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Durk Pearson & ’s® News™ … P 22

Health Matters: Ask Dr. Ward Dean … P 3 Potassium for Healthy Bones … P 9 Mastic Improves Crohn’s Disease … P 19

Berberine Overturns Menopause Comorbidities … P 10 HesperidinLithium With& A brilliant idea: In order to … GALANTAMINE FEED YOUR HEAD… , … you need the Mind Food™ Brain Quercetin, an impor- Maintenance Tool kit,™ the three-part tant polyphenol found formulation that represents a paradigm in wine and many other shift in the way that braincare is foods that has been shown approached, fully parallel to the success- to inhibit and destabilize ful model for cardiovascular health care amyloid-beta* developed over the last few decades. Lithium, an important brain food What’s the point of living to 100, 110, that is found in the bottled waters of 120, or 130 if your memories fade when American and European health spas … you’re 90, 80, 70, 60, or earlier? that also lowers the toxicity of amy- Featuring: loid-beta while causing an increase in neurotrophic factors that help induce Galantamine, with its dual mechanisms neurons to repair themselves when of boosting acetylcholine levels and en- under stress … that helps cause an hancing nicotinic cholinergic activity* increase in gray matter and helps Choline, along with all the needed enhance the neurogenesis of hippo- cofactors, to help maintain the brain campal neurons* acetylcholine levels of a young adult* DHA and EPA, essential omega-3 fatty Taurine, which can help protect against acid brain foods that operate to the deleterious effects of amyloid-beta prevent excessive excitation as well as excitotoxicity, neurotoxicity, and free enhance the body’s natural anti- radicals in your brain* inflammatory protection* Green Tea Polyphenols, a class of anti- oxidants, operating together as a system, that can also So get & Sandy Shaw’s® personal Mind Food fight amyloid-beta toxicity* Brain Maintenance Toolkit, to be sure that you’re on track Vitamin C (as calcium ascorbate) and Vitamin E toward preserving and (as d-alpha-tocopheryl succinate), which have protecting proper memory been shown to work together to help protect and cognitive functions— your brain’s hotbeds of free radical activity* which has been one of Turmeric Curcuminoids, a system of antioxidants that Durk & Sandy’s core goals helps protect your neurons from damage or death caused all along—today!* by amyloid-beta* Folic Acid, Vitamin B6, & Vitamin B12, Omega-3 Heart & Mind 600™ GalantaMind Plus™ important vitamins that help prevent by Durk Pearson & Sandy Shaw® damage to mitochondria (where they SUPPLEMENT FACTS help repair DNA damage), cofactor the SUPPLEMENT FACTS Serving size: 2 capsules Amount Daily production of nitric oxide, and help Servings per container: 90 Per Serving Value Serving size: 2 capsules Amount Daily Vitamin C (as calcium ascorbate) 600 mg 1000% maintain normal levels of homocysteine Servings per container: 75 Per Serving Value Vitamin E (d-alpha-tocopheryl 155 IU 515% acid succinate) Calories 13 (a neurotoxin)* Vitamin B6 (as pyridoxine) 5 mg 250% Total fat (polyunsaturated fatty acids) 1 g 2%† Folate (as folic acid) 267 mcg 67% ™ Memory Upgrade III Sugar-Free Marine lipid concentrate 1200 mg ‡ Vitamin B12 (as cyanocobalamin) 166 mcg 2767% Calcium (as calcium ascorbate) 132 mg 13% EPA (eicosapentaenoic acid) 460 mg ‡ Green tea (Camellia sinensis) leaf extract 233 mg * DHA (docosahexaenoic acid) 240 mg ‡ (min 50% EGCG, 90% polyphenols) SUPPLEMENT FACTS Turmeric (Curcuma longa) root 233 mg * † Percent daily values are based