RESEARCH-DRIVEN BOTANICAL INTEGRATIVE ORTHOMOLECULAR INNOVATIVE

Relief of Pain for Diabetic Neuropathy

Weight Loss: More than Calories

Calorie Restriction & BenaGeneTM

Obesity and Type 2 Diabetes

Confused About

Cholesterol?

Red Yeast Rice with

Ankascin-568RTM

ANNIVERSARYANNIVERSARY

ADVANCESINNOVATIONS IN HEALTH

NATURE • SCIENCE • WELLNESS

CONTENTS

AOR's Collaborations with Academia040608131416

26AOR's INNOVATION TRACK RECORD

1991 1993 1996 1998 1999 2000 2001 2002 2005

AOR is founded PantethineFirst in Canada

R-Lipoic AcidFirst in World

BenfotiamineFirst in AmericaVitamin K2 First in World

Sustained Release R-Lipoic AcidFirst in World

Glucosamine Sulfate First in Canada

D-RiboseFirst in World

SAMeFirst in Canada

Strontium CitrateFirst in World

Broccoli Sprouts as Powerful Anti-Oxidants

Obesity and Type 2 Diabetes: Burning Less Fat Might Help… No, Really!

Natural Therapies for the Relief of Pain in Patients with Diabetic Neuropathy

Weight Loss: More than Calorie Cutting!

Red Yeast Rice with Ankascin-568RTM: Cholesterol Lowering Without the Side-Effects

AOR's 2017 Product Catalogue

24 Calorie Restriction and BenaGeneTM: The Key to Longevity?

20 Confused About Cholesterol? We Are Here to Help

By Dr Christopher Hillyar MSc DPhil (Oxon), Advances Editor

Welcome to Advances! As ever, Advances aims to showcase AOR's latest thinking and research in the field of natural health products. We continue our celebration of AOR’s 25th anniversary with 2017's 3rd issue of Advances, with articles focused on diabetes, pain relief, weight loss, longevity (life extension), and cardiovascular health and cholesterol. Our external collarborators open proceedings on page 6, where Dr Jerome Y Yager MD (Professor, University of Alberta) covers the powerful anti-oxidant effects of broccoli sprouts. On page 8, Dr Paul A. Spagnuolo PhD (Associate Professor, University of Guelph) provides insight into the complex balance of glucose and fatty acid metabolism, and explains why blocking fatty acid metabolism may be an appropriate therapeutic option for obese and type 2 diabetic patients. On page 13, Dr Trajinder Nibber (CEO and Scientific Director, AOR) discusses the use of natural therapies for the relief of pain in patients with diabetic neuropathy. On page 14, Dr Tranjinder Nibber continues with an article on weight loss, which, he says, may involve "many contributing factors and the simple reality is that cutting calories is not a clear solution for losing weight".The focus of the next two articles is cardiovascular health and cholesterol. On page 16, Dr Anjan Nibber (Advances Editor, AOR) discusses the mechanism of action of statins - blood pressure lowering drugs which may cause side-effects with long-term use - in comparison to AOR's statin-free Red Yeast Rice - a natural product free from side-effects that can be taken by patients with high cholesterol. Page 20 continues the theme of cardiovascular health, as Dr NavNirat Nibber (Medical Advisor, AOR) discusses 'good' and 'bad' cholesterol and the research supporting the use of bergamot extract in AOR's Opti-Cholest for the reduction of 'bad' cholesterol.Finally, Dr Paul Hrkal ND (Medical Advisor, AOR) and Dr Anjan Nibber shift the discussion to BenaGeneTM - a thermally stabilized form of oxaloacetate and a key intermediate in the energy producing processes of mitochondria - which "mimics the effects of calorie restriction". On page 24, Drs Paul Hrkal and Anjan Nibber discuss how oxaloacetate supplementation with BenaGeneTM may mimic the beneficial effects of calorie restriction.

On behalf of the entire team at AOR, I hope that you enjoy this latest issue of Advances.

AOR ADVANCES: Innovations in Health

Published by Advanced Orthomolecular Research Inc.

Editors Dr Anjan Nibber DPhil (Oxon), Dr Christopher Hillyar MSc DPhil (Oxon), Dr Trajinder Nibber MSc PhD (Imp Lond)

ContributorsDr Anjan Nibber DPhil, Dr NavNirat Nibber ND, Dr Christopher Hillyar MSc DPhil, Dr Trajinder Nibber MSc PhD, Dr Paul Hrkal ND, Dr Jerome Y Yager MD, Dr Paul A Spagnuolo PhD

Graphic DesignDr Christopher Hillyar MSc DPhil

Advances is published and distributed through integrative physicians, healthcare practitioners, and progressive health food retailers.

The content of this magazine is provided for informational purposes only and is not intended as a substitute for medical advice. Please consult a qualified healthcare professional for advice or concerns related to any topics discussed. Supplements mentioned are not intended to diagnose or cure medical conditions except for those health claims approved by the NNHPD.

Content and design © 2017 AOR Inc. Any reproduction in whole or in part and in print or electronic form without express permission is strictly forbidden. Permission to reproduce selected material may be granted by contacting publisher.

Letter From The Editor

2005 2007 2009 2011 2012 2016

Sustained Release R-Lipoic AcidFirst in World

Red Yeast RiceFree of Monocolin K and CitrininFirst in World

2006

Kampferol MyricetinFirst in World

2015

Oxaloacetate (BenaGene)First in World

Curcumin NanoparticesFirst in World

NOx3,2,1 TechnologyFirst in WorldHibiscus SabdariffaFirst in World

LongVida CurcuminFirst in CanadananoVAILABLE BosweliaFirst in WorldProbiotic 3First in America

Complete line of vegetarian soft gelsFirst in World

2017

Curcumin Ultra(CurQfen and Turmacin)First in World

29 COLLABORATIONS WITH ACADEMIA

Ottawa Integrative Cancer Centre,ON, CanadaExploring the impact of advanced integrative care delivered by NDs for patients with advanced cancer (T-POISE Study)

Ulster University, Coleraine, Northern IrelandNutrient-gene interactions and the development of personalized nutrition

University of Waterloo, ON, CanadaMethods of isolating and extracting the bioactivity from novel, natural plant ingredients

University of British Columbia, BC, CanadaUse of novel anti-fibrogenic factors in the development of an anti-scarring cream to improve the outcome of wound healing

University of Guelph, ON, CanadaIsolation of bovine lactoferrin by membrane filtrationIsolation & characterization of Bowman Birk Inhibitor from various beansStudying a novel lipid for inhibition of fatty acid oxidationPhosphopeptides and diphospho-serine to combat oxidative stress in chronic bowel disease

McMaster University, ON, CanadaBenefit of Strontium Support II in post-menopausal women

University of Alberta, AB, CanadaL-Glutamine vs. maltodextrin in the Cardiovascular Intensive Care UnitDevelopment of a functional flour with low GI, high fibre and low caloric contentOptimizing conditions to produce natural molecules with anti-hypertensive properties

CHU Sainte-Justine, QC, CanadaLactoferrin’s effect on premature neonate survival

University of Calgary, AB, CanadaBioactive components from milk proteins: Beneficial effects on body weight, diabetes, and cardiovascular disease

University of Amsterdam, Amsterdam, HollandEffects of gamma butyro betaine in healthy adults with

impact on lipid and acyl carnitine metabolism

Queens University, ON, CanadaBovine lactoferrin in the prevention of infection in

mechanically ventilated, critically ill adult patients

University of Manitoba, MB, CanadaEffects of a pea protein hydrolysate in

hypertensive rats and humansStructural and functional

characterization of ferritin from Manitoba legumeslogical effects

of pea protein hydrolysate in chronic kidney disease

Memorial University of Newfoundland, NF, Canada

Development of esters of EGCg and other bioactives as natural health

products

Rutgers State University, New Jersey, USADevelopment of nano/micro emulsions and organogels for improving bioavailability of

various bioactivesDevelopment of potent polymethoxylated flavonoids as hypocholesterolemic,

anti-obesity and anti-cancer agents

North Carolina Ag & Tech State University,

North Carolina, USAPurification and

structure elucidation of avenanthramides from oat bran

University of Wisconsin, Wisconsin, USA

Topical and oral formulations against inflammation, UV damage,

oxidation, and ageing

Université Laval, QC, CanadaUse of electrodialysis with ultrafiltration

technology for separation and concentration of bioactives

University of Windsor, Ontario, CanadaExtraction of bio-actives with potent anti-cancer

activities

PAST PROJECTSAlbert Einstein Medical College,

New York, USAEffects of benfotiamine, and R-lipoic acid on blood

glycating indices HbA1c

University of East Anglia, UKEffect of an anti-homocysteine formulation on CVD markers in humans

University of Toronto, Ontario, CanadaEffect of CoQ10 in women undergoing IVF for infertility

Washington University School of Medicine, Missouri, USAVitamin MK-4, VKORC1 Polymorphism, and osteoporotic fractures

It may well be true that if we had listened better to what our grandparents and parents taught us about the importance

of eating fruit and vegetables, we would be living healthier and perhaps longer lives. Research is beginning to show us that aging, and the diseases that accompany that process, may well be the result of the decreasing ability of our bodies to deal with oxidative stress. There is also substantial evidence showing that eating adequate amounts of fruits and vegetables de-creases our chances of developing can-cer, high blood pres-sure, heart disease, stroke and diabetes.

