Home > Stuff

Why my customers buy supplements from me, what extra element do I offer

Through the last 38 years I have accumulated thousands of hours of research on nutrition, supplements, and vitamins. Customers buy from me because I can explain what each supplement does in their body and why it is important to take the correct amount.

The most highly rated peer-reviewed, primary research journal in nutrition and dietetics, The American Journal of Clinical Nutrition (AJCN) published an article about a survey they conducted with all of the accredited medical schools in the United States. They found that on average, students received 23.9 hours of nutrition instruction during medical school. The schools ranged from 2 hours of nutritional training to 70 hours. A recent Washington Post article stated that 71% of graduating doctors do not even get the minimum 25 hours recommended by the National Academy of Sciences.

As a wholesaler I have realized that most people don't know how critical vitamins and supplements are to the health of their cells which are responsible for everything we do from talking, seeing, catching a ball, making dinner, or thinking.


If we don't get any of these vitamins and supplements, we die, if we don't get enough, our body doesn’t function well, we get sick, we get diseases. A healthy body makes many supplements, which is why it is imperative to have periotic blood tests to measure all the supplements we need to stay healthy. The only doctors that do this kind of blood test are nutritionists. Life Extension offers comprehensive nutritional blood tests at a fraction of the cost of your doctors test using the same labs, nationwide. Our doctors will go over every aspect of the blood test with you for free.


When our cells fall apart, we fall apart and get cancer, heart disease, Alzheimer's, and all the rest.


If I gave you the task of reading about how to nourish your cells and even rebuild them to enable you to live a healthy productive life past 100 and it took you hours to read and understand it all, would you devote a few hours of your life to enable you to live an extra 20 or 30 years in great health?


If this sounds too good to be true realize that I am on the conservative side compared to many successful wealthy people. Larry Ellison has put hundreds of millions of dollars into life extension research, he wants to live forever. In 2014, he was listed by Forbes as the third wealthiest man in America and as the fifth wealthiest person in the world, with a fortune of 56.2 billion dollars. The president of Life Extension, William Faloon, my boss, has donated 150 million dollars to hospital and University research programs pertaining to life extension. There is a movement in recent years by the rich, super rich, and scientists to increase life spans hundreds of years and they are reaching for the possibility to live forever. Google the word “CRISPR” and you can find numerous articles about how people can live indefinitely in great health by changing the DNA of their individual cells.

The good news for us is that all this research is uncovering how to stay healthy in the life we presently have and even to extend it 20 or 30 years, right now.


My goal is to show people how to live well past 100 in great health and to develop a database with all of our results so that we can prove that following this plan and taking the necessary supplements will enable us to extend our lifespan, in great health, that no government or prescription drug company can argue with.

________________________________________________________________________________________________


Beyond Heart Health

More Reasons to Take Fish Oil

February 2018

By Sean Field

Clinical trials have focused on the cardiovascular benefits of omega-3 fatty acids derived from fish oil.

More recent data show the biological effects that omega-3s confer extend beyond cardiovascular issues and impact virtually every aspect of our health.

A meta-analysis published last year found that the highest consumption of omega-3s from fish oil was associated with a 14% reduction in the risk of dying from any cause, compared to the lowest category of consumption.1

Fish oil benefits range from improved cognition to reduction of metabolic disorders.

In this article, we describe recent studies that evaluate the effects of fish oil on human health and longevity.

What you need to know

  • Fish oils, rich in anti-inflammatory omega-3 fats, are well-established as cardioprotective nutrients.
  • New evidence supports the benefits of omega-3 supplementation in a wide range of metabolic disorders, including obesity, diabetes, metabolic syndrome, and fatty liver disease.
  • Omega-3s have been shown to help with depression and some types of dementia, perhaps largely through their powerful anti-inflammatory effects.
  • Even cancer, autoimmune disease, and kidney disorders are showing signs of responding favorably to omega-3 supplements.
  • Like many inflammation-fighting strategies, fish oil may work best before major clinical disease is evident, highlighting the importance of prevention.

Fish Oil Reduces Death Rates

Fish Oil Reduces Death Rates

In 2017, a study was published that looked at the effects of fish oil ingestion on human mortality rates. The implications from this report pertain to us all.

This analysis revealed a significant 14% reduction in the risk of dying from any cause in the group consuming the highest, versus the lowest amount of omega-3 fish oil.

