280 g/week), that TG/HDL-C had a negative correlation with BAPWV (β = − 30.7, 95%CI (− 53.1, − 8.4)), and the P for interaction was less than 0.05,</div>
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Conclusion</h3>
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The relationship between TG/HDL-C and baPWV is non-linear. TG/HDL-C was positively related with baPWV when TG/HDL-C is less than 5.6. In addition, while the trend is opposite in excessive alcoholic subjects.</div>
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Brachial-ankle pulse wave velocity (baPWV) is served as an indicator to quantify arterial stiffness [<span style="max-width: 100%;"></span>]. As an independent risk factor of cardiovascular events, baPWV is used in clinical for early evaluating the functions and structural changes of vascular wall [<span style="max-width: 100%;"></span>, <span style="max-width: 100%;"></span>]. Despite of the fact that western countries have not fully accepted baPWV, more and more publications on this research methodology came from these countries since 2009 [<span style="max-width: 100%;"></span>]. Atherosclerosis Risk in Communities (ARIC) study and the Bogalusa Heart Study, the two large-scale studies in U. S, have used baPWV as indicator to assess arterial stiffness [<span style="max-width: 100%;"></span>, <span style="max-width: 100%;"></span>].</div>
<div style="max-width: 100%;" xmlns:func="http://oscar.fig.bmc.com" xmlns="http://www.w3.org/1999/xhtml">
Previous studies have revealed that triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio (henceforth TG/HDL-C) is one of major risk factors of cardiovascular diseases, insulin resistance and metabolism syndrome [<span style="max-width: 100%;"></span><span style="max-width: 100%;">, <span style="max-width: 100%;"></span>, <span style="max-width: 100%;"></span>, <span style="max-width: 100%;"></span>, <span style="max-width: 100%;"></span>, </span><span style="max-width: 100%;"></span>]. Some scholars consider that TG/HDL-C can better predict vascular risk than either does [<span style="max-width: 100%;"></span>]. However, there are fewer scientific dissertations about the correlation between TG/HDL-C and bapWV. In only a few dissertations [<span style="max-width: 100%;"></span><span style="max-width: 100%;">, <span style="max-width: 100%;"></span>, </span><span style="max-width: 100%;"></span>], as authors used the TG/HDL for analyzing categorical variables. In addition, they used GLM as a sole method of data analysis, in which the independent variables and dependent variables must be linear. But in biomedical research, connection between exposures and outcomes may be non-linear. In that case, researchers need a more effective method to deal with non-linear relationship.</div>
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</section></div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-79760555301614748332018-10-21T06:10:00.000-07:002018-10-21T06:10:34.881-07:00Increase Mitochondrial Mass for a Hotter, Healthier Metabolic Rate<div class="original-url" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Walking is a vagal tone relaxing endeavor that does not increase mitochondrial mass.</div>
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Mitochondrial mass is higher in professional athletes than moderately activated amateurs.</div>
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Why this is important?</div>
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Lower mitochondrial mass persons with activity reach their lactate threshold earlier in exercise. </div>
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Lactate inhibits fat burning relative to carbohydrate metabolism.</div>
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The goal is to burn more fat per day or fat per time whether one is resting (basal metabolic rate) or exercising (activity metabolic rate maximum.)</div>
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In effect, more mitochondria raises both metabolic rates and eliminates STORED ENERGY FAT and a high fat western diet fat content.</div>
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Higher metabolism, higher fat burning, lower BMI AT THE SAME LIFESTYLE.</div>
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One makes more antioxidant enzymes or bullets whenever one is burning fat.</div>
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Mitochondrial biogenesis is increased relatively by the following.</div>
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Exercise where high intensity interval exercise is better than steady state exercise.</div>
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Diet where Mediterranean diet food supplements INCREASE ANTIOXIDANT ENZYMES, because they are like "young cells" which make more antioxidant enzymes because they contain more chemical signals that produce them.</div>
