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Adrenal Physiology and the stress response correlated with methylation status and its effects on mood behavior and mental health* Dr. Loren Marks, D.C., DACBN Founder Integrative Assessment Technique CEO On The Mark Health and Wellness 200 W 57 St. Suite 1010 New York, NY 10019 [email protected] *These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease. Why nutrigenomics and epigenetics • Nutrigenomics• Nutrients exhibit powerful effects on our genes. The right nutrients help, the wrong ones hurt! • Foods exhibit profound effects on our genes and physiology. Immuno-competence vs. immune dysregulation • Epigenetics encompasses dietary, environmental and emotional experiences that influence genetic expression • Adrenal physiology must follow these same principles 2 Origins of stress Emotional Chemical Physical Adrenal Response 3 Adrenal Physiology • Stress is first perceived through the nervous system with resultant hormonal activation, thus a neuro-endocrine response. • Hans Seyle considered the father of stress, wrote the classic text on stress in the 1930’s where he developed the General adaptation syndrome (GAS) which is the manifestation of stress in the whole body over time. 4 STRESS Hormonal Activation Neuro-Endocrine Response Perceived through the nervous system 5 Adrenal Physiology • In humans, any stressor good or bad stimulates the hippocampus to activate the hypothalamus to release corticotropic releasing factor (CRF) which travels through the hypophysial portal system to the pituitary stimulating the adrenocorticotropic hormone (ACTH). • ACTH then travels through the systemic circulation to the adrenal cortex, where it releases the glucocorticoid cortisol. 6 Adrenal Physiology • It is estimated that 75-90% of all visits to primary care physicians, are for stress related problems • Unmanaged reactions to stress have been shown to be greater risk factors for cancer and heart disease than cigarette smoking or eating high cholesterol foods! 7 Adrenal Physiology • Immediately upon activation of this pathway the body begins an alarm reaction provoking: • Gluconeogenesis • Decreased insulin sensitivity • Amino acid mobilization • Protein catabolism • Mobilization of free fatty acids from adipose tissue • Decreased phagocytosis and white blood cell migration • Decreased lymphocyte production • Disappearance of blood-born eosinophils and lymphocytes • Increased red blood- cell production 8 Adrenal Physiology • It is imperative to understand the pivotal role adrenal physiology plays, in not only the apparent stress we see in our patient population and perceive in our own lives, but the long term effects over-stimulation of the gland produces in chronic disease states. 9 Adrenal Physiology • An incalculable amount of human morbidity and perhaps mortality exists due to the failure of physicians to understand and effectively treat “The chronic stress response.” • As long as we have been on this planet, stress has been part of the human experience. 10 Adrenal Physiology • Stress can come from how we perceive and deal with the world around us, as well as how healthy our internal organs function. • Dealing with financial woes, marital issues, stress at work, guilt, worry, frustration, anxiety, depression are all contributing factors. • Organ dysfunction such as GI disturbances, microbial overgrowth, cardiac disease, chronic musculoskeletal pain, injury etc. collectively these issues constitute our stressor load otherwise known as “allosteric stress.” 11 Adrenal Physiology In the presence of stressors, the body almost immediately attempts to increase cortisol levels. This increase is associated with both endocrine and autonomic responses in preparing the body to defend itself normally. However, elevated cortisol levels for extended periods negatively affect virtually every aspect of physiology. 12 Adrenal Physiology For example: it becomes more difficult to maintain proper blood sugar levels; to slow down for rest, recovery, and repair; to get good quality sleep; to balance hormones; to maintain mucosal immune integrity; to maintain bone mass; to produce effective general immune function; to effectively regulate inflammatory processes; or to detoxify the body. Without proper intervention, continued high adrenal stimulation can lead to adrenal exhaustion and lowered cortisol levels. Eventually adrenal or cardiac failure can occur. 