on a 2,000 calorie diet. Serving size: 1 heaping tsp (5.7 g) Amount Daily ‡ Daily Value not established. Hesperidin 100 mg * Servings per container: 90 Per Serving Value Quercetin 43 mg * Other ingredients: Gelatin, glycerin, water. Galantamine hydrobromide (extracted 8 mg * Vitamin C (as niacinamide ascorbate) 36 mg 60% Vitamin C (as ascorbyl palmitate), Vitamin E (as mixed toco- from Galanthus nivalis) Vitamin E (as d,l-alpha-tocopheryl) 30 IU 100% pherols), and rosemary extract added to prevent autoxidation of Lithium (from lithium sulfate monohydrate) 2 mg * marine (including omega-3) oils. Not a significant source of Thiamine (vitamin B1 as 3 mg 200% these nutrients. * Daily Value not established. thiamine hydrochloride) Riboflavin (vitamin B2) 3 mg 177% Niacin (vitamin B3 as nicotinic acid 75 mg 375% ™ ™ Factory and niacinamide ascorbate) Mind Food Brain Maintenance Toolkit 1 Direct Vitamin B6 (as pyridoxine) 5 mg 250% Includes 1 to 1 ⁄2 month’s supply of each formulation: Vitamin B12 (cyanocobalamin) 100 mcg 1667% Prices Biotin 300 mcg 100% ™ Pantothenic acid (vitamin B5 as 500 mg 5001% GalantaMind Plus (180 caps, 1–6 caps per day) $118.97 calcium pantothenate) ™ Calcium (as calcium pantothenate) 46 mg 5% Memory Upgrade III Sugar-Free(90 servings, CLICK Zinc (as zinc gluconate) 3 mg 20% 2–3 servings/day in a delicious lemon drink mix) $45.97 HERE Copper (as copper gluconate) 399 mcg 20% TO Chromium (as chromium polynicotinate) 26 mcg 21% Omega-3 Heart & Mind 600™ ORDER Choline (as choline dihydrogen citrate) 1 g * NOW Taurine 1000 mg * (150 softgels, 2 softgels per serving) $26.97 Glycine 150 mg * * Daily Value not established. 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*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. Editorial 2 Achieving Longevity Escape Velocity Health Matters 3 Ask Ward Dean • Dealing with Irregular Heartbeat New Studies • Potassium Good for Bone Health MAY 2015 • Mastic Improves Crohn’s Disease 3 Brief Summaries of Leading Articles in this Issue Loss of brain immunity may add to the causes of dementia … 4 Can Brain Arginine Reduce Alzheimer’s? Researchers have found that in AD, immune cells that normally protect the brain instead begin to consume arginine Will Block Women rarely suffer cardiovascular insult until perimenopause … 10 Berberine Overturns Menopause Comorbidities Page 4 With increasing lifespans, women are now spending as much as one-third of their lifetime in postmenopausal state Will Block Available Online Durk Pearson & Sandy Shaw’s® 22 Life Extension News™ 1. Use of strong anticholinergics may be associated with an increased risk of DEMENTIA or ALZHEIMER’S DISEASE 2. REALLY LOW DOSE LITHIUM stabilizes cognitive function in Alzheimer’s disease patients for 15 months 3. Here’s to your health with BEER Product Guide 4. Killing food borne pathogens with liquid We have a complimentary 56-page Product Guide with smoke additional information about many of our best-selling products. Download it today: 5. Weight and the perception of sexual www.life-enhancement.com/documents/LEP_catalog.pdf attractiveness 6. Marketing data show sharp drop in confidence Ingredients Index among more affluent consumers during 4th Our comprehensive index of ingredients in our products is now easier to access on our improved Web site. (See it on the quarter of 2014 right side of the home page). We hope this list will prove useful to you in gaining further insight into the ways in which many Exercise Your Brain natural substances can be beneficial to your health. 30 Can Brain Arginine Reduce Alzheimer’s?