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(Antioxidant enzymes are directly related to mitochondrial biogenesis.)</div>
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Heat as in sauna, climate, hot tubs and exercise which activate heat shock proteins which are directly related to mitochondria and is an exercise mimetic.</div>
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Thinner persons have higher mitochondrial mass and or better lower lactate producing diets (Carbohydrate).</div>
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HIIE increases mitochondrial mass 14% and jogging 60 minutes aerobically 9% and walking 0 to less.</div>
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Are women "hotter" before or after sauna, Mediterranean diet and high intensity exercise?</div>
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I know they are "healthier" and with intermittent fasting able to maintain high metabolic rate and burn faster excessive fat stores.</div>
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The above discussion is also relevant to the single cell and cell biology.</div>
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Exercise related lactate threshold, like aerobic exercise testing, indicates ability to burn fats and not produce lactate from carbohydrates.</div>
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Metabolic rates directly correlate to aerobic fitness and mitochondrial mass.</div>
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Paradoxically lactate also signals the muscles to increase mitochondrial mass. This occurs because 30% of lactate produced by type 2 muscle fibers engaged in high intensity exercise is converted into pyruvate and acetylCoA which signals mitochondrial biogenesis.</div>
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<br /><a href="https://link.springer.com/article/10.1007/s40279-017-0751-x">https://link.springer.com/article/10.1007/s40279-017-0751-x</a><br /></div>
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Assessment of Metabolic Flexibility by Means of Measuring Blood Lactate, Fat, and Carbohydrate Oxidation Responses to Exercise in Professional Endurance Athletes and Less-Fit Individuals</h1>
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<time class="date" datetime="2018-02" style="display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;">February 2018</time></div>
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Abstract</h2>
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Background</h3>
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<b>Increased muscle mitochondrial mass is characteristic of elite professional endurance athletes (PAs), whereas increased blood lactate levels (lactatemia) at the same absolute submaximal exercise intensities and decreased mitochondrial oxidative capacity are characteristics of individuals with low aerobic power. </b>In contrast to PAs, patients with <b>metabolic syndrome (MtS) are characterized by a decreased capacity to oxidize lipids and by early transition from fat to carbohydrate oxidation (FATox/CHOox), as well as elevated blood lactate concentration [La<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">−</sup>] as exercise power output (PO) increases, a condition termed ‘metabolic inflexibility’.</b></div>
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Objective</h3>
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The aim of this study was to assess metabolic flexibility across populations with different metabolic characteristics.</div>
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Methods</h3>
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We used indirect calorimetry and [La<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">−</sup>] measurements to study the metabolic responses to exercise in PAs, moderately active individuals (MAs), and MtS individuals.</div>
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Results</h3>
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<b>FATox was significantly higher in PAs than MAs</b> and patients with MtS (<em style="max-width: 100%;">p</em> < 0.01), while [<b>La<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">−</sup>] was significantly lower in PAs compared with MAs and patients with MtS.</b> <b>FATox and [La<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">−</sup>] were inversely correlated in all three groups</b> (PA: <em style="max-width: 100%;">r</em> = −0.97, <em style="max-width: 100%;">p</em> < 0.01; MA: <em style="max-width: 100%;">r</em> = −0.98, <em style="max-width: 100%;">p</em> < 0.01; MtS: <em style="max-width: 100%;">r</em> = −0.92, <em style="max-width: 100%;">p</em> < 0.01). The correlation between FATox and [La<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">−</sup>] for all data points corresponding to all populations studied was <em style="max-width: 100%;">r</em> = −0.76 (<em style="max-width: 100%;">p</em> < 0.01).</div>