13 Adrenal Cortex • The cortex can be divided into three distinct layers of tissue based on their organization. • Layer, Name, Primary product: • 1- Most superficial cortical layer • zona glomerulosa mineralocorticoids (e.g., Aldosterone) • 2- Middle cortical layer • zona fasciculata glucocorticoids (e.g., cortisol) • Deepest cortical layer • 3- zona reticularis weak androgens (e.g., dehydroepiandrosterone- DHEA) 14 Adrenal Cortex • All adrenocortical hormones are synthesized from cholesterol. Cholesterol is transported into the inner mitochondrial membrane by steroidogenic acute regulatory protein (STAR), where it is converted into pregnenolone by the enzyme CYP11A1. • Accordingly, production of hormones in all three layers of the adrenal cortex is limited by the transportation of cholesterol into the mitochondria and by its conversion into pregnenolone. 15 16 Functional adaptation Now that we have reviewed the biochemical and physiological output of the adrenals we must be able to utilize this knowledge and apply it in a clinical setting. Short term stress is largely mediated by the catacholamines adrenaline and noradrenaline, but there is always a cortisol output in response to stress. 17 Functional adaptation • Long term stress is regulated by Cortisol and DHEA • This relationship is critical to understand because the stress response induces alterations in these hormones which effect our cellular energy and a plethora of other functions that are quite diverse and profound 18 How stress can make you sick • We are hard wired for stress • Short term stress is a healthy and normal response • Long term stress is a detriment • Cortisol, Epinephrine and Nor epinephrine (Adrenalin) causes your heart to beat faster and raises your BP over time causing hypertension. Cortisol can cause your endothelium to become dysfunctional 19 How stress can make you sick • This has been shown to induce atherosclerosis and cholesterol plaque build up in arterial walls. • Collectively increasing your risk of heart attack or stroke. • The autonomic nervous system activates and sends signals to your “enteric brain” or gut, changing motility and leading to IBS. 20 How stress can make you sick • It also increases your gut sensitivity to acid making you more likely to feel heartburn. • Via the guts nervous system, stress can also change the composition and function of your gut bacteria, which is your microbiome. • This alters your many signaling molecules and can have far reaching effects on ones health. 21 Does chronic stress effect your waistline? • YES! • Cortisol can increase your appetite-it tells your body to replenish your energy stores with energy dense foods and carbs, causing you to crave comfort foods. • High Cortisol leads to increased visceral or deep belly fat. This type and area of fat becomes an organ actively releasing hormones and cytokines that increase your risk of developing chronic disease, such as heart disease and insulin resistance. 22 SeroCort TM 1 VegiCap provides: D3 267iu 5HTP 33mg L Theanine 67 mg Relora 250mg Rhodiola 120mg • Serocort provides raw material your body uses to upregulate serotonin, support weight loss, stress management and mood support. • Lowers cortisol and helps adaptation leading to a positive outlook. Stress and Immunity • Initially stress helps prepare your immune system by up-regulating immune modulation, and healing after injury • Chronic stress can dampen immunity making you more susceptible to infection and slows the rate of healing • SIgA First line mucosal defense 24 Longevity and stress • Want to live long? • Reduce your stress! • Chronic stress has been shown to shorten telomeres! Shortened telemeres reduce the cells reproductive capacity- no division- life ends! 25 Stress And if that is not bad enough, prolonged stress causes: • Hair loss • Sexual dysfunction • Headaches & muscle tension • Chronic subluxations of the spine • Difficulty concentrating • Fatigue and irritability 26 Adaptation • Your life will always be filled with stressful situations, it is how you react to and process stress that is important. • If you can view these situations as challenges you can control and master, rather than as threats that are insurmountable, you will perform better in the short run and stay healthy in the long run. 27 DHEA • DHEA (dehydroepiandrosterone ) is a metabolic hormone intermediate (a building block for hormones) that has some hormonal characteristics of its own. • It is an important precursor for estrogens and testosterone. The most accurate way to measure DHEA is to measure it in the stable form that the body keeps it in; DHEA-S when blood testing (dehydroepiandrosterone sulfate). 28 DHEA • Even DHEA that is taken by mouth is quickly converted to this more stable form by the body. • DHEA-S levels are usually much higher in men than they are in women. Levels peak at about 25-30 years of age and decline with aging. • The decline of DHEA levels with aging correlates with a general decline in immunity, and lowering resistance to age-related diseases. • Decreased DHEA levels are noted in many chronic illnesses, obesity, decreased sex drive (low libido), chronic fatigue, rheumatological disorders, insomnia, and depression. 