Oxidative stress is the result of an imbalance of pro-oxidant/anti-oxidant homeostasis that leads to the overproduction of reactive oxygen species (ROS). At abnormal levels, ROS can have toxic effects including 1) damage to DNA (cancer-causing effects) or 2) damage to structural components of the brain (neurodegenerative effects, e.g. Alzheimer’s disease). A complex network of enzymes and transcriptional factors exist to counteract the effects of oxidative stress. The balance between pro-oxidant and anti-oxidant activity is weighted such that with additional stress or injury to the cell, oxidant stress leads to aging of cells, disease and damage.

Interestingly, the young broccoli sprout of about 3-4 days old is upwards of 100 times more potent as an anti-oxidant than the mature broccoli plant and most other cruciferous vegetables (cabbage, cauliflower, bok choy, and brussel sprouts). Broccoli sprouts contain a metabolite that increases the oxidant

fighting capacity of the cells in our body. The anti-oxidant potential is released from the sprout when it is chewed, and the plant is broken down. A chemical in the sprout, known as glucoraphanin, combines with the enzyme myrosinase, to form the active chemical sulforaphane.

It is sulforaphane which is the bioactive constituent of the broccoli sprout.

Sulforaphane acts through a host of anti-oxidant enzymes, such as superoxide d ismutase and glutathione. One of the best studied downstream effects of sulforaphane is the increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a protein normally s e q u e s t e r e d (trapped) in the cytoplasm within each cell. Once released from the cell, Nrf2 enters the nucleus (control centre) of the cell and binds to a protein

commonly known as antioxidant response element (ARE). ARE is the master regulator of the antioxidant system available in all human cells. By binding ARE, Nrf2 is capable of eliminating thousands, if not millions of free radicals. As such, sulfurophane acts to prevent cells from oxidative stress, slowing down the aging process and protecting cells against disease and damage. Indeed, extensive research has been completed to show the protective properties of sulforaphane in several disorders associated with oxidative stress such as cerebral ischemia, brain inflammation, and acute renal failure (1-3).

But what about newborn babies and young children? It appears that the majority of

It may well be true that if we had listened better to what our grandparents and

parents taught us about the importance of eating fruit and vegetables, we would be living healthier

and perhaps longer lives.

"

"

Broccoli Sprouts as Powerful Anti-OxidantsDr Jerome Y Yager MD, Edmonton, Alberta, Canada

ADVANCES IN ANTI-OXIDANT RESEARCH

Oxidative StressOxidative stress is the result of an imbalance of pro-oxidant and anti-oxidant homeostasis that leads to the overproduction of reactive oxygen species (ROS). At abnormal levels, ROS can have toxic effects including 1) damage to DNA (cancer-causing effects) or 2) dam-age to structural components of the brain (neurode-generative effects, e.g. Alzheimer’s disease).

Key Terms

6

causes of injury to the newborn brain actually occur during pregnancy and late gestation (4). In many, there is an underlying, often unrecognized infection, or a reduction in blood flow from the placenta to the fetus. This can result in a build up of free radicals causing brain and other organ damage. There are a number of conditions such as cerebral palsy and other developmental disabilities in childhood (attention deficit disorder and autism spectrum disorder), which have underlying oxidative stress aetiologies due to placental insufficiency. Babies, in particular, have a lower capability of fighting free radical oxidant stress than adults do, and therefore are often more sensitive to injury.

Generally, the approach to interventions has focused on rescue therapies that will target and help recover the damaged brain tissue (5). In order for rescue therapies to be effective, they must be administered shortly after injury. Unfortunately, newborn brain injury is difficult to time and therefore treatment is complicated. As such, attention has shifted to preventing injury from occurring, and animal studies have shown promise.

The Perinatal Research Laboratory (University of Alberta), under the supervision of Dr Jerome Y Yager MD, has looked at the potential of protecting the newborn brain from injury, by supplementing the diet of pregnant rodents with broccoli sprouts. In these studies (6), pregnant rodents underwent bilateral uterine artery ligation, which mimics the placental insufficiency of cerebral palsy. The researchers have found

that when supplemented with broccoli sprouts (200 mg/kg) during the last trimester of pregnancy and early infancy, newborns did not show the same developmental deficits, nor the brain injury that is often associated with children who have cerebral palsy. This was in contrast to the newborns from mothers that were not fed with broccoli spouts in their third semester of pregnancy. In other words, it appears that by enhancing the activation of Nrf2 in either the mother or the fetus, with added broccoli sprout supplementation, and presumably the activation of sulforaphane, injury to the brain, and therefore behavioural abnormalities, was prevented.

Though results in the fields of cancer, diabetes, stroke, high blood pressure and autism have also been promising regarding the use of sulforaphane and/or broccoli sprouts , th is

work s tands alone in the field of the vulnerable f e t u s a n d newborn. Much work c lear ly needs to be done to advance th is sc ience . However, given that the majority of injury to the newborn brain occurs during p r e g n a n c y , rather than labor and delivery, work with this powerful anti-oxidant appears promising as a preventive

a p p r o a c h , a n d perhaps one that may reduce the risk for developing brain damage to the millions of newborns affected around the world each year.

ADVANCES IN ANTI-OXIDANT RESEARCH

SulforaphaneSulforaphane is the bioactive constitu-ent of the broccoli sprout. Sulfora-phane is formed when a chemical in the sprout, known as glucoraphanin, combines with the enzyme myrosi-nase. Sulforaphane acts through a host of anti-oxidant enzymes, such as superoxide dismutase and glutathione, with one of the best studied down-stream effects of sulforaphane being the induction of the antioxidant system available in all human cells.

Key Terms

References

1. Noyan-Ashraf MH, et al. Dietary approaches to positively influence fetal determinants of adult health. FASEB J. 2006;20(2):371-3. doi: 10.1096/fj.05-4889fje.

2. Wu L, et al. Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system. PNAS. 2004;101(18):7094-9.

3. Zhao J, et al. Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neurosci. Lett. 2006;393(2-3):108-12.

4. Ferriero DM. Neonatal brain injury. N. Engl. J. Med. 2014;351:1985-95.5. Nguyen A et al. Evidence for Therapeutic Intervention in the Prevention of Cerebral Palsy: Hope

from Animal Model Research. Semin. Pediatr. Neurol. 2013;20:75-83.6. Black AM et al. Broccoli sprout supplementation during pregnancy prevents brain injury in the

newborn rat following placental insufficiency. Behav. Brain Res. 2015;15(291):289-98.

The Perinatal Research Laboratory (University of

Alberta)...has looked at the potential of protecting the newborn brain from injury, by supplementing the diet of pregnant rodents with

broccoli sprouts.

"

"

7

The link between obesity and diabe-tes is unquestionable, so the glob-al rise in obesity and type 2 diabetes

(T2D) rates is no surprise. A 2014 report from Statistics Canada suggests that more than five million Canadian adults are obese, out of which more than three million were diag-nosed with T2D. In 2010, diabetes and pre-di-abetes cost the Canadian health care system over two billion dollars. With all these num-bers expected to double in the next decade, there is a glaring need for interventions to slow down this North American epidem-ic. T2D is a chronic disease where insulin - a hor-mone that controls blood glucose levels - can no longer stimulate body tissues to utilize glu-cose for energy. The direct result of this insulin resistance is elevated glucose, which is lethal to nerves, blood vessels, and numerous tis-sues including liver, skeletal muscle, pancreas, heart and adipose tissue. Patients with diabe-tes have elevated levels of blood glucose, in-sulin, and free fatty acids. The increase in free fatty acids is of particular interest, as free fatty acids can stimulate glucose production in the liver (gluconeogenesis) further perpetuating the disease (1). Normally, a well-established balance exists between utilizing glucose and fat as fuels. In the fasted state, fat metabolism is increased, which decreases glucose oxi-dation and increases gluconeogenesis, thus preserving blood glucose for use by the brain. Conversely, fatty acid oxidation is decreased in the fed state, which increases glucose oxida-tion and decreases gluconeogenesis (2).