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Conclusions</h3>
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Blood <b>lactate accumulation is negatively correlated with FATox and positively correlated with CHOox during exercise across populations with widely ranging metabolic capabilities</b>. Because both lactate and fatty acids are mitochondrial substrates, we believe that measurements of [La<sup style="font-size: 0.75em; line-height: 1; max-width: 100%;">−</sup>] and FATox rate during exercise provide an indirect method to assess metabolic flexibility and oxidative capacity across individuals of widely different metabolic capabilities</div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-78765716228195642622018-10-10T04:34:00.000-07:002018-10-10T04:34:53.317-07:00Preventing and Reversing Aging 1,2,3<div dir="ltr" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Is anything more quintessential of aging as sensory loss of hearing (and vision?)</div>
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Here age related decline in Nrf2 expression (lack of bullets) leads to cortical auditory degeneration.</div>
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Step 1. More antioxidant enzyme bullets. Step 2. Increase Vagal tone, calm down microglia. Step 3. BrainHQ.com to increase BDNF and rebuild a parallel processing auditory cortex.</div>
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This is something I literally did in a study N of 1.</div>
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This statistically valid research of step 3 alone produces a 135% increase in auditory processing speed and 230% increase in visual processing speed. </div>
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Why is the processing speed so important?. The sharp area of central focal vision is small, like a flashlight beam, that uses scanning and processing to see the bigger picture. PROCESSING, important for seeing, hearing, comprehending and remembering. Auditory sampling speed determines processing speed and accuracy.</div>
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Bullets, Vagal tone and BDNF build. Age related Epigenetic switching off of Nrf2, alpha 7 Nicotinic acetylcholine receptors and BDNF CpG gene promoter sites is directly correlated to aging and disease in cells, tissues, organs and people.</div>
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<br /><a href="https://europepmc.org/abstract/med/30272261">https://europepmc.org/abstract/med/30272261</a><br /></div>
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Age-associated decline in Nrf2 signaling and associated mtDNA damage may be involved in the degeneration of the auditory cortex: Implications for central presbycusis.</h1>
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<a accesskey="U" class="byline" href="https://www.blogger.com/" style="color: #416ed2; display: inline !important; font-size: 1em !important; margin: 0px; max-width: 100%;" target="_top"><span style="font-size: 1em !important; margin: 0px; max-width: 100%;">Europe PMC</span></a></div>
Central presbycusis is the most common sensory disorder in the elderly population, however, the underlying <b>molecular mechanism remains unclear</b>. NF‑E2‑related factor 2 (Nrf2) is a key transcription factor in the cellular response to oxidative stress, however, the role of Nrf2 in central presbycusis remains to be elucidated. The aim of the present study was to investigate the pathogenesis of central presbycusis using a mimetic aging model induced by D‑galactose (D‑gal) in vivo and in vitro. The degeneration of the cell was determined with transmission electron microscopy, terminal deoxynucleotidyl transferase‑mediated deoxyuridine 5'‑triphosphate nick‑end labeling staining, and senescence‑associated β‑galactosidase staining. The expression of protein was detected by western blotting and immunofluorescence. The quantification of the mitochondrial DNA (mtDNA) 4,834‑base pair (bp) deletion and mRNA was detected by TaqMan quantitative polymerase chain reaction (qPCR) and reverse transcription‑qPCR respectively. Cell apoptosis and intracellular ROS in vitro were determined with flow cytometry. The <b>levels of nuclear Nrf2, and the mRNA levels of Nrf2‑regulated antioxidant genes, were downregulated in the auditory cortex of aging rats, which was accompanied by an increase in 8‑hydroxy‑2'‑deoxyguanosine formation</b>, an accumulation of mtDNA 4,834‑bp deletion, and neuron degeneration. In addition, <b>oltipraz, a typical Nrf2 activator, was found to protect cells against D‑gal‑induced mtDNA damage and mitochondrial dysfunction by activating Nrf2 target genes </b>in vitro. It was also observed that <b>activating Nrf2 with oltipraz inhibited cell apoptosis and delayed senescence.</b> Taken together, the data of the present study suggested that the <b>age‑associated decline in Nrf2 signaling activity and the associated mtDNA damage in the auditory cortex may be implicated in the degeneration of the auditory cortex</b>. Therefore, the restoration of Nrf2 signaling activity may represent a potential therapeutic strategy for central presbycusis.</div>