CALL 800-543-3873 FAX 775-267-1544 www.life-enhancement.com MAY 2015 1 Editorial Product Advertising Index AGEless™* ...... 19 Achieving Longevity Escape Velocity Berberine Grape Power™ ...... 8 BLAST™ family* ...... C3 n late April, I gave a presentation called Achieving Longevity Escape Veloc- Bye-Lori™ ...... 36 ity at the Platinum Hotel in Las Vegas. If you recall (or attended!), that was Eye D’Clare™ ...... 21 I GalantaMind™ Plus* ...... C2, 16 the same milieu of Life Enhancement’s Symposium in March of 2013. How- ever, the audience was different, and did not gather simply for the reason of Greater Rewards™* ...... C4 health knowledge. InnerPower™* ...... 9 Accordingly, the April presentation wasn’t designed for the knowledgeable InsuLife™† ...... 8 attendees of the Symposium but instead Lithium Plus™* ...... 20 for an audience that is—to a significant Memory Upgrade III™* ...... C2, 17 degree— new to life enhancement and Mind Food™ Brain Maintenance Toolkit™* . . . . .C2 life extension. Call the presentation “101 Omega-3 Heart & Mind 600™* ...... C2 longevity.” Personal Radical Shield™* ...... 18 I began with the concept of squaring Potassium Basics™* ...... 18 the aging curve (see Fig. 1), This is how Premiere Signature Line™ ...... C4 many of us once saw the future. ResQue™ ...... 17 SunPower Vitamin D™* ...... 7 However, the more advanced map of the ThyroPlex™† ...... C3 future has been changed by the notion of Turmeric Root Power™* ...... 15 Figure 1. The goal of anti-aging physi- something substantially better. cians and scientists is to not only “square Longevity escape velocity (sometimes * by Durk Pearson & Sandy Shaw® † by Jonathan V. Wright, M.D. the aging curve” but to extend it. See http://warddeanmd.com referred to as “actuarial escape velocity”) See Product Guide, page 31 CONTINUED ON PAGE 21 NUTRITIONAL SUPPLEMENTS TO ENHANCE YOUR QUALITY OF LIFE Innovation Is Our Driving Force We were the first company to market DHEA, making it commercially available in 1995. We were also first to market pregnenolone, 5-HTP, vinpocetine, mastic gum, the world’s first DNA-support supplement, galantamine, and MHCP. We’ve been out there “pushing the envelope” and building acceptance for the enhancement of life since 1985, when the concept of life extension supplementation first gelled. Often we Publisher/Editorial Director Will Block hear from doctors that they really appreciate what we’re doing in this field. Art Director Paul Dushkind Medical Editor Ward Dean, M.D. Quality Control Is Paramount Medical/Scientific The raw materials we purchase for our products are the safest, highest-quality, pharmaceutical-grade Don Kleinsek, Ph.D. Advisors ingredients available in the world. We package under the purest possible clean-room conditions, and Michael Rosenbaum, M.D. materials undergo lab testing to confirm purity greater than 98% (or we reject them). Gary Ross, M.D. Jonathan Wright, M.D. Advisor Biographical Notes All materials in this publication are provided for in- Dr. Jonathan Wright is the best-selling author of Dr. Wright’s Guide to formational purposes only and should not be con- Healing with Nutrition, Dr. Wright’s Book of Nutritional Therapy (over 600,000 copies strued as medical advice or instruction. You are sold), Maximize Your Vitality & Potency for Men Over 40, and Natural Hormone cautioned not to begin, alter, or discontinue a health Replacement for Women Over 45. He is the medical director of the Tahoma Clinic regimen based only on the contents of this publica- in Tukwila, Washington and publisher of his own newsletter, Nutrition & Healing. tion. You are advised to consult with appropriate health professionals on any matters related to your Dr. Don Kleinsek is president of GeriGene, Inc., a health and well-being. You should not use the infor- Wisconsin biotech company devoted entirely to life mation in this publication for diagnosis or treatment extension through . Dr. Kleinsek was the of any health problem or alter your use of prescrip- hand-chosen successor to life extension pioneer Dr. tion medications or other treatment. You should not stop or alter your use of any medication without Johan Bjorksten as President and Director of the first consulting your treating physician. Bjorksten Research Foundation. According to two-time Nobel laureate Linus Pauling, Dr. Bjorksten was an The opinions and information provided in this publi- innovator and “one of the most active and effective cation are believed to be accurate based on the best judgment of the editors and authors. The pub- students of longevity in the world.” lisher is not responsible for errors or omissions. Will Block is a researcher, writer, and speaker specializing in the life extension, © 2015 Life Enhancement Products, Inc. life enhancement, and cognitive enhancement aspects of nutritional science. His 2555 Business Parkway, Minden, Nevada 89423 writings have appeared widely in newsletters, magazines, and books. He is also All rights reserved. the author of The 5-HTP Archives and Tools for Privacy, a book about public-key encryption, and he speaks about futurology, nootropics, nanotechnology, and freedom.