This transition from fatty acid to glucose oxidation from the fasted to fed state is

heavily impaired in obese and diabetic patients where all metabolically active tissue types are locked in an inflexible fatty acid dependent state (3) (see Figure 1). Despite this finding, the clinical focus for many decades has been increasing fatty acid oxidation to clear surplus fat stores in obese and diabetic individuals, as an intuitive approach to improve insulin sensitivity. This article aims to discuss how blocking fatty acid oxidation in the context of inactivity, over-nutrition, obesity, and diabetes may be an established, alternative therapeutic strategy. In other words, burning less fat may be better!

A simple recap on how our cells breakdown glucose and fat for energy (ATP), makes this concept easier to grasp (see Figure 2). Glucose metabolism involves three key steps: glycolysis, Krebs cycle and oxidative phosphorylation. First, glycolysis involves the enzymatic conversion of glucose to pyruvate in the cytosol, after which pyruvate enters the mitochondria to take part in the Krebs cycle. Once in the mitochondria, pyruvate is converted to acetyl-CoA and then citric acid, which goes through eight enzymatic rearrangements to create Krebs cycle intermediates (keto acids) as well as reducing equivalents (NADH and FADH

2). The reducing equivalents from the Krebs cycle are used in oxidative phosphorylation where a series of redox reactions occur in the inner mitochondrial membrane producing an electrochemical gradient that generates ATP. Fatty acids, on the other hand, must be esterified to fatty acyl-CoA prior to oxidative degradation in the mitochondrial matrix via the fatty acid-oxidation pathway. Fatty acyl-CoA uptake into mitochondrial matrix

Obesity and Type 2 Diabetes: Burning Less Fat Might Help… No, Really!

ADVANCES IN DIABETES RESEARCH

Type 2 Diabetes (T2D)A chronic con-dition primarily caused by obesity, whereby cells of the body are no longer responsive to insulin. As such, patients with insulin resistance have raised blood glucose levels.

Fatty Acid Oxida-tion (β-Oxidation)A process by which fatty acid mole-cules are broken down and used to generate energy. In the fasted state, fatty acid oxidation is increased, whilst in the fed state, fatty acid oxidation is reduced.

Dr Paul A Spagnuolo PhD, Associate Professor, Department of Food Science, University of Guelph, Guelph, Ontario, Canada

Key Terms

Despite the clinical focus on increasing fatty acid oxidation to clear surplus fat stores in obese and diabetic individuals, new research suggests that increasing fatty acid metabolism does more harm than good. This article provides insight into the complex balance of glucose and fatty acid metabolism, and why blocking fatty acid metabolism may be a more appropriate therapeutic option for obese and type 2 diabetic patients.

Simply put...

8

is dependent on the conversion of fatty acyl-CoA to fatty acyl-carnitine by carnitine palmitoyltransferase-1 (CPT-1), which is the rate limiting enzyme for fatty acid uptake (2). The beta-oxidation pathway is initiated upon entry of the fatty acids into the mitochondrial matrix in an appropriate form. Much like how pyruvate from glucose is converted to acetyl-CoA to be used by the mitochondria, each long chain fatty acyl-CoA molecule has two carbons removed every oxidation cycle to yield acetyl-CoA and the reducing equivalents, which take part in the Krebs cycle and oxidative phosphorylation to produce energy (ATP).

Having reviewed how glucose and lipids both have to use the Krebs cycle and oxidative phosphorylation to be completely metabolized, one should appreciate how important it is for the mitochondria to shift from lipid metabolism during the fasted state and to glucose metabolism during the fed state, a process termed the Randle cycle (2). The dietary lipid surplus and low physical activity status in obese individuals usually precedes the onset of diabetes, as excessive fatty acids get converted into fatty acyl-CoAs and accumulate in the mitochondria causing overload (4). Mitochondria overloaded with fatty acyl-CoA begin to undergo excessive βoxidation that i) immediately shuts down glycolysis (and thus glucose utilization) (2), ii) causes incomplete oxidation of fatty acids as mitochondrial control is lost (4) and iii) depletes several substrates and intermediates of the Krebs cycle, impeding oxidative phosphorylation for ATP production (4). All of these events play a significant role in causing weight gain, insulin resistance, and T2D for two reasons. First, the excessive fatty acid oxidation reduces glucose metabolism and chronically raises blood sugar, which impa i rs g lucose stimulated insulin secretion and depletes insulin stores in pancreatic beta-cells as they try to compensate (5, 6). Second, the incomplete oxidation of fatty acids leaves behind un-metabolized fatty acyl-CoAs and

other intermediates that further deplete pancreatic beta-cell insulin stores and also produce harmful reactive oxygen species (7). Many of these observations have been made in skeletal muscles of rodents and humans; skeletal muscles account for more than 70% of all glucose utilization in the body (2, 8). For these reasons, inhibiting fatty acid oxidation in skeletal muscle is a therapeutic strategy to improve whole-body insulin sensitivity and glucose tolerance in obese and diabetic individuals.

Research to date comprehensively points to blocking fatty acid oxidation as an established therapeutic approach for the treatment of T2D. In animal models of obesity and diabetes, CPT-1 inhibitors (e.g. etomoxir and oxfenecine) were lead candidates for clinical development as they i) improved glucose utilization by causing a shift towards the more thermogenic oxidative phosphorylation and glycolysis (1, 9), ii) reduced hyperglycemia via inhibiting liver gluconeogenesis and improving glucose homeostasis (10, 11), and iii) increased the expression of mitochondrial uncoupling proteins, which protect against oxidative stress and boost glucose stimulated insulin secretion (12). Despite the pre-clinical promise of CPT-1 inhibitors, human clinical trials on etomoxir revealed adverse cardiovascular and hepatic toxicity as the high effective clinical dose was impeding mitochondrial function in muscle, liver and heart tissue (13, 14).

CPT-1 inhibitors are certainly not the only avenue for achieving fatty acid oxidation

ADVANCES IN DIABETES RESEARCH

Fatty Acyl-CoAFatty acyl-CoA is a fatty acid which has undergone esterification. This process is crucial for uptake into the mitochondria and the initiation of β-oxidation. An overload of fatty acyl-CoA in the mitochondria can lead to excessive β-oxidation, and a reduction in glucose metabo-lism.

Figure 1. Chronic nutrient overload in obese and diabetic individu-als drives up fatty acid oxidation and leaves metaboli-cally active tissue in a rigid fatty acid dependent state. Excessive fatty acid oxidation chron-ically suppresses glucose utilization and drives the pro-duction of glucose in the liver, further worsening insulin resistance.

Figure 1

Key Terms

Figure 1: Legend

9

1. Karpe, F., et al. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60(10):2441-9.2. Randle, P.J. Regulatory interactions between lipids and carbohydrates: The glucose fatty acid cycle after 35 years.

Diabetes-Metabolism Reviews. 1998;14(4):263-283.3. Bayeva, M. Taking diabetes to heart--deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J. Am.

Heart Assoc. 2013;2(6):e000433.4. Koves, T.R., et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin

resistance. Cell Metab. 2008;7(1):45-56.5. Vernier, S., et al. Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets. Islets.

2012;4(6):379-92.6. Erion, K.A., et al. Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-

stimulated Insulin Secretion in Pancreatic beta-Cells. J. Biol. Chem. 2015;290(26):16191-201.7. Prentki, M., et al. Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced

insulin secretion. J. Biol. Chem. 1992;267(9):5802-10.8. DeFronzo, R.A., et al. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry

and hepatic and femoral venous catheterization. Diabetes. 1981;30(12):1000-7.9. Gao, S., et al. Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese

mice with insulin resistance. Mol. Metab. 2015;4(4):310-24.10. Conti, R., et al. Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces

gluconeogenesis and improves glucose homeostasis. Diabetes 2011;60(2):644-51.11. Keung, W., et al. Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced

obese mice. Diabetes. 201362(3):711-20.12. Li, Y., et al. UCP-2 and UCP-3 proteins are differentially regulated in pancreatic beta-cells. PLoS ONE. 2008;3(1):e1397.13. Bayeva, M., et al. Taking Diabetes to Heart-Deregulation of Myocardial Lipid Metabolism in Diabetic Cardiomyopathy.

Journal of the American Heart Association. 2013;2(6).14. Holubarsch, C.J., et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two

doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. (Lond.) 2007;113(4):205-12.

15. Muoio, D.M. and C.B. Newgard. Fatty acid oxidation and insulin action: when less is more. Diabetes. 2008;57(6):1455-6.

INNOVATIONS IN TECHNOLOGY

References

Carnitine Palmi-toyltransferase-1 (CPT-1)A rate-limiting enzyme for the uptake of fatty acyl-CoA from the cytosol into the mitochondria. This step is crucial for β-oxidation.

CPT-1 InhibitorsDrugs that inhibit the enzyme CPT-1, preventing fatty acid oxidation. These drugs improve glucose utilization, reduc-ing blood glucose levels. Side effects include cardiovas-cular stress and hepatotoxicity.