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Joseph Thomas (Tony) Liverma</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-34100137188414229292018-08-11T05:15:00.000-07:002018-08-11T05:15:34.595-07:00Chronic Disease and Network Theory Paradigm for RESILIENCE<div style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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Theses concepts, in abstract below, are relevant to disease prevention and management.</div>
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Globally they imply RESILIENCE of each of three barrier defenses or compartments; outer, intermediate and inner.</div>
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A breach or increased permeability of successive compartments promotes inflammation and weakening of each successive layer. (Increased CRP)</div>
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One can extend the organism, organ compartment fractal further into tissue, cell, cellular organelle and then to sub-sub compartments like the MAM or mitochondrial associated membrane with the endoplasmic reticulum or the nuclear membrane pore.</div>
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The integrity of each compartment depends on the integrity and bioenergetics of each "barrier membrane."</div>
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Disease management requires cell, tissue and organ survival first, then membrane leak repair, then recovery of bioenergetics. </div>
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A strategy of increased antioxidant enzyme capacity, immune response moderation and increased and improved mitochondrial energy production reverses and prevents disease and death while promoting RESILIENCE.</div>
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Oxidative stress is reduced by Nrf2 activators.</div>
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Immune stress is reduced by vagal activation and bicarbonate (Win Hof hyperventilating breathing technique) inactivation of the acetylcholine antagonist (acetylcholinesterase) via mesothelial cell stimulation.</div>
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One of the most potent transcriptional Nrf2 activators is <u>butyrate</u> and beta hydroxybutyrate, (a ketone produced by fasting and exercise.)</div>
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One of the most potent cellular (including brain) energy substrates under stress is <u>lactate</u>.</div>
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Both butyrate and lactate therefore potentially restore the"outer barrier" meaning the skin, mucous membrane and intestinal endothelial lining.</div>
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Both butyrate and lactate are produced in lactobacillus ruggeri homemade yogurt which leads to the following:</div>
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Thickening of barrier cells. Restoration of cell tight junctions and barrier function.</div>
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Reduced barrier cell layer inflammatory cells.</div>
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Increased collagen and reduced MMP the enzyme that destroys collagen and the tight junction proteins that function like mortar in a brick wall.</div>
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Increased oxytocin and stronger larger muscles.</div>
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Therefore, the supplements in that yogurt, restores the outer barrier compartment.</div>
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Butyrate is also absorbed and effects all other barrier and tissue cells to promote RESILIENCE.</div>
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<br /><a href="https://www.sciencedirect.com/science/article/pii/S0306987717304255">https://www.sciencedirect.com/science/article/pii/S0306987717304255</a><br /></div>
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<h1 class="title" style="-webkit-hyphens: manual; font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
A new model for chronic diseases</h1>
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<a href="https://www.blogger.com/topics/medicine-and-dentistry/chronic-disease" style="color: #416ed2; max-width: 100%;" title="Learn more about Chronic Disease">Chronic diseases</a> are defined diseases whose symptoms last for at least six months and tend to worsen over time. In Europe, they cause at least 86% of deaths.</div>