2 LIFE enhancement MAY 2015 inflammatory indicator, and is the last factor in the clotting Health Matters cascade. Fibrinogen combines with thrombin to form fib- rin, the substance of the clot. Elevated fibrinogen is a more Ask Dr. Dean significant indicator of cardiovascular risk than cholesterol levels. Keep your fibrinogen low with turmeric to reduce Dealing with Irregular Heartbeat the likelihood of further stroke or heart attack-producing I had open-heart surgery over 5 years ago. The surgery emboli. was successful, but I unfortunately ended up with an ir- Another suggestion is an enzyme-rich formulation con- regular heartbeat that produced some small clots to the taining Exclzyme® EN, a proprietary mixture of: the en- brain. I take 100 mg slow-release aspirin and also con- zymes Peptizyme SP® EN (serrapeptase), bromelain, sume an organic natural diet that contains garlic and papain, amylase, and lipase; the flavonoid rutin; and an turmeric. extract of amla (Indian gooseberry, Emblica officinalis). It Recently I ordered your CardioBeat (Magnesium-Potas- also contains the enzymes trypsin, chymotrypsin, and Nat- sium Aspartate), which I have started taking. I am also toSEB® (nattokinase) and an extract of Boswellia serrata, going to start Thyroplex for Men, soon. For brain regen- which will reduce intra-vascular and articular (joint) in- eration, I also have Lithium Plus. flammation, as well as help to prevent further blood I will start that in a week or so. clots.1,2 To accomplish these goals, it is best to take such a Are there any other products formulation on an empty stomach (one hour before or two that you may have that I have hours after a meal). missed, that can help? Berberine is an herb with a number of cardiovascular GEORGE, Slacks Creek, benefits. It has positive inotropic (increases the forces of Queensland, AUS the heart’s contractions), negative chronotropic (slows Dear George, down the heart rate), antiarrhthmic, and vasodilator prop- As you have experienced, the erties.3,4 For atrial fibrillation, it is more important to con- greatest fear of those with atrial trol the heart rate than the rhythm. Berberine helps by fibrillation is the increased likeli- slowing the pulse, as well as by its demonstrated anti-ar- hood of stroke-inducing blood rhythmic effects. clots. That is the reason for the requirement to take as- Ward Dean, MD pirin, and perhaps other platelet aggregation inhibitors or REFERENCES anticoagulants. 1. Jang JY, Kim TS, Cai J, et al. Nattokinase improves blood flow by inhibit- ing platelet aggregation and thrombus formation. Lab Anim Res. 2013 Supplemental turmeric is a wise choice for your regi- Dec;29(4):221–5. men, in that it will reduce fibrinogen. Fibrinogen is an CONTINUED ON PAGE 9 BRIEF SUMMARIES OF LEADING ARTICLES IN THIS ISSUE Can Brain Arginine Reduce Alzheimer’s? Berberine Overturns Menopause Comorbidities Duke University researchers believe they have found a A new review describes the cellular and clinical effects asso- new cause of Alzheimer’s disease. In a very recent paper, ciated with the use of the nutritional supplement berberine. they report that immunity decline in the brain is due to a The review scientists found abundant evidence showing deficiency of the vital amino acid arginine. Arginine that berberine is beneficial for the full range of lifestyle makes nitric oxide—a vasculature relaxing factor, which changes and concomitant diseases that appear frequently as is instrumental for proper brain functioning. women enter perimenopause, and move closer to menopause. The researchers show that microglia and arginase work Among the perimenopausal challenges are overweight together in a mouse model to cause arginine breakdown, and obesity and many comorbidities that lead to type 2 which inhibits the brain’s immune system. Microglia are diabetes and cardiovascular disease. Cardiovascular diseases certain immune cells that normally protect the brain, but are one of the leading causes of morbidity and mortality start to consume arginine with the help of arginase, an in women after menopause and 56% of all causes of enzyme that breaks down arginine. death in Western European countries. With increasing While the Duke researchers lifespans, women spend approxi- show that an anticancer drug mately one-third of their lifetime can suppress arginase, and dis- in postmenopausal state. Conse- rupt arginine breakdown—thus quently, the development of new protecting the mice from Alz- strategies to improve the prevention heimer’s-like pathology—they and treatment of menopause-as- did not consider increased con- sociated pathologies is important sumption of arginine to accom- topic in clinical practice, especially plish the same thing. involving nutritional applications. CALL 800-543-3873 FAX 775-267-1544 www.life-enhancement.com MAY 2015 3 Loss of brain immunity may add to the causes of dementia … Can Brain Arginine