Figure 2. Key steps of glucose and lipid metab-olism.

Key Terms inhibition in obese and diabetic individuals. Fatty acid oxidation inhibition can be achieved more downstream of fatty acid uptake into mitochondria; for instance, certain enzymes of beta-oxidation can be inhibited. Additionally, a glucose-derived metabolite, malonyl-CoA, is known to block fatty acid oxidation as part of the Randle cycle. As such, boosting levels of malonyl-CoA has also

been found, though only pre-clinically, to decrease insulin resistance (15). The clinical dose limiting toxicity of synthetic fatty acid oxidation inhibitors like etomoxir does not place questions over the science behind this therapeutic strategy. Rather, it highlights the need for a natural bioactive that can be developed as a fatty acid oxidation inhibitor for metabolic diseases.

Figure 2: Legend

Figure 2

ADVANCES IN DIABETES RESEARCH

10

Natural Therapies for the Relief of Pain in Patients with Diabetic NeuropathyDr Trajinder Nibber MSc PhD, CEO and Scientific Director, AOR, 3900 - 12 Street NE, Calgary, Canada, T2E 8H9

ADVANCES IN PAIN RELIEF

In the article on page 8, obesity and type 2 diabetes (T2D) were discussed in the con-text of fatty acid oxidation. While there is

a definite need to identify natural products that could aid in the reduction of fatty acid oxidation, a variety of natural products for the improvement of diabetic neuropathy symptoms have been identified and contin-ue to be explored.

Diabetic neuropathies comprise a group of heterogeneous disorders caused by poorly managed or untreated T2D. Prolonged hyperglycemia (high blood sugar levels) induces increased production of free radicals, which can damage nerve fibres and cause nerve cell death. As such, patients with diabetic neuropathy often experience pain, numbness, hypersensitivity, and reduced function in the legs and arms. There is no known cure for this painful disease. Doctors generally suggest lifestyle changes, such as smoking cessation, weight loss, and blood pressure management. However, lifestyle changes may not always be enough to alleviate symptoms. Unfortunately, it is very difficult to treat neuropathic pain with medication. Medications used for the treatment of neuropathic pain include antidepressents, antiepileptics and opioids, which are limited in their effectiveness and have considerable side effects (1). Therefore, there has been increased focus on identifying new effective natural products that do not have associated side-effects. A few evidence-based natural products worth considering are highlighted below.

Vitamin B ComplexVitamin B complex is a group of eight vitamins that have many essential roles in the body including energy production, mood regulation, and nerve function. Interestingly, vitamin B12 deficiency is often associated with diabetes and diabetic neuropathy, and supplementation has been proposed to improve nerve function. A systematic review of seven controlled trials suggested that patients with diabetic neuropathy showed a symptomatic improvement (in pain relief) when treated with vitamin B complex (2).

R-Lipoic AcidR-(alpha) lipoic acid (ALA) is a powerful antioxidant that protects brain and nerve cells from hyperglycemia-induced oxidative stress. Research has found that ALA is actually better tolerated than prescription analgesic drugs for diabetic neuropathy, and has the benefit of a more rapid onset

of action, with substantial symptom improvement noted after only 3-5 weeks of supplementation (3). Furthermore, several human trials have shown that ALA supplementation improved pain, tingling, muscle strength, and prevented worsening in patients with diabetic neuropathy (4). These improvements are more likely to be seen in patients with diabetes with early neuropathic symptoms, as opposed to treating patients with progressive disease.

Acetyl-L-CarnitineAcetyl-L-carnitine (ALC) is an amino acid that is capable of accessing the central nervous system (brain and spinal cord). It is a versatile nutrient that helps to improve energy production in the mitochondria of nerve cells, especially when trying to heal damaged nerves. Patients with diabetic neuropathy have been found to have low levels of ALC in their bodies, in comparison to patients with well managed diabetes and without neuropathies. Supplementation with ALC has been associated with a decrease in neuropathy pain and better nerve function. The evidence-based dose for treating diabetic neuropathy is 2000 mg/day of ALC for six months (5). ALC is thought to decrease insulin resistance and improve cellular uptake of glucose, thereby aiding in the regulation of blood sugar and preventing further diabetic damage to the nerves (6). Animal studies have actually shown that ALC can help with regrowth of damaged nerve cells. Much like ALA, ALC supplementation should be recommended early on in the disease process for maximum benefit (7).

Whilst more large-scale clinical trials are needed to further elucidate the effects of vitamin B complex, ALA and ALC in the context of neuropathy, these initial results of are encouraging. These products offer a natural alternative to current medications, which are associated with side-effects and limited efficacy.

References1. Mijnhour et al. The Journal of Medicine.

2010;4:158-162.2. Sun et al. DARE Reviews. 2005. 3. Papanas N and Ziegler D. Expert. Opin.

Pharmacother. 2014;15(18):2721-31.4. Ziegler et al. Diabetes Care. 2011;34:2054-

2060.5. Onofrj et al. Int. J. Clin. Pharm. Res. 1995;15:9-

15.6. Acetyl-L-Carnitine Monograph. Alternative

Medicine Review. 2010;15(1):76-83.7. Evans et al. Ann. Pharmacother.

2008;42(11):1686-91.

Diabetic NeuropathyA group of disor-ders caused by poorly managed type 2 diabe-tes. Symptoms often include pain, numbness, hy-persensitivity and reduced function in the legs and arms.

Vitamin B ComplexVitamin B complex is a group of eight vitamins that have many essential roles in the body including energy production, mood regulation, nerve support and offset-ting the effects of stress.

R-Lipoic AcidR-(alpha) lipoic acid (ALA) is a powerful antioxidant that protects brain and nerve cells from free radicals.

Acetyl-L-CarnitineAcetyl-L-carnitine (ALC) is an amino acid and a versatile nutrient that helps to improve energy production in the mitochondria of nerve cells, espe-cially when trying to heal damaged nerves.

Key Terms

13

Every day, we are bombarded with advertisements for new weight loss diets, supplements, and exercise

routines. The vast majority of us spend our entire lives struggling to maintain a weight that is healthy or desirable. There are cer-tainly many people that are over-eating or under-exercising for their caloric require-ments, and this contributes to obesity and a plethora of other disease states, such as diabetes. However, for some individuals, it doesn’t matter how little we eat, or how much we exercise, be-cause the weigh-ing scale doesn’t seem to budge! Weight loss can be quite complex with many con-tributing factors, and the simple reality is that cut-ting calories is not a clear solution for losing weight.

Here’s why:

Calorie Counting is Good… In Theory

When we eat food, we are c o n s u m i n g energy. When we exercise or create movement, we are burning energy. When attempting to lose weight, the simplest goal is to eat less energy relative to the amount of energy that your body uses. In fact, it is often stated that an energy deficit of 3500 kcal will lead to fat loss of exactly one pound. But this simple equation does not take into account the type of macronutrients or micronutrients that you are actually consuming, nor does it consider the strong influence of hormones.

A Calorie is Not Just a Calorie

Most people that have done their own dietary

research know that the human body does not respond to refined carbohydrates (i.e. added sugars) the same way that it does to protein, fats, or even complex carbohydrates. When we eat natural sugars found in fruit paired with high fibre content, we have a blunted rise in blood glucose and insulin. If you eat the same number of calories from a donut, your sugar spikes and excess sugars become converted and deposited into fat. Similarly, low-carbohydrate d i e t s h a v e consistently shown greater weight loss

when compared to low-fat diets w i t h e q u a l calor ic intake. Physiologically, the body treats fats, proteins, and carbohydrates differently.

What About Hormones?

T h e t h y r o i d i s l a r g e l y responsible for maintaining the body’s metabolic rate, through the release of thyroid hormones. These hormones dictate how fast or slow the cells

in our body burn energy. This explains why individuals with hypothyroidism (low thyroid function) often present with weight gain or the inability to lose weight. Other hormones that are integral in the maintenance of a healthy weight include: estrogen, progesterone, testosterone, insulin and cortisol. Factors such as stress, poor liver function, and nutritional deficiencies can all imbalance these crucial hormones, resulting in difficulty in losing weight!

Weight Loss: More than Calorie Cutting!

ADVANCES IN WEIGHT MANAGEMENT

CalorieA unit of energy commonly used on food packaging to describe how much energy is obtained through the consumption of a specific food product.

HormonesSignalling mole-cules that are used for communication between various organs in the body for physiological regulation over processes such as metabolism.

Dr Trajinder Nibber MSc PhD, CEO and Scientific Director, AOR, 3900 - 12 Street NE, Calgary, Canada, T2E 8H9

Key Terms

For some individuals, it doesn’t matter how little we eat, or how much we exercise, because the weighing scale doesn’t seem to budge! Weight loss can be quite complex with many contributing

factors and the simple reality is that cutting calories is not a clear solution for losing weight.