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In this speculative unifying model I set a new hypothesis for the <a href="https://www.blogger.com/topics/medicine-and-dentistry/etiology-medicine" style="color: #416ed2; max-width: 100%;" title="Learn more about Etiology (medicine)">etiology</a> of the majority of chronic diseases. The main aim is to put order and observe our organism in a systemic way, connecting pathologies we now see as disconnected phenomena, with the <b>conceptual frameworks of complex systems and network medicine</b>.</div>
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<span style="max-width: 100%;">Chronic diseases could be caused by a first unsolved acute infection. In case the pathogen cannot be completely eliminated, it becomes a persistent infectious. After the acute episode, some mild symptoms will occur and probably disappear; the chronic disease will remain latent over time. It will manifest even after years or decades, in the presence of another acute infection, a particular stress, trauma, or another event. The presence of the persistent infectious elicits changes in the immune and systemic regulation, and these processes degenerate over time. They will assume their rules and patterns, being independent from the initial stimulus. The <b>key to understand the dynamics and individuality of chronic diseases is the immune system and its networks</b>. The immune mechanisms that can lead to the persistent response are <b>mainly the switch from the Th1 to the <a href="https://www.blogger.com/topics/biochemistry-genetics-and-molecular-biology/t-helper-cell" style="color: #416ed2; max-width: 100%;" title="Learn more about T helper cell">Th2</a> </b>immunity and the </span><a href="https://www.blogger.com/topics/medicine-and-dentistry/molecular-mimicry" style="color: #416ed2; max-width: 100%;" title="Learn more about Molecular Mimicry">molecular mimicry</a>.</div>
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The first persistent infectious will also modify the susceptibility to other pathogens, facilitating new infections and new consequent persistent infectious.</div>
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<span style="max-width: 100%;"><span style="max-width: 100%;">From the immune point of view, <b>our organism is divided into three compartments: the outer one, which comprehend all the surfaces in contact with the environment, the intermediate one, which comprehend the internal organs and tissues, and the innermost one, comprehending the Central Nervous System</b> and the adluminal compartment of the <a href="https://www.blogger.com/topics/biochemistry-genetics-and-molecular-biology/seminiferous-tubule" style="color: #416ed2; max-width: 100%;" title="Learn more about Seminiferous tubule">seminiferous tubule</a>. The <b>immune key-role is played respectively by the </b></span><b><a href="https://www.blogger.com/topics/medicine-and-dentistry/mucosa-associated-lymphoid-tissue" style="color: #416ed2; max-width: 100%;" title="Learn more about Mucosa-associated Lymphoid Tissue">mucosa-associated lymphoid tissue</a>, the </b></span><a href="https://www.blogger.com/topics/medicine-and-dentistry/endothelium" style="color: #416ed2; max-width: 100%;" title="Learn more about Endothelium"><b>endothelium</b></a><span style="max-width: 100%;"><b>, the <a href="https://www.blogger.com/topics/medicine-and-dentistry/blood-brain-barrier" style="color: #416ed2; max-width: 100%;" title="Learn more about Blood-brain Barrier">blood–brain barrier</a> </b>and blood-testis barrier. The chronic diseases follow a progressive scheme, involving the three compartments from the outer to the innermost one.</span></div>
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<span style="max-width: 100%;">The <a href="https://www.blogger.com/topics/medicine-and-dentistry/primer-molecular-biology" style="color: #416ed2; max-width: 100%;" title="Learn more about Primer (molecular biology)">primer</a> microorganism at the origin of the majority of diseases could be streptococcus, or </span><a href="https://www.blogger.com/topics/medicine-and-dentistry/staphylococcus" style="color: #416ed2; max-width: 100%;" title="Learn more about Staphylococcus">staphylococcus</a>. Both cause acute in children, with a great variability of responses and symptoms, and both cause molecular mimicry.</div>
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This model can be tested and proved in more ways, I propose here some of them.</div>
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It could pave the way to a radical change in our comprehension and therapeutic approaches to chronic diseases.</div>