Researchers have found that in Alheimer’s immune cells that

Will Block cell loss and other AD pathology has remained largely unexplored. ccording to a very recent study conducted at Duke University, Alzheimer’s disease (AD) results Lower Nitric Oxide Levels Increase Alzheimer’s from altered brain immune response disturbances.1 The Duke paper suggests that when immune-mediated ni- This idea is not new. Other scientists have in- tric oxide (made from arginine) is lowered to mimic human creasingly offered evidence showing that immu- levels, the fundamental features of AD — amyloid deposi- nityA loss may play a causal role in AD. tion, hyper-phosphorylated and aggregated tau, behavioral However, what is new is the finding that immunity de- changes, and age-dependent hippocampal neuronal loss cline in the brain is due to dwindling supplies of the vital — become more evident. This makes sense, given our nutrient arginine, an amino acid. What is also new is the knowledge about the value of nitric oxide in maintaining finding that in AD, immune cells that normally protect the healthy blood vessels in the body as well as the brain. brain instead begin to consume arginine. “If indeed arginine consumption [destruction] is so im- portant to the disease process, maybe we could block it [the What is new is the finding that consumption mechanism] and reverse the disease,” said Carol Colton in a press release. Dr. Colton is the senior au- immunity decline in the brain is due thor of the new paper and professor of neurology at the to dwindling supplies of arginine. Duke University School of Medicine.2 Yet this new idea of reversing AD is far flung, given the research that must still be done in other animal studies and in humans, not to Blocking Arginine’s Decline in the Brain mention the lengthy (over 10 years) and very costly process When the researchers used a small-molecule drug to block (more than $1 billion) to meet the FDA’s requirements. the decline of arginine in a special AD prone breed of mice (called CVN-AD mice), the principle characteristics of Alz- The Duke study may represent new heimer’s disease dissipated — i.e., plaques and tangles were reduced. The study not only points to a new potential ground by revealing that specific cause of Alzheimer’s, but also may lead to a new treatment immune cells and degradation of strategy — or the reconsideration of an old therapy (more on this later). arginine might be linked to Alzheimer’s disease development. Is Suppression of Brain Immunity Related to AD? A few prior studies suggest that along with increased ex- pression of proinflammatory mediators in AD, the inflam- Degradation of Arginine Inhibits Brain Immunity matory locale in the brain may also include As explained in the study, in accord with the model used, immunosuppressive components. This immunosuppressive when AD develops, certain immune cells called microglia, bias is consistent with the brain’s status as an immune which normally protect the brain, instead start a pattern privileged site. This means that it is able to tolerate the in- of activity that inhibits the immune system. The Duke troduction of antigens (antibody generators) without study may represent new ground by revealing that specific producing inflammatory immune responses. Nonethe- immune cells and degradation of arginine might be linked less, the contribution of immunosuppression to neuronal to Alzheimer’s disease development. The researchers ob- served that in AD, immune cells that normally protect the Will Block is the publisher and editorial director of Life Enhancement magazine. brain instead begin to consume the vital nutrient arginine.