29 DHEA • DHEA-S is one of the most important hormones produced by the adrenal glands, and should be evaluated with cortisol. • It should also be looked at whenever testosterone levels are low, since it is a precursor to testosterone • Never look at testosterone in men (40+) without looking at Estradiol 30 Functional adaptation • Three distinct phases of adrenal exhaustion have been isolated. • While blood markers have a place in defining adrenal physiology, Cortisol levels are bound by protein fractions and do not always reveal what is biologically active, therefore salivary levels being unbound reflect a greater degree of accuracy. • In addition, Cortisol goes through a diurnal variation and it is too difficult to have a patient go to a blood lab 4 times in one day. Salivary capture allows for patient compliance and the ability to see where the patient spikes or depresses in their output. DHEA and other hormones are increasingly being tested this way for assessment in functional medicine. Standard allopathic models have yet to adopt this model. 31 DHEA to Cortisol • DHEA is the counter-regulatory hormone to Cortisol. According to BioHealth Diagnosic Labs- the preferential pathway under chronic stress is called pregnenolone Steal or Cortisol Escape. When the body is in a Chronic stress response pregnenolone, the precursor to all the rest of the steroidal hormones, is diverted to cortisol-cortisone. 32 DHEA to Cortisol • This is to the detriment of all the other steroidal hormones; i.e. progesterone, aldosterone, DHEA and it’s metabolites; the sex hormones, estrogens and testosterone. • As pregnenolone is diverted to cortisol-cortisone, DHEA depletion begins. • The result is an elevated cortisol to DHEA ratio. A normal ratio is approximately 5:1 to 6:1. • The ratio is obtained by dividing the cortisol sum by the DHEA-S average 33 Salivary Hormone Levels • While the reference ranges for the four separate salivary captures are listed on the lab report, these values represent the Cortisol Sum and DHEA-S average. Normal range for Cortisol Sum: 23-42.0 nM Optimal range: 34-36 nM Normal range for DHEA-S: 2.00-10.00ng/ml Optimal range: 7.00-8.00ng/ml 34 Phases of Adrenal Exhaustion • Phase I is characterized by an increased output of Cortisol with a normal, low normal or low DHEA level. (Total Cortisol high) At least one cortisol is high. • Phase II is characterized by depressed cortisol levels, with a borderline low or low DHEA level. (Total Cortisol normal) Am, noon or afternoon cortisols low or borderline low. • Phase III is characterized by depressed Cortisol levels, with a Borderline low or low DHEA level. (Total Cortisol low) most cortisols low. 35 Phase 3 Adrenal Exhaustion 36 37 Interpretation • Common inducers of cortisol include tissue damage, inflammation, pain, glycemic dysregulation, GI disturbances as well as mental and emotional stressors. • Underlying physiological stressors that may not be demonstrated by obvious symptoms include gluten (gliadin), lactose and sucrose intolerance, as well as delayed food hypersensitivity, pathogens, and other inflammatory conditions. 38 39 HPA axis/HPT axis • The well know HPA axis provides the template for adrenal physiology, however a less known axis is the Hypothalamic pituitary thyroid axis. • As endocrine systems interact with each other, keep in mind that the production of T3 has a regulatory mechanism through these axis's, and as cortisol elevates there can be suppression of T4 conversion to T3 via(Reverse T3) 40 ALWAYS TREAT FUNDAMENTALS! 41 Glycemic status • It’s imperative to assess glycemic status regardless of a patients weight. • Fasting glucose is insufficient! • HbA1c and a fasting insulin is critical. • GTT also offers you the ability to determine reactive hypoglycemia (must do matched insulin’s). • Cortisol increases blood glucose levels in response to stress. Be aware of long term effects! 42 Interpretation Defining the perpetuators or inducers of adrenal exhaustion via a functional medicine platform requires a careful consultation and history, followed by additional laboratory testing to assist in etiologic mechanisms. One of the many benefits of the IAT model is rapid determination through an algorithmic model that allows the practitioner a means of isolation and cross-reactivity yielding either greater specificity in diagnostic choice or therapeutic options. Bioenergetics meets Biochemistry through an integrative model! 