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The Importance of Stress

When we are stressed, our body needs energy to deal with the stressful event. During stress, the hormone cortisol is released, which prompts gluconeogenesis (glucose production). However, when cortisol is elevated for prolonged periods of time, high glucose levels leads to insulin resistance, which can cause type 2 diabetes. Despite high glucose levels, the glucose cannot be taken up by the cells, which consequently become starved for energy. Hunger signals are sent to the brain, and the result is increased food consumption. Furthermore, cortisol levels can promote fat deposition, and sugar cravings! Some researchers have found stress-management programs with n o d i e t a r y changes to be more effective for weight loss than dietary changes alone, highlighting the i m p o r t a n c e o f s t r e s s management.

Sleep and its Role in Weight Management

In 2010, Hairston and colleageus conducted a l a r g e - s c a l e study examining sleep habits in over 86,000 postmenopausal women. The group found a strong a s s o c i a t i o n b e t w e e n a b n o r m a l sleep patterns (both lack of sleep and excess sleep) and obesity risk. Other studies have also found shorter and longer sleep durations to be associated with

greater body mass and greater abdominal fat measurements. The association between sleep deprivation and obesity appears to be not only linked with behavioural changes (such as exercising less when you’re tired), but also to hormonal dysregulation. Sleeping less than six hours per night results in blood sugar imbalances, insulin resistance and, ultimately, widespread inflammation in the body.

Environmental Toxins

There is now a mountain of evidence to show that toxins in our environment can play a great role in body size. Studies have shown that prolonged exposure to chemicals such as hexachlorobenzene, polybrominated biphenyl, and phthalates can disrupt normal endocrine function, leading to weight gain. This is one reason why it is advised to eliminate plastic containers and opt for glass

instead, and to avoid unnecessary pesticides and chemical laden cleaners.

Conclusion

Weight loss is a complex process and there is much more to consider than just counting your calories. Eating the right type of food, getting restful sleep, avoiding exposure to toxic chemicals, and minimizing stressors in your life will all help to normalize

your hormones and endocrine system, and promote healthy weight in the long-run.

ADVANCES IN WEIGHT MANAGEMENT

CortisolA hormone released by the adrenal gland during times of stress to increase the production of glucose for energy.

Key Terms

1. Jenkins DJ et al. Glycemic index: overview of implications in health and disease. Am. J. Clin. Nutr. 2002;76(1):266S-73S.

2. Krebs NF et al. Efficacy and safety of a high protein, low carbohydrate diet for weight loss in severely obese adolescents. J. Pediatrics. 2010;157(2):252-258.

3. Diana Fernandez et al. Images of a Healthy Worksite: A Group-Randomized Trial for Worksite Weight Gain Prevention with Employee Participation in Intervention Design. American Journal of Public Health. 2015;e1.

4. Patel SR et al. The association between sleep duration and obesity in older adults. Int. J. Obes. (Lond.) 2008;32(12):1825-1834.

5. Hairston KG et al. Sleep duration and five-year abdominal fat accumulation in a minority cohort: the IRAS family study. Sleep. 2010;33:289-295.

6. Tang-Péronard JL et al. Endocrine-disrupting chemicals and obesity development in humans: a review. Obes. Rev. 2011;12(8):622-36.

References

As you can clearly see, weight loss is a complex pro-

cess and there is much more to consider than just calorie count-ing. Eating the right type of food,

getting restful sleep, avoiding exposure to toxic chemicals, and minimizing stressors in your life

will all help.

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Red Yeast Rice with Ankascin-568RTM: Cholesterol Lowering Without the Side-Effects Dr Anjan Nibber DPhil (Oxon), AOR, 3900 - 12 Street NE, Calgary, Canada, T2E 8H9

PRODUCT SPOTLIGHT

High-Density Lipoprotein (HDL) and Low-Density Lipoprotein (LDL)HDL and LDL cholesterol are the two main types of cholesterol, and are often termed 'good' (HDL) and 'bad' (LDL) cho-lesterol. The ideal objective of choles-terol management is the reduction of ‘bad’ LDL cho-lesterol with the improvement of the level of ‘good’ HDL cholesterol (increased HDL:LDL ratio).

Hypercholester-olemiaHypercholester-olemia is the term for high blood cholesterol. High blood cholesterol may result in the formation of fatty deposits (plaques) in the walls of blood vessels, re-sulting in the nar-rowing (stenosis) of the blood vessel, the obstruction of blood flow, and an elevated risk for heart disease.

StatinsStatins are a class of drugs commonly prescribed for the management of high blood choles-terol. The mecha-nism of action of statins is shown in Figure 1.

Key Terms

High Blood Cholesterol

Cholesterol is a sterol obtained from animal fat and synthesized in the liver. It is a key component of cell membranes, accounting for 10%-50% of membrane lipids (fats). There are two types of cholesterol that are typically referenced when discussing health: high-density lipoprotein (HDL), referred to as ’good’ cholesterol, and low-density lipoprotein (LDL), referred to as ’bad’ cholesterol. Cardiovascular issues arise when there are abnormally high levels of total cholesterol in the blood, and when there is an imbalance of LDL and HDL cholesterol (high LDL:HDL ratio). This imbalance can result in the formation of plaques, which are fatty deposits of cholesterol that build up along blood vessels, narrowing the blood vessels. Blood vessel narrowing (stenosis) increases a person’s risk of heart disease. The ideal outcome of the management of high blood cholesterol is the reduction of a person’s risk of heart disease. This is achieved through the lowering of total cholesterol and LDL cholesterol and with an improvement in the level of HDL cholesterol (increased HDL:LDL ratio).

The prevalence of high blood cholesterol (hypercholesterolemia) is at a global all time high. In a recent report published by Canadian Health Measures Survey, it was reported that 38% of Canadian adults over the age of 18 have a high total blood cholesterol (1). Generally, lifestyle changes such as healthier eating, increased exercise, weight loss, and smoking cessation are

encouraged before patients are given medication. However, depending on the rate of progress, dietary and lifestyle changes may not be adequate, and patients may be prescribed statins to help reduce high blood cholesterol.

Statins

Statins work by blocking the HMG-CoA reductase enzyme, which converts HMG-CoA into mevalonate, a building block of cholesterol (see Figure 1). Although statin medications have a great deal of research to support their use and ability to lower cholesterol levels, there are some problems associated with prolonged usage. First, the action of statins is not specific to LDL cholesterol, meaning that statins block the production of both HDL and LDL cholesterol. Therefore, statins may not address the imbalance of ‘good’ and ‘bad’ cholesterol – ‘good’ HDL cholesterol is vital for the production of vitamin D and various other hormones. Additionally, the levels of co-enzyme Q10 (CoQ10), a co-enzyme that contributes to proper energy production in the body, is also affected by statins. CoQ10 levels are often diminished during statin treatment because, like cholesterol, CoQ10 is synthesized from mevalonate (Figure 1). Patients on long-term statin treatment may also suffer from muscle pain and weakness, liver damage, poor memory and confusion. As such, safer, natural alternatives are needed.

AOR has recently developed a new, exciting formulation of Red Yeast Rice with Ankascin-568R for the effective lowing of cho-lesterol levels without the side effects of statins. The mechanism

of Ankascin-568R:

• Effectively reduces total cholesterol levels• Reduces ‘bad’ LDL cholesterol levels• Increases ‘good’ HDL cholesterol levels, and • Does not reduce CoQ10 levels or cause the toxic side-effects

associated with statins (e.g. monacolin K).

Simply put...

16

Red Yeast Rice (RYR)RYR is produced from the fermen-tation of rice with Monascus pur-pureus yeast, and is commonly used in traditional Chinese medicine for the maintenance of normal cholesterol levels.

Monacolin K (MK)MK is a naturally occurring statin present in most RYR products. As it is chemi-cally similar to a synthetic statin called Lovastatin®, MK may cause the same toxic side effects caused by statins.

Figure 1. Mechanism of Action of Statins Statins block the action of HMG-CoA reductase, an en-zyme that converts an intermediate molecule in cho-lesterol synthesis called HGM-CoA into mevalonate. Mevalonate, also an intermediate molecule, is a building block of both cholesterol and co-enzyme Q10 (CoQ10). Therefore, blocking the action of HGM-CoA reductase with statins reduces the synthesis of both cholesterol and CoQ10. Arrows represent interme-diate steps in the pathway.