4 LIFE enhancement MAY 2015 Reduce Alzheimer’s?

normally protect the brain instead begin to consume arginine

Mice Designed to Possess Immune System Similarity is that the brain releases molecules that boost the immune To explore their hypotheses, the researchers used a spe- system, potentially leading to brain tissue damage. cific mouse model (CVN-AD), an engineered species de- From studying changes in brain immunity in relation signed to have an immune system more similar to that to neuronal loss, and contrary to the predominant view found in humans. The CVN-AD mouse model can de- that AD pathology is driven by proinflammatory factors, velop features of human-like AD, namely plaques and tan- the researchers found that the pathology in CVN-AD mice gles in the brain, neuronal loss and behavior is caused by local immune suppression. changes. However, CVN-AD mice have only recently been used in research, starting in Microglia and Arginase Result in 2013 by Dr. Colton and her team. Arginine Breakdown CVN-AD mice lack inducible nitric Some hippocampal neuronal death oxide synthase (iNOS), making was associated with the presence them different than humans.3 It of immunosuppressive microglia is interesting to note that one of and extracellular arginase, re- the reasons galantamine is ben- sulting in arginine catabolism eficial for AD is because it in- and reduced levels of total hibits the production of brain arginine. iNOS.4 Pharmacologic disruption of the arginine utilization path- Immune Components the way by an inhibitor of arginase Same Except for Microglia and ornithine decarboxylase By searching for immune anom- protected the mice from AD-like alies throughout the lifespan of pathology and significantly de- CVN-AD mice, the Duke re- creased microglia expression. The searchers found that the majority of findings strongly implicate local im- the immune components remain the mune-mediated amino acid catabolism same, with one exception: microglia. Mi- as a novel and potentially critical mecha- croglia are a type of brain-resident white blood nism mediating the age-dependent and re- cell that act as the main immune defense mechanism gional loss of neurons in humans with AD. in the central nervous system (the brain and spinal cord). Arginase: An Enzyme that Breaks Down Arginine Altered Gene Expressions Before the mice began showing AD, the Colton team In CVN-AD mice, microglia were found to divide and blocked arginase, an enzyme that breaks down arginine, change early in the disease course. By analyzing gene ac- using the drug difluoromethylornithine, also known as tivity patterns in microglia cells, the researchers found a DFMO. As a result, the scientists saw fewer microglia and higher expression of genes linked to immunosuppression, plaques develop in the brains of the mice, and the mice and a reduced expression of genes that stimulate the im- performed better on memory tests. DFMO has been used mune system. for cancer therapy with mixed results. High doses for pro- “It’s surprising, because [suppression of the immune longed periods cause diarrhea, abdominal pain, and eme- system is] not what the field has been thinking is happen- sis, as well as moderate anemia, leukopenia, and ing in Alzheimer’s disease,” said the study’s first author thrombocytopenia. These serious side effects brought Matthew Kan in the Duke press release.2 The general idea early cancer treatment usage to a halt.