43 Why Correlation With Chemistries Are Key! 1.You cannot attain all the information about human health from muscle testing alone - but if you do it right, you can define a lot! 2. Corroborating your findings between muscle testing, blood chemistries and functional medicine algorithms, provide a solid template for correlation and enhanced clinical outcomes. 44 45 D e m o n s t r a t I o n Demonstration Adrenal Reflex4 o'clock at ring of the breast 46 DR. MARKS ADRENAL EXHAUSTION ALGORITHM™ Choose one or more interventions From each list using the established procedures for all IAT testing PHASE I ADRENAL EXHAUSTION PHASE II B6, Vitamin C, various botanicals, DHEA, Pregnenolone, Phos. Serine, ADAPTOGENS* Adrenal glandulars DHEA, cal-mag-potassium, Pregnenolone, Licorice Root, Sea salt ADAPTOGENS* * ELEUTHERO, ASHWAGANDHA, MACA, LEMMON BALM, RHODIOLA , HOLY BASIL, BACOPA, CORDYCEPS, Fo-Ti, Devils Club etc PHASE III Check for all Items in Phase II. Licorice root, glandulars Late stageDHEA/Pregnenolone Cortef-(P-hydrocortisone) Rx? ADAPTOGENS* 47 Serenelin Most anti-stress supplements work by sedating the central nervous system, causing drowsiness and impairing mental function. Serenelin alleviates the physical and psychological symptoms of occasional stress — while actually increasing energy and focus. The Stress Response Stress hormones released: epinephrine, norepinephrine, cortisol Brain waves go on high alert Body reacts to stress: fight or flight Increase in heart rate, blood pressure, and breathing rate Elevation in blood sugar to provide energy for action Shutdown of non-essential functions: digestion and reproduction Mind reacts to stress: anxiety, depression, irritability, moodiness Balance & Calming Sensoril®, a proprietary extract of ashwagandha, has been clinically shown to balance 2 hormones: Reduces levels of stress hormone cortisol, Boosts levels of energizing hormone DHEA L-theanine, an amino acid found in green tea, generates alpha brain waves within 30-40 minutes. GABA, an inhibitory neurotransmitter, takes longer to exert an effect (60 minutes), but is even better at producing alpha brain waves than L-theanine. Multiple Actions of Serenelin Balances stress hormones Produces calming brain waves Reduces symptoms of chronic stress Improves stress-induced negative mood Reduces Symptoms of Chronic Stress Sensoril Ashwaganda was shown in a double-blind, placebo-controlled study to reduce: Anxiety Heart palpitations Irritability Inability to concentrate Fatigue Sleeplessness Alleviates Stress-Induced Negative Mood In a double-blind clinical trial, a single dose of lemon balm alleviated negative mood of study subjects compared to placebo. NEUROTRANSMITTER FLOW CHART Serotonin Gaba Histamine Acetyl Choline PEA Acetyl choline Taurine OR Histamine PEA Pulse>10 Pulse <10 Glutamate Serotonin Nor epinephrine Gaba Dopamine Glutamate Taurine Nor epinephrine Dopamine Epinephrine Epinephrine IAT LOREN MARKS D.C., DACBN ALL RIGHTS RESERVED 2015 54 IAT Neurotransmitter(NT) Assessment • Gaba_________________ • PEA__________________ • Taurine________________ • Serotonin_______________ • Dopamine_______________ Pulse to attain a value of each. A pulse of 10 is normal As your skills improve, you will be able to define the major NT. Imbalances • Epinephrine______________ • Nor-epinephrine___________ • Glutamate________________ • Histamine_________________ • Acetylcholine_______________ 55 Positiva • Serving size: 3 caps (2 caps am/1 pm) • Vitamin D3 600iu • Folate(as Quatrefolic) 400mg • Venetron 125mg • Rhodiola 276mg • Lavender oil 80mg • Safely uplifts mood • Promotes feelings of calm • Encourages restful sleep • This formula supports all three aspects of mood related stress disturbances Nutrigenomics • Nutrigenomics is a branch of nutritional genomics and is the study of the effects of foods and food constituents on gene expression.[1] • This means that nutrigenomics is research focusing on identifying and understanding molecular-level interaction between nutrients and other dietary bioactives with the genome. • Nutrigenomics has also been described by the influence of genetic variation on nutrition, by correlating gene expression or SNPs with a nutrient's absorption, metabolism, elimination or biological effects. By doing so, nutrigenomics aims to develop rational means to optimize nutrition with respect to the subject's genotype. 57 Future Forecasting 2020> • The genomic understanding of how food interacts with our genes and SNP’s, is likely to change the way we have been diagnosing and treating people, from the foods that are right for us to the medicines that we use. • The MTHFR SNP is a perfect example. 