Traditional Red Yeast Rice Products

Red yeast rice (RYR) is the name given to rice that has been fermented with the yeast Monascus purpureus, and is used in traditional Chinese medicine to lower cholesterol. The active ingredient in most RYR products is monacolin K (MK). MK is chemically identical to the statin drug lovastatin (Mevacor®; Merc) and works by inhibiting HMG-CoA reductase (a similar mechanism to that shown in Figure 1). As such, traditional RYR may cause similar toxic side-effects as those associated with statin usage. Regulatory bodies (Health Canada and the FDA) have stipulated that any product that contains more than 12 ppm of MK is to be considered a prescription drug. Despite this, many if not all RYR supplements on the market contain levels of MK that are above the regulated limit. Furthermore, studies have shown that up to one third of all RYR products on the market contain citrinin, a compound that is toxic to kidneys (nephrotoxic).

AOR’s RYR with Ankascin-568RTM

AOR has launched a revolutionary RYR product that is clinically superior to all others on the market and addresses the safety issues associated with RYR that contains MK and citrinin. AOR’s RYR is formulated to contain patent-protected Ankascin-568RTM, which is produced using a conventional RYR fermentation process, but, unlike other RYR products, a patented extraction process removes the toxic byproducts MK and citrinin. Therefore, AOR’s RYR is the world’s first RYR product that is certified to be free of MK and citrinin, and therefore is completely compliant with Health Canada and FDA regulations.

Instead of MK and citrinin, the patented Ankascin-568RTM

formulation contains the active ingredients ankaflavin and monascin. In hamsters fed a high cholesterol diet for six weeks, these potent active ingredients have been shown to lower ‘bad’ LDL cholesterol without negatively affecting the level of ‘good’ HDL cholesterol. In fact, Ankascin-568R increased HDL levels,

while MK decreased HDL levels. It has also been shown that Ankascin-568RTM does not affect the levels of creatine phosphokinase (a marker of muscle damage), in contrast to MK which elevates creatine phosphokinase activity. Finally, pathological examination of the liver of hamsters fed high fat and fructose diets revealed that Ankascin-568R supplementation reduced lipid accumulation in the liver and effectively lowered blood glucose and insulin concentrations (2). To the best of our knowledge, no study has reported any toxic side-effects due to Ankascin-568R supplementation. Thus, AOR’s revolutionary RYR with Ankascin-568RTM has superior benefits, such as the reduction of total and LDL cholesterol and increase in HDL cholesterol without any of the toxic side-effects associated with other RYR products or statin drugs.

PRODUCT SPOTLIGHT

Key Terms

Figure 1: Legend

Figure 1

17

1. Statistics Canada. Cholesterol levels of adults, 2012 to 2013. http://www.statcan.gc.ca/pub/82-625-x/2014001/article/14122-eng.htm Accessed: 4th May 2017.

2. Lee et al. Monascin and ankaflavin have more anti-atherosclerosis effect and less side effect involving increasing creatinine phsophokinase activity than monacolin K under the same dosages. J. Agrric. Food Chem. 2013;61(1): 143–50.

3. Hsu et al. Improvements of ankaflavin isolatedfrom Monascus-fermented products on dyslipidemia in high-fat diet-induced hasmster. J. Func. Food. 2013;5(1):434-443.

4. Wang et al. A randomized, double-blind clinical study to determine the effect of ankascin 568 plus on blood glucose regulation. Journal of Food and Drug Analysis. 2016;25(2):409-416.

RYR Ankascin-568RTM: Unique Mechanism of Action

AOR’s RYR with Ankascin-568RTM may be more effective than MK and statin drugs due to its unique mechanism of action. Instead of merely reducing total cholesterol production, RYR with Ankascin-568RTM works to remove LDL cholesterol from the body. In addition to effects on cholesterol, AOR’s RYR with Ankascin-568RTM may also be useful in the management of the symptoms of diabetes. A study by Wang et al. showed that in a cohort of 39 patients with high fasting blood glucose levels, daily supplementation with Ankascin-568RTM for 12 weeks reduced fasting blood glucose, total cholesterol and LDL cholesterol levels more significantly than placebo (4). Other studies conducted in-house by Sunaway Biotech Ltd have shown that Ankascin-568RTM has blood pressure lowering effects in spontaneously hypertensive rats, following a single administration of RYR with Ankascin-568RTM. Ankascin-568RTM may also have neuroprotective effects, as amyloid beta plaques (a hallmark of Alzheimer’s disease), accumulating as a result of infusion of amyloid beta, were

reduced when rats supplemented with RYR with Ankascin-568RTM (Sunaway Biotech Ltd, unpublished data). A small human pilot study to investigate the blood pressure and neuroprotective effects of RYR with Ankascin-568RTM is currently underway.

Conclusion

AOR’s RYR with Ankascin-568RTM is new, exciting, regulatory compliant formulation that:

• Effectively reduces total cholesterol levels

• Reduces ‘bad’ LDL cholesterol levels

• Increases ‘good’ HDL cholesterol levels, and

• Does not reduce CoQ10 levels or cause the toxic-side effects associated with statins (MK).

PRODUCT SPOTLIGHT

References

RYR with Ankascin-568RTM

AOR’s RYR with Ankascin-568R is a revolutionary formulation and the world’s first RYR product that is free of MK and citrinin. RYR with Ankascin-568RTM contains a combi-nation of the active ingredients monas-cin and ankaflavin, which have been shown to be clinically superior to MK at lowering blood cholesterol.

Table 1. Compari-son of the Choles-terol Lowering Ef-fects of RYR with Ankascin-568R and Statins (MK) RYR with Ankas-cin-568R lowers total cholesterol levels (enhanced excretion of total cholesterol as bile acid) and specifi-cally reduces ‘bad’ LDL cholesterol (promotion of the break-down of LDL choles-terol in the liver). Ankascin-568R also improves the ratio of ‘good’ HDL cholesterol to ‘bad’ LDL cholesterol by promoting the synthesis of HDL cholesterol in the liver. Unlike statins (MK), which block HGM-CoA reductase, Ankas-cin-568R does not interfere with the synthesis of CoQ10 or cause any toxic side-effects.

Key Terms

Table 1

Reduction of total cholesterol levels

Total cholesterol

'Bad' LDL cholesterol

Mechanism of Action Ankascin-568R Statins (MK)

No inhibition of HGM-CoA reductase

No inhibition of CoQ10 synthesis

Enhanced excretion of cholesterol as bile acid

Reduction of ‘bad’ LDL cholesterol

Specific break-down of LDL cholesterol in liver

Increase in ‘good’ HDL cholesterol

Improved ratio of ‘good’ to ‘bad’ (HDL-to-LDL) cholesterol

Free of toxic side effects (muscle pain/weakness, liver damage, poor memory and confusion)

‘Good’ HDL cholesterol

HDL-to-LDL cholesterol ratio

Toxic side effects

Yes Yes

Yes No

Yes No

Yes No

Yes Yes

Yes No

Yes No

Yes No

Yes No

Table 1: Legend

18

Cholesterol, an animal sterol, is a waxy substance found in every cell in our body. Cholesterol is used as a base

for the production of steroid hormones, bile salts, and vitamin D, as well as maintaining cell membrane fluidity. Without cholester-ol we would not be able to properly digest foods, our cell structure would not be able to withstand any changes in temperature, and a significant number of important hormones, such as estrogen and testosterone, could not be produced.

Cholesterol is produced in the liver, from the molecule acetyl-coenzyme-A. A key step in the pathway of cholesterol synthesis is the conversion of HMG-CoA into mavalonate, a process that is controlled by the enzyme HMG-CoA reductase (see Figure 1 of the article 'Red Yeast Rice with Ankascin-568RTM: Cholesterol Lowering without the Side Effects' on page 16). This enzyme can block the production of cholesterol making it an important target for cholesterol lowering drugs called statins, but it also controls the production of many other molecules such as co-enzyme-Q10.

That’s why there are so many side-effects of taking these drugs. Nearly 10-12% of patients on statin drugs will experience statin-induced muscle pain. Other potential adverse reactions to statin drugs include elevated liver enzymes, lung disease, and in a small subset of patients can even increase risk for type 2 diabetes mellitus.

The majority of cholesterol is synthesized, recycled, and degraded in the liver. But how does the cholesterol you eat get to the liver from the gut? And, how is cholesterol transported from the liver to every cell in the body?