CALL 800-543-3873 FAX 775-267-1544 www.life-enhancement.com MAY 2015 5 Does the study suggest that people should eat more doses” of caffeine were shown to decrease arginase activity arginine or take dietary supplements? in the brain.6 The results indicated that caffeine’s in- According to the press release, but not the study, the answer hibitory effect on arginase left more arginine available for is ‘no,’ Colton said, partly because a dense mesh of cells use by the nitric oxide synthase pathway. and blood vessels called the blood-brain barrier determines As the authors explained, caffeine is an inhibitor of how much arginine will enter the brain. While this may be adenosine receptors, decreasing adenosine bound to its so, it is only conditionally true that eating more arginine receptors and increasing free adenosine. Adenosine, ade- may not help more get into the sites of the brain that need nine, inosine, and uric acid are competitive inhibitors of it. Besides, if the scientists’ theory is correct, then the en- arginase. Valine, leucine, isoleucine, and ornithine are also zyme arginase, unless it’s blocked, would still break down reported to have inhibitory effects on arginase activity. the arginine. No evidence is offered for this. Caffeine and compounds related to caffeine, such as Oral arginine supplementation has been used in vari- theophylline and theobromine, increase cellular levels of ous studies to improve endothelium-dependent nitric cyclic AMP that are hypothesized to possibly be, at least oxide-mediated vasodilation. It is worth noting that the in part, a reason for caffeine’s depression of arginase ac- amino acid citrulline is more readily absorbed and at least tivity. Durk & Sandy wonder too, whether the prescrip- in part converted to arginine — so it too, may play a role tion drug pentoxifylline, a prescription methylxanthine in supplying more arginine to the brain.5 drug used in the treatment of poor circulation in the ex- tremities (especially legs), might reduce arginase activity (thus increasing arginine’s availability to be converted to Analysis of gene activity nitric oxide), which (if true) might account for some of patterns in microglia, found a higher the drug’s beneficial effects. expression of genes linked to Local Immune Mediated Amino Acid Catabolism immunosuppression and a reduced Implicated expression of genes that stimulate The Colton et al study concludes that arginase reduces arginine in the brain of their mouse model, decreasing the the immune system. beneficial effects of nitric oxide. Also they find that a drug can inhibit the activity of arginase, thereby protecting the In a recent issue of Life Extension News, Durk Pearson & mice from AD-like pathology. Quoting the paper, “Our Sandy Shaw wrote that there has been considerable re- findings strongly implicate local immune mediated amino search on nitric oxide synthase because of the importance acid catabolism as a novel and potentially critical mecha- of nitric oxide in functions such as vasodilation, in the body nism mediating the age-dependent and regional loss of and in the brain. They go on to report that an inadequate neurons in humans with AD.” supply of arginine, or too little of the cofactor tetrahydro- biopterin (BH4), (which can be mimicked by folic acid), Arginine Improves Brain Function can uncouple nitric oxide synthase from the production of We have already voiced our opinions about the sup- nitric oxide, producing a bunch of free radicals. posed “uselessness” of arginine (and citrulline) to help Colton and colleagues also report that an increase in the solve this problem in accordance with the researchers arginase pathway can inhibit arginine production of nitric oxide. Among the causes of this increase in arginase rerout- Arginase ing are reperfusion injury, asthma, psoriasis, arthritis, and male and female cancers. The increased arginase decreases eNOS arginine’s availability to be converted to nitric oxide, as well L-Arginine as increasing ornithine, which can be converted to polyamines and procellular proliferation factors (see Fig. 1).

Arginase in the Brain According to Durk & Sandy (see “The Arginine Metabolic Pathways: Nitric Oxide Synthase and Arginase” in the Figure 1. Competition between arginase and eNOS for the sub- April 2004 issue), “Not only is arginine in the brain vital strate arginine in endothelial cells decreases NO production, which for the manufacture of nitric oxide, it is also used in brain represents a novel mechanism for atherosclerotic endothelial dys- protein synthesis and is the substrate for the production function and may explain the controversy of supplemental arginine of urea (detoxification of ammonia), along with other im- therapy in patients with coronary heart disease. It may also shed light on the controversy of arginase in the brain. Ming XF, portant products. Barandier C, Viswambharan H, et al. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: Decreasing Arginase in the Brain implications for atherosclerotic endothelial dysfunction. Circulation. In the same article Durk & Sandy cite a rat study, “small 2004 Dec 14;110(24):3708–14.