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<div id="AppleMailSignature" style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
Joseph Thomas (Tony)</div>
Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-50875136405769722572018-07-31T04:53:00.000-07:002018-07-31T04:53:07.475-07:00Bioenergetics Nrf2 and Spermidine; Mitochondria and Endoplasmic Reticulum<div class="original-url" style="-webkit-text-size-adjust: auto; font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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<span style="font-size: small;">Hydrogen rich water reduces senescence by reducing ROS directly and indirectly by activating Nrf2. Nrf2 activation slows cell aging in trisomy 21.</span></div>
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<span style="font-size: small;">Mitophagy ultimately removes ROS producing mitochondria and replaces them with efficient cleaner mitochondria.</span></div>
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<span style="font-size: small;"><br /></span></div>
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<span style="font-size: small;">It is oxidative damage by ROS that damages the MAM mitochondrial associated membrane shared with the endoplasmic reticulum. That blocks the local production of melatonin and other antioxidants that protects the marriage of mitochondria and endoplasmic reticulum. This results in less exchange of "goods and services" needed to safely produce energy.</span></div>
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<span style="font-size: small;">Consequences?</span></div>
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<span style="font-size: small;">Metabolic failure triggers SENESCENCE or CANCER. Both are age and and disease related. Both lead to stem cell failure and decline.</span></div>
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<span style="font-size: small;">Reversal from Nrf2 activators and spermidine restores metabolic success and REVERSES aging, carcinogenesis and stem cell failure, the ultimate cause of death.</span></div>
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<span style="font-size: small;">p53 leads either to restoration or senescence and apoptosis depending on energetic capability/ROS ratio signaling.</span></div>
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);"><br /></span></span></h2>
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<span style="font-size: small;"><span style="background-color: rgba(255, 255, 255, 0);">Highlights</span></span></h2>
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<dt class="list-label" style="box-sizing: border-box; clear: left; float: left; margin: 0px 2px 0px 0px; padding: 0px;"><span style="background-color: rgba(255, 255, 255, 0);">•</span></dt>
<dd class="list-description" style="box-sizing: border-box; margin: 0px 0px 0px 48px; padding: 0px;"><div id="par0005" style="box-sizing: border-box; margin-bottom: 16px; padding: 0px;">
<span style="background-color: rgba(255, 255, 255, 0);">Hydrogen alleviates the senescence process of BMSCs <a href="https://www.blogger.com/topics/medicine-and-dentistry/in-vivo" style="-webkit-text-decoration-skip: objects; box-sizing: border-box; margin: 0px; padding: 0px; text-decoration: none;" title="Learn more about In vivo">in vivo</a>.</span></div>
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<dt class="list-label" style="box-sizing: border-box; clear: left; float: left; margin: 0px 2px 0px 0px; padding: 0px;"><span style="background-color: rgba(255, 255, 255, 0);">•</span></dt>
<dd class="list-description" style="box-sizing: border-box; margin: 0px 0px 0px 48px; padding: 0px;"><div id="par0010" style="box-sizing: border-box; margin-bottom: 16px; padding: 0px;">
<span style="background-color: rgba(255, 255, 255, 0);">Hydrogen decreases the intracellular ROS levels.</span></div>
</dd>
<dt class="list-label" style="box-sizing: border-box; clear: left; float: left; margin: 0px 2px 0px 0px; padding: 0px;"><span style="background-color: rgba(255, 255, 255, 0);">•</span></dt>
<dd class="list-description" style="box-sizing: border-box; margin: 0px 0px 0px 48px; padding: 0px;"><div id="par0015" style="box-sizing: border-box; margin-bottom: 16px; padding: 0px;">
<span style="background-color: rgba(255, 255, 255, 0);">Hydrogen reduces the expression of senescence-related <a href="https://www.blogger.com/topics/medicine-and-dentistry/protein-p53" style="-webkit-text-decoration-skip: objects; box-sizing: border-box; margin: 0px; padding: 0px; text-decoration: none;" title="Learn more about Protein P53">proteins p53</a><span style="box-sizing: border-box; margin: 0px; padding: 0px;"> and <a href="https://www.blogger.com/topics/medicine-and-dentistry/p21" style="-webkit-text-decoration-skip: objects; box-sizing: border-box; margin: 0px; padding: 0px; text-decoration: none;" title="Learn more about P21">p21</a>.</span></span></div>