58 Genetics and MTHFR 101 • Genes regulate enzymesMTHFR is the primary gene responsible for Folic Acid metabolism • SNP’s or Single nucleotide polymorphisms are mutations on genes • The 2 SNP’s possible for MTHFR are A1298c and C677t 59 Genetic possibilities • If a person has 1copy of C677t or A1298c there is a mild decrease in that persons ability to metabolize folates. This is termed heterozygous. • If you have 2 copies of either SNP, one is homozygous for the trait and has a higher risk of expressing this genotype. • If you have 1 copy of each C677t and A1298c you are compound heterozygous and at a similar risk to being homozygous 60 C677t vs A1298c • If a person is homozygous for C677t we know this mutation regulates Homocysteine synthesis. • If a person is homozygous for A1298c we know this mutation has a higher affinity for neurotransmitter synthesis via BH4 and can directly influence: Serotonin, Dopamine and Norepinephrine 61 WHAT’S ALL THE FUSS ABOUT MTHFR? • Folate is a vital component of the single carbon pool that participates in basic cellular processes such as amino acid metabolism, synthesis of nucleotides (DNA, RNA, ATP), and methylation (including epigenetic methylation of DNA). Low levels of folate are implicated in increased risk of cardiovascular disease, stroke, dementia, depression, cancers, and birth defects. Similarly, high levels are also associated with carcinogenesis (1). • http://www.cortjohnson.org/blog/2014/08/12/folic-acid-controversy-mthfr-chronic-fatigue-syndrome/ 62 What’s all the fuss about MTHFR? • The folate cycle feeds into other key biochemical cycles as well • The end product of folate metabolism, 5-MTHF, is an essential precursor for neurotransmitter metabolism and the synthesis of dopamine, serotonin, and norepinephrine • It is also necessary for the production of SAMe, which participates in over 200 enzymatic reactions in the body. • http://www.cortjohnson.org/blog/2014/08/12/folic-acid-controversy-mthfr-chronic-fatigue-syndrome/ 63 SNP’s and Methylation CH3Methyl 64 **Methylation status • Of all the various methylation functions in the body, the key is to determine overall status • **Despite looking at the primary MTHFR SNP and what alleles are present, it is whole blood histamine concentration or the SAMe to SAH ratio that determines ones methylation status. 65 Over or under? • If whole blood histamine is high, the patient is under methylated. • If whole blood histamine is low, the patient is over methylated. • DO NOT GIVE 5MTHF(methyl folate to under methylated patients who present with mood, behavior and mental health issues or they will get worse! (William J Walsh PhD) 66 WHY? • It has taken William J. Walsh, phD 25 years to solve this problem via epigenetic science Despite Methyl folate being an excellent methylator, under methylated depressives are intolerant to folates. Over methylators thrive on them. 67 Why? • Folic Acid generates acetylase enzymes that alter histones & promote expression of SERT. • SERT increases serotonin reuptake, thus reducing serotonin activity • For low serotonin depressives, the harmful impact of folic acid at the synapse exceeds the benefits of normalizing methylation! 68 Neurotransmitters • A global understanding of how the brain works neurochemically is that excitation must be balanced by inhibition. • Examples of inhibitory NT’s are gaba, taurine and serotonin. • Excitatory are glutamate, PEA, epinepherine and Nor- epinephrine • Dopamine is primarily inhibitory but can play a excitatory role. 69 Neurotransmitters • When considering etiologic mechanisms that induce HPA axis disruptions, look for emotional discord as a primary driver. • Identification of neurotransmitter status and the role of natural medicines can produce profound changes in your patient population, when balancing patterns of adrenal exhaustion. 70 GABA (Gamma aminobuteric acid) GABA or gamma-aminobutyric acid, discovered in 1950, is the most important and widespread inhibitory neurotransmitter in the brain. Excitation in the brain must be balanced with inhibition. Too much excitation can lead to restlessness, irritability, insomnia, and even seizures. GABA is able to induce relaxation, analgesia, and sleep. Barbiturates and benzodiazepines are known to stimulate GABA receptors, and hence induce relaxation. Several neurological disorders, such as epilepsy, sleep disorders, and Parkinson’s disease are affected by this neurotransmitter. GABA is made in the brain from the amino acid glutamate with the aid of vitamin B6. 