6 LIFE enhancement MAY 2015 hypothesis. Even though it seems reasonable it is cer- low doses of oral arginine (1.6 g/day) for 3 months. Their tainly not the final word. And we have our doubts about cognitive function was evaluated using the Hasegawa De- the safety of the drug that they proffer. mentia Scale (HDS-R) before treatment started, after 3 months of treatment, and finally 3 months after treatment stopped. The HDS-R is a widely used measure in Japan. The Colton et al study A score of 30 on the HDS-R is considered normal, while concludes that arginase reduces a score of 20 or lower indicates dementia. After 3 months of treatment with arginine, cognitive arginine in the brain of their mouse function improved significantly in all subjects from a model, decreasing the beneficial mean of 16 to 23. Within 3 months of stopping arginine treatment, the HDS score returned to pretreatment levels effects of nitric oxide. (17) (Fig. 1). Lipid peroxide levels (an indicator of oxida- tive stress) also declined significantly during arginine Furthermore, among the large amount of literature in- treatment compared with the baseline and post-treatment dicating that arginine may be helpful for dementia is a measurements. The authors hypothesized that arginine clinical study7 showing that arginine has been found to treatment improved cognitive function by increasing nitric be effective in reducing lipid peroxidation and increasing oxide levels, by reducing oxidative stress, or both. cognitive function (see Fig. 2). There are many good reasons to keep our blood pres- In this study, 16 elderly people with cardiovascular sure under control; reducing the risk of heart attack, stroke disease (mean age, 79 years), who had been living in a and kidney failure are the most commonly mentioned. nursing home for 2 to 4 years, were treated with relatively Now we know that blood pressure control with arginine ❇ 30 may also help preserve our cognitive function. REFERENCES 25 * 1. Kan MJ, Lee JE, Wilson JG, et al. Arginine deprivation and immune sup- 20 pression in a mouse model of Alzheimer’s disease J. Neurosci. 2015;35(15):5969 – 82. 15 2. A New Potential Cause for Alzheimer’s: Arginine Deprivation. Duke Today. April 14, 2015. https://today.duke.edu/2015/04/arginine. Accessed 10 April 15, 2015.

Dementia Score Dementia 3. Hoos MD, Richardson BM, Foster MW, Everhart A, Thompson JW, Mose- 5 ley MA, Colton CA. Longitudinal study of differential protein expression in an Alzheimer’s mouse model lacking inducible nitric oxide synthase. J 0 Proteome Res. 2013 Oct 4;12(10):4462 – 77. Baseline 3 Months Post-treatment 4. Tsvetkova D, Obreshkova D, Zheleva-Dimitrova D, Saso L. Antioxidant Arginine Treatment activity of galantamine and some of its derivatives. Curr Med Chem. 2013;20(36):4595 – 608. Figure 2. Cognitive effect of arginine treatment (1.6 g/day) in 16 5. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmaco- elderly people (mean age 79). Cognitive function was measured dynamic properties of oral L-citrulline and L-arginine: impact on nitric using the revised Hasegawa Dementia Scale (HDS-R). A perfect oxide metabolism. Br J Clin Pharmacol. 2008 Jan;65(1):51 – 9. 6. Nikolic J, Bjelakovic G, Stojanovic I. Effect of caffeine on metabolism of score = 30; scores <20 (shaded area) indicate dementia. 3 Months L-arginine in the brain. Mol Cell Biochem. 2003 Feb;244(1 – 2):125 – 8. vs. Baseline and 3 Months vs. Post-treatment. Adapted from Oht- 7. Ohtsuka Y, Nakaya J. Effect of oral administration of L-arginine on senile suka and Nakaya, 2000. dementia. Am J Med. 2000;108:439.

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