Figure 1 (below) shows the processes underpinning the absorption, transportation, utilisation and excretion of fat and cholesterol in the body. First, cholesterol molecules are transported to the liver via the lymph in complexes called chylomicrons. Chylomicrons are relatively large cholesterol-containing lipid (fat) particles that are processed in the liver, forming ever smaller lipid particles containing a mixture of cholesterol, triglyceride, and protein. These heterogeneous particles are

Confused About Cholesterol? We Are Here to HelpDr NavNirat Nibber ND and Dr Chris Hillyar MSc DPhil (Oxon), AOR, 3900 - 12 Street NE, Calgary, Canada, T2E 8H9

ADVANCES IN CHOLESTEROL MANAGMENT

Figure 1.Absorption, Transportation, Utilisation, and Excretion of Lipid (Fat) and Choles-terol.After dietary fat and cholesterol enters the small intestine, 1) chy-lomicrons formed in the intestine are transported, via lymphatics, to the blood vessels of the circulatory sys-tem. 2) An enzyme called lipoprotein lipase, present on blood vessel walls, breaks up (hydro-lyses) fats (triacyg-lycerols) contained in chylomicrons, transferring glycerol and fatty acids to tissues to be used as energy. 3) Chylomicron remnants are taken up and processed by the liver, which 4) synthesises vHDL particles and releases them into circulation. 5)Lipoprotein lipase breaks up (hydrolyses) fats (triacyglycerols) contained in vHDL particles (trans-ferring glycerol and fatty acids to tissues to be used as energy). 6) This process forms LDL particles, which 7) are taken up by tissues through a process called endocytosis.

Figure 1. Legend

Figure 1

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called lipoprotein complexes and are utilized by the body to ‘chaperone’ cholesterol to where it is needed.

It is useful to think of lipoprotein complexes as cholesterol ‘carriages' that transport cholesterol around the body via the blood stream. There are several different types of lipoprotein complex, which are classified based on the ratio of proteins-to-lipid/cholesterol that they contain. Low-density lipoprotein (LDL) contains a low proportion of protein (or a high proportion of lipid/cholesterol); the main function of LDL is to transport cholesterol to tissues where it is utilized for energy. In contrast, high-density lipoprotein (HDL) contains a high proportion of protein (or a low proportion of cholesterol); its main function is to collect excess cholesterol from tissues and transport it back to the liver for processing and excretion. Chylomicrons, LDL, and a further class of lipoprotein called very low density lipoproteins (vLDL), all have very high fat and cholesterol content as compared with protein-rich HDL.

The net effect of this lipoprotein system is that chylomicrons absorbed from the gut, transport cholesterol to the liver which synthesizes and secretes vLDL and LDL particles. vLDL and LDL particles circulating in the blood are taken up by blood vessels and tissues which use their lipid/cholesterol content as energy. Excess LDL particles in circulation return to the liver where they are taken up by liver cells via LDL receptors. Liver cells also release HDL particles into circulation that scavenge excess cholesterol deposited in blood vessels and tissues. LDL and HDL cholesterol returning to the liver via circulation can be stored or eliminated from the body (excreted) as bile acid.

Cholesterol and Cardiovascular Health

High levels of cholesterol, triglycerides, LDL, and trans-fats are linked to increased risk of cardiovascular events such as heart attacks and strokes. The build-up (deposition) of cholesterol in blood vessels and tissues can be due to increased cholesterol synthesis, decreased cholesterol utilisation (for energy), or decreased excretion of cholesterol (as bile acid). The nature of the cause of cholesterol build-up, as well as the form of cholesterol in the plasma (i.e. LDL or HDL), is important when determining disease risk and treatment.

Genetic disorders can influence the function of the LDL receptor at the surface (plasma membrane) of liver cells. Reduction in uptake of LDL cholesterol into liver cells via the LDL receptor can result in an increased amount of LDL cholesterol in circulation.

Elevated levels of LDL cholesterol in circulation due to genetic effects can lead to an increased risk of adverse cardiovascular events, irrespective of diet and lifestyle in these patients. However, genetic causes of the increase of cholesterol levels affect only a small proportion of the population diagnosed with high cholesterol; the vast majority of cases of high cholesterol in North America are linked to diet and lifestyle.

Indeed, increased consumption of cholesterol-rich foods can result in increased levels of LDL cholesterol in circulation, which can cause atherosclerosis. Atherosclerosis is defined as the loss of arterial elasticity due to blood vessel stiffening and thickening (narrowing). During atherosclerotic plaque formation, excess LDL cholesterol in circulation is deposited as ‘fatty streaks’ in the innermost layer of the lining of large and medium-sized blood vessels. As LDL cholesterol infiltrates into the lining of blood vessels it promotes the production of reactive oxygen species (ROS; highly reactive molecules such as •OH, H2O2, and •O2

-) that attract immune cells (white blood cells) called macrophages. Although the precise mechanism is not fully understood, macrophages attracted to the site of the fatty streak become ‘foam cells’ which accumulate in the blood vessel lining.

The formation of an atherosclerotic plaque results in the recruitment of more and more immune cells, which initiate an inflammatory process that contributes to the narrowing of the blood vessel. As the plaque continues to grow it may begin to disrupt blood flow and even completely block (occlude) the hollow tube (lumen) of the blood vessel. Narrowing of a blood vessel is called stenosis, and atherosclerotic plaques weaken blood vessels, which can lead to potentially fatal ruptures.

The ‘arthrogenic triad’ is an important set of parameters to be aware of and are known to increase a person’s risk for developing atherosclerosis. The triad includes 1) high blood LDL levels, 2) low blood HDL levels, and 3) high blood triglyceride levels. The risk of atherosclerosis is further increased by the consumption of a low fiber diet – as this reduces the excretion of cholesterol – and an inactive lifestyle – which may increase the likelihood of the LDL cholesterol adhering to blood vessels.

Managing Cholesterol with Bergamot Extract

In order to promote healthy cholesterol levels, it is helpful to think of HDL cholesterol as ‘good’ cholesterol and LDL cholesterol

ADVANCES IN CHOLESTEROL MANAGEMENT

8) Excess LDL par-ticles are taken up by the liver, which also 9) synthesiz-es and secretes HDL particles into circulation. 10) Circulating HDL particles scavenge excess cholesterol from blood vessels and tissues, and 11) return excess cho-lesterol to the liver. 12) In the liver, excess cholesterol is processed into bile acid, which is excreted (eliminat-ed) from the body. A person may be at risk of developing 'fatty streaks' in blood vessels due to the consump-tion of a high cho-lesterol diet, with excess cholesterol in LDL particles being deposited in the lining of large and medium-sized blood vessels. Over time, fatty streaks may lead to the formation of ather-osclerotic plaques through patholog-ical inflammatory processes, increas-ing a person's risk for cardiovascular events. Increasing a person's HDL cholesterol levels may actually help to scavenge excess cholesterol from blood vessels/tissues, and return excess cholesterol to the liver for excretion. Strate-gies for managing cholesterol focus on reducing total cholesterol and LDL cholesterol, while increasing HDL cholesterol levels.

Figure 1. Cont.

21

as ‘bad' cholesterol. This is because HDL cholesterol is able to scavenge excess cholesterol in blood vessels and tissues (transporting it back to the liver for processing/excretion), while LDL cholesterol deposits cholesterol in blood vessels and tissues (contributing to the build-up of fatty streaks and atherosclerotic plaques). Management of cholesterol levels is therefore aimed at increasing the levels of HDL cholesterol – with a diet that is rich in ‘good’ fats, i.e. unsaturated, non-trans-fats, such as those found in olive oil or fish oil – and reducing LDL cholesterol (and total cholesterol) – with a diet that is low in ‘bad’ fats, i.e. saturated and trans-fats.

HDL cholesterol may also be improved by eating the citrus fruit Bergamot (often added to Earl Grey tea), which contains relatively high levels of flavonoids (i.e. neoeriocitrin, neohesperidin, and naringin). A study by Toth et al. (2016) found that supplementation with Bergamot extract reduced total cholesterol levels, LDL cholesterol levels, and triglyceride levels, but increased the level of HDL cholesterol in 80 human patients with

moderate hypercholesterolemia (high blood cholesterol). Other studies by Glizzoli et al. (2013, 2014) demonstrated similar findings (reduced total cholesterol levels, LDL cholesterol levels, and triglyceride levels, but improved HDL cholesterol levels or LDL/HDL ratio) in a group of 77 human patients with hypercholesterolemia and 107 human patients with metabolic syndrome (a risk factor for the development of cardiovascular disease). Together, these clinical trials support the use of Bergamont extract as a stand-alone or complimentary therapy (to be taken in conjunction with cholesterol-lowering statin drugs) that contributes to cardiovascular health.

In summary, understanding how cholesterol is processed in the body is key to managing healthy cholesterol levels. Natural supplements, such as Bergamot extract, may contribute to reducing total cholesterol and LDL cholesterol, while increasing HDL cholesterol levels and therefore may be useful additions in the management of healthy cholesterol levels.

ADVANCES IN CHOLESTEROL MANAGEMENT

Total cholesterolThe total amount of cholesterol present in a sam-ple of blood (or pasma), regard-less of whether a component of chylomicron, vLDL, LDL, or HDL parti-cles. The reduction of total cholesterol, through modifica-tion of diet (i.e. low cholesterol diet) is a key strategy for the management of healthy choles-terol levels.