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<dt class="list-label" style="box-sizing: border-box; clear: left; float: left; margin: 0px 2px 0px 0px; padding: 0px;"><span style="background-color: rgba(255, 255, 255, 0);">•</span></dt>
<dd class="list-description" style="box-sizing: border-box; margin: 0px 0px 0px 48px; padding: 0px;"><div id="par0020" style="box-sizing: border-box; margin-bottom: 16px; padding: 0px;">
<span style="background-color: rgba(255, 255, 255, 0);">Hydrogen alleviates senescence of BMSCs via ROS/p53/p21 pathway.</span></div>
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<a href="https://www.sciencedirect.com/science/article/abs/pii/S0753332218328403">https://www.sciencedirect.com/science/article/abs/pii/S0753332218328403</a><br /></div>
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<h1 class="title" style="-webkit-hyphens: manual; font-size: 1.95552em; line-height: 1.2141em; margin-bottom: 0.5em; margin-top: 0px; max-width: 100%;">
Hydrogen alleviates cellular senescence via regulation of ROS/p53/p21 pathway in bone marrow-derived mesenchymal stem cells in vivo</h1>
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Senescence has become a hot point issue in recent decades and requires urgent attention. As a novel and effective antioxidant, hydrogen has been proved to alleviate cellular senescence in endothelial cells in vitro. However, the <b>effects and mechanisms of hydrogen on senescence in vivo are still unclear.</b> In the present study, 12-month-old Sprague Dawley (SD) rats were intraperitoneal administration of hydrogen-rich saline (HRS, 10 ml/kg). Subsequently, bone marrow-derived stem cells (BMSCs) were harvested for the detection of hydrogen antisenescence effects and mechanisms. The results showed that the number of senescence-associated β-galactosidase (SA-β-Gal) positive cells was reduced in BMSCs from rats treated with HRS. BMSCs in rats treated with HRS possessed a better proliferation ability, showed more effectively tri-lineage differentiation potential, and had less percentage of cells in G1 cell cycle arrest than the control cells. Additionally, <b>HRS administration inhibited the production of intracellular reactive oxygen species (ROS) and decreased the expression of senescence-related proteins <a href="https://www.blogger.com/topics/medicine-and-dentistry/p53" style="color: #416ed2; max-width: 100%;" title="Learn more about P53">p53</a> and p21. Our results revealed that hydrogen could alleviate cellular senescence in vivo. </b>And the underlying <b>mechanism</b> of antisenescence effects of hydrogen in BMSCs was via the <b>ROS/p53/p21 signaling pathway</b>. Thus, hydrogen could be a new and convenient strategy for alleviating senescence and for therapy of age-related diseases.</div>
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Anonymoushttp://www.blogger.com/profile/06710048808516581060noreply@blogger.com0tag:blogger.com,1999:blog-4970294685564632059.post-54528798235990484942018-07-28T05:32:00.000-07:002018-07-28T05:32:52.841-07:00RESILIENCE is Two Sides of a Reciprocal COIN<div style="font-family: UICTFontTextStyleTallBody; font-size: 17px;">
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There are two models of premature aging; progeria and trisomy 21.</div>
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What protects rapidly aging cells protects our shower aging cells.</div>
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Nrf2 slows aging and cell senescence in trisomy 21.</div>
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Nrf2 slows aging in every cell.</div>
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Therefore Nrf2 is one target of the coin of RESILIENCE.</div>
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The flip side is reducing autoimmunity that results from inflamaging.</div>
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Tails is increasing Vagal tone and activating the cholinergic anti inflammatory pathway via slow paced breathing with or without augmentation by facial cooling.</div>
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<b>RESILIENCE includes Nrf2 activation and autoimmunity deactivation.</b></div>
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<br /><a href="https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12812">https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12812</a><br /></div>
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Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells - Zamponi - - Aging Cell - Wiley Online Library</h1>
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Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.</div>
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Joseph Thomas (Tony) Liverman, Jr.</div>
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