71 What is a Pyrrole Disorder? • Pyrrole disorder (Pyroluria) is an abnormality in biochemistry resulting in the overproduction of pyrrole molecules, normal byproducts of hemoglobin synthesis and other processes in the body. • Excess pyrroles have little or no function in the body and are effectively secreted in the urine; however, pyrroles have an affinity for Zinc and B6 and may contribute to zinc deficiency by increasing urinary loss. • When elevated in the urine, they represent a marker for functional deficiencies in B6 and Zinc. 72 Pyrrole disorders • • • • • AKA Pyroluria Can be heritable or acquired Stress intolerance Chronic anxiety The loss of zinc can induce high copper levels; as these minerals balance each other. • High Copper can be toxic as well as a driver of adrenal fatigue. • High copper drives excitation because Dopamine in the presence of high copper converts to NorEpinepherine. 73 Pyrrole disorders • 85% of Irish and Scandinavian people have been found to have Pyroluria • All Autistic and ADHS patients should be screened for both methylation and Pyrrole status • Plasma Zinc and Serum Copper as well as testing the pyroluria in the urine is how one makes the diagnosis • These people tend to respond better to Omega 6 and not Omega 3. N-3’s actually makes them worse! 74 Pyrrole testing • Direct Healthcare access labs (Chicago) • http://pyroluriatesting.com/shop/contact/ • This is the preeminent lab for Pyrrole testing • It’s simple, easy for the doctor and patient, yet so revealing for many cases of anxiety, ADD, ADHD, alcoholism etc. • Physicians should screen for pyrroles before administering benzodiazepines!! 75 Pyrrole disorders do not cause the following conditions, but can be exacerbated by Pyrrole • • • • • • • • • • Alcoholism Epilepsy Autism/Asperger’s Learning disability Anxiety disorder Mood Swings Anti Social personality disorder Neurosis AD(H)D Psychosis Bipolar disorder Oppositional defiant disorder Criminal behavior Substance abuse Depression Schizophrenia Tourette syndrome Down syndrome 76 Oxidative load • It is well established that prolonged stress induces increased free radicals, elevating ones oxidative load. • From poor diets, high stress, disease states, and environmental exposures, keeping our oxidative burdens in check should be part of a healthy diet. 77 Zinc copper ratios • Various markers of oxidative load have been identified. • Serum Copper, Ceruloplasmin and Plasma zinc levels are easily attainable via any blood laboratory. • Plasma Zinc below 90 and Copper above 110 can be an expression of elevated oxidative load. Clinically Zinc should always be equal to or above the copper. 78 High Copper ramifications • Zinc is an antioxidant-Copper is an oxidant • They must oppose each other; it is the balance and state of copper that is important. • Copper is present bound and unbound in the blood • Ceruloplasmin is copper bound to protein. When the adrenals are under long term stress, the liver can become impaired; effects Ceruloplasmin production. This results in elevations of unbound or free copper. 79 High copper ramifications • In the presence of high copper, dopamine converts into norepinephrine, which drives chronic anxiety. • Chronic anxiety= adrenal overstimulation • Racing mind, sleep disturbances etc. 80 Copper Calculator • • • • • • • Attain your lab values as previously discussed. Take your Ceruloplamin and x 3 = ____ Subtract the serum copper, this gives you the general % of free copper. 5 to 20% = normal 20 to 30% = high normal 30 to 40% = elevated (high oxidative stress) > 50% = severe elevation (severe oxidative stress) 81 Metasol Oligonol, developed in Japan, is a proprietary polyphenol extract derived from lychee fruit and green tea that contains high levels of low-molecular weight flavanols for enhanced absorption and efficacy. Oligonol polyphenols are absorbed 3x better than polyphenols from regular lychee extract. Polyphenols in particular have been suggested to regulate the metabolism of fats. Oligonol: Research Oligonol reduced oxidative stress among healthy subjects with initially high scores and was superior to lychee fruit polyphenols. In male subjects with elevated fasting blood sugar, Oligonol suppressed postprandial hyperglycemia (recognized as a cardiovascular risk factor) compared to placebo. Oligonol improved post-prandial hyperlipidemia and inhibited matrix metalloproteinase (which plays a role in the initiation and progression of atherosclerosis) in healthy subjects compared to control. Oligonal reduced post exercise cortisol in healthy male subjects. Phos serine has previously been the supplement of choice for this purpose. Consider this as an additional or supplemental option for this purpose. WHAT YOU DO MATTERS Active pursuit K N O W L E D G E IAT Muscle Testing Functional Medicine Testing Blood Chemistries Outstanding Clinical results! Objective tools To measure outcomes Loren Marks D.C., DACBN 85