LDL cholesterolLow-density lipoprotein (LDL) cholesterol refers to lipoprotein particles synthe-sised and secreted into circulation by the liver. This type of lipoprotein par-ticle is low-density because it contains a low ratio of protein-to-lipid. LDL particles are also called 'bad' choleterol because they a reletaively rich in cholesterol, and deposit excess cholesterol in blood vessels and tissues. Reduction of LDL cholesterol is a key strategy for the management of healthy choles-terol levels.

HDL cholesterolHigh-density lipo-protein (HDL) has a high protein-to-lipid ratio and is relatively poor in cholesterol. HDL particles actually scavenge excess cholesterol from blood vessels/tissues. Increasing HDL cholesterol is a key strategy in managing healthy cholesterol levels.

Key Terms

1. Adams SP, et al. Lipid-lowering efficacy of rosuvastatin. Cochrane Database Syst. Rev. 2014;21(11):CD010254. doi: 10.1002/14651858.CD010254.pub2.

2. Babish JG, et al. Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation including Citrus bergamia, in subjects with moderate cardiometabolic risk factors. Can. J. Physiol. Pharmacol. 2016;31:1-10.

3. Cappello AR, et al. Bergamot (Citrus bergamia Risso) Flavonoids and Their Potential Benefits in Human Hyperlipidemia and Atherosclerosis: An Overview. Mini Rev. Med. Chem. 2016;16(8):619-29.

4. Giglio RV, et al. The effect of bergamot on dyslipidemia. Phytomedicine. 2015;30:S0944. doi: 10.1016/j.phymed.2015.12.005.

5. Gliozzi M, et al. Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia. Int. J. Cardiol. 2013;170(2):140-5. doi: 10.1016/j.ijcard.2013.08.125. Epub 2013 Sep 8.

6. Gliozzi M, et al. The effect of bergamot-derived polyphenolic fraction on LDL small dense particles and non alcoholic fatty liver disease in patients with metabolic syndrome. Advances in Biological Chemistry. 2014;4(2):129.

7. Mollace V, Sacco I, Janda E, Malara C, Ventrice D, Colica C, Visalli V, Muscoli S, Ragusa S, Muscoli C, Rotiroti D, Romeo F. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: From animal models to human studies. Fitoterapia. 2011;82(3):309-16. doi: 10.1016/j.fitote.2010.10.014.

8. Mora S, et al. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation. 2013;128(11):1189-97. doi: 10.1161/CIRCULATIONAHA.113.002671.

9. Toth PP, et al. Bergamot Reduces Plasma Lipids, Atherogenic Small Dense LDL, and Subclinical Atherosclerosis in Subjects with Moderate Hypercholesterolemia: A 6 Months Prospective Study. Front. Pharmacol. 2016;6:299. doi: 10.3389/fphar.2015.00299.

References

AOR’s Opti-Cholest

A nutritional supplement containing 1000mg of Bergamot extract for the support of cardiovascular health

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Calorie Restriction and BenaGeneTM: The Key to Longevity?Dr Paul Hrkal ND and Dr Anjan Nibber DPhil (Oxon), AOR, 3900 - 12 Street NE, Calgary, Canada, T2E 8H9

What is Calorie Restriction?

Increasing longevity (or life span) is often considered nothing more than the goal of fictional mad scientists and sorcerers. However, caloric restriction (CR) has been extensively studied over the last 70 years, with numerous studies suggesting that a reduction in total calorie intake by 30% to 50%, can significantly extend one’s lifespan. Simply put, CR is a dietary regimen that reduces the caloric intake of an individual, without resulting in malnutrition or a reduction in the intake of essential nutrients. In add i t ion to increas ing longev i ty, CR has been found t o p r o m o t e i m p rove m e nt s in metabolism, e n e r g y production, and delay and reduce the incidence o f c a n c e r and diabetes. Currently, the m e c h a n i s m by which CR ex te n d s l i fe remains to be elucidated, but continues to be a major focus of the scientific c o m m u n i t y . In addit ion, the focus has also shifted to the discovery of products that can be taken to mimic the effects of CR, for longevity and also for the treatment of diseases.

How does CR work?

Whilst a reduction in free radicals was originally suggested as a potential mechanism of action of CR, the common consensus now is that CR is linked to energy production mechanisms of mitochondria. The key role of mitochondria

is to produce energy (in the form of ATP) for the cell, through a series of complex metabolic processes. One of the key lynch-pins in the mitochondrial energy production processes is a substance called nicotinamide adenine dinucleotide (NAD). NAD is present in two forms; NAD+ (which is the oxidized form) and NADH, (the reduced form). The NAD+/NADH ratio plays and important role in controlling how much energy the mitochondria produces. Higher NAD+ levels are thought to have a stimulatory effect on anti-aging genes and

increase energy p r o d u c t i o n . On the other h a n d , h i g h NADH levels l imits energy p r o d u c t i o n . During CR, the N A D + / N A D H ratio is increased, with the oxidized form of NAD being favoured. In a nutshell CR promotes a high N A D + / N A D H ratio, stimulating specific genes, which in turn m e a n s t h a t m i t o c h o n d r i a increase energy p r o d u c t i o n . T h e r e f o r e ,

consuming fewer calories can actually equate to increased energy production!

BenaGeneTM

Despite strong evidence showing that CR can result in increased lifespan, many people are unwilling to reduce their caloric intake by 30%-50%. As such, the focus has also shifted to identifying CR mimetic (mimicking) agents. One such promising agent is BenaGeneTM. BenaGeneTM is a thermally stabilized form

BenaGeneTM is a thermally stabilized form of oxaloacetate, which is a key intermediate of

the energy producing processes of mitochondria. Increasing ox-aloacetate via supplementation has been shown to promote a

higher NAD+/NADH ratio, which is associated with all the beneficial effects of CR.

"

"

ADVANCES IN ANTI-AGEING RESEARCH

Calorie Restriction (CR)A dietary regimen that reduces the caloric intake of an individual without resulting in malnutrition or a reduction in the intake of essential nutrients.

NAD+/NADH RatioA high NAD+/NADH ratio increases the stimulation of a variety of genes in the mitochondria and is associated with high energy production. CR and BenaGeneTM both increase the NAD+/NADH ratio.

Key Terms

24

of oxaloacetate, which is a key intermediate of the energy producing processes of mitochondria. Increasing oxaloacetate via supplementation has been shown to promote a higher NAD+/NADH ratio, which is associated with all the beneficial effects of CR that we have already discussed. What has scientists and anti-aging enthusiasts so excited is that animal studies have shown that life span was extended by 30% after supplementing with BenaGeneTM. It has also been shown to induce over 350 anti-aging genes in animals, with a genetic profile similar to CR. Whilst human studies investigating BenaGeneTM’s effects on life extension have not yet been conducted, human studies have confirmed that BenaGeneTM supplementation caused a reduction in glucose levels and an improved uptake of glucose without negative side-effects. Further, BenaGeneTM appears to down-regulate pathways that

create and store fat and protects DNA from damage that is thought to exacerbate the aging process. These actions may have tremendous beneficial effects on numerous disease processes such as diabetes and cardiovascular disease.

Conclusion

CR has numerous health benefits, including increased longevity and disease prevention. The mechanism of action of CR involves an increase in the NAD+/NADH ratio in the mitochondria, which optimizes energy production and expression of CR genes. Supplementation with a specific stabilized form of oxaloacetate called BenaGeneTM has shown promising positive effects that can mimic the effect of a CR diet. This may translate into clinical applications for almost every chronic disease.

ADVANCES IN ANTI-AGEING RESEARCH

Key Terms

1. Fontana, et al. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. PNAS. 2004;101(17):6659-6663.

2. Hursting S, et al. Calorie Restriction, Aging and Cancer Prevention: Mechanisms of Action and Applicability to Humans. Annual Review of Medicine. 2003;54:131-152.

3. Lin SJ and Guarente L. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Current Opinion in Cell Biology. 2003;15:241-246.

4. Lin S, et al. Calorie restriction extends yeast life span by lowering the level of NADH”. Genes & Development 2004;18:12-16.

5. Lin SJ. Molecular Mechanisms of Longevity Regulation and Calorie Restriction. In: Kaput J and Rodriguz R. Nutritional Genomics: Discovering the Path to Personalized Nutrition. Wiley and Sons, Inc. NY. 2006.

6. Castro-Marrero J, Cordero MD, Segundo MJ, et al. Does Oral Coenzyme Q10 Plus NADH Supplementation Improve Fatigue and Biochemical Parameters in Chronic Fatigue Syndrome? Antioxidants & Redox Signaling. 2015;22(8):679-685. doi:10.1089/ars.2014.6181.

References

BenaGeneTM

A thermally stable version of oxaloac-etate, which is a CR mimetic (mimick-ing) agent. BenaGeneTM increases the NAD+/NADH ratio, and stimulates many anti-aging genes.

25

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