Epidemiologists call this “all-cause mortality,” and it serves as an important metric in evaluating the overall effect of any intervention on lifespan.1

To study the longer-term effects of omega-3 consumption, the researchers combined data from more than one million subjects whose fish and fish oil consumption had been evaluated in 23 separate studies. A separate sub-analysis of six studies involving over 400,000participants yielded information on omega-3 fats from fish, specifically.1

The researchers undertook this study to resolve lingering questions. Regular consumption of the major omega-3s in fish oil (EPA + DHA) has been found to reduce specific health threats like heart arrhythmias, and risk factors for disease and death, like endothelial dysfunction, lipid disturbances, and inflammation.2

Data on all-cause mortality, however, had been clouded by differences in study design and populations.1

In this 2017 published analysis, researchers found a modest but significant 6% reduction in all-cause mortality risk among those eating the most fish compared with those having the lowest fish consumption.

That’s encouraging, but not everyone can manage the US government recommendations of two fish servings per week.3

For this reason, the researchers also evaluated the pooled data from six of the 23 studies relating to intake of the most relevant components of fish, the omega-3s EPA and DHA.1

They found a greater impact against the risk of dying from any cause among those subjects consuming the most omega-3s. They showed that all-cause mortality risk was 14% lower in those consuming the most EPA/DHA. This is more than double the figure calculated for fish consumption alone.1

Further analysis revealed a 7% reduction in overall risk of dying for each additional 200 mg of fish oilconsumed per day.1

From this enormous study, it is clear that people who consume more fish oil are at substantially lower risk of dying from any cause—a worthwhile finding in its own right.

But people die from specific causes that include cardiovascular disorders, obesity, diabetes, fatty liver, cancer, neurodegenerative diseases, and even major depression.

Underlying these degenerative conditions are pathological processes like inflammation, which we know is strongly associated with most age-related illnesses.

Here, we examine specific ailments that rob us of life quality, and, when severe enough, of life quantity as well.

Anti-Inflammatory Fats

Studies have shown that omega-3 fatty acids like EPA and DHA have benefits in metabolic disorders such as obesity and diabetes, in neurological disorders like depression and Alzheimer’s, as well as in cancer and autoimmune disease.

Omega-3s favorably affect this wide variety of conditions because they reduce the body’s overall burden ofinflammation.4

Chronic inflammation plays a key role in the diseases associated with aging.5 By combatting inflammation, omega-3s help us combat numerous age-related issues.

This is especially evident in metabolic disorders.

Metabolic Disorders

Metabolic syndrome is a cluster of conditions that includes some combination of high blood pressure, belly fat, high blood sugar, and abnormal lipid profiles. Metabolic syndrome is associated with a sharp increase of risk for heart disease, stroke, and diabetes.6

Omega-3 supplements show remarkable effects on the causes7—and the consequences—of metabolic syndrome. And one of the main driving forces behind metabolic syndrome is obesity.

Obesity is a major risk factor for chronic illnesses, in large part because in obese individuals, fat cells churn out massive amounts of inflammation-inducing proteins (called cytokines).8 These cytokines play a role in promoting insulin resistance as well as two related diseases: non-alcoholic fatty liver disease and type II diabetes.9-12

Omega-3 oils from fish exert beneficial effects against obesity. A study published in 2016 concluded that fish oil supplementation reduced waist circumference and blood pressure.13,14

Human studies confirm that supplementing with omega-3s each day may reduce weight, body mass index (BMI), waist/hip ratio, and total fat mass—when combined with sensible diet and exercise.15,16

Omega-3s achieve these effects through mechanisms that include enhancing oxygen consumption (indicating increased fuel-burning), boosting levels of the protective signaling molecule adiponectin (which mitigates insulin resistance and inflammation), and favorably modulating the gut microbiome.16-18

Type II diabetes is a common consequence of obesity, because the inflammation it causes leads to insulin resistance, high blood sugar, and worsening obesity—creating a vicious cycle.19

Fish oil supplementation has been shown to have remarkable benefits in people with type II diabetes. These include decreasing fasting blood sugar, markers of sustained high blood sugar (e.g., hemoglobin A1c), and insulin requirements, as well as reducing episodes of dangerously low blood sugar.14,20

Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a major consequence of obesity and diabetes that occurs when fat cells build up in the liver causing massive amounts of inflammation.21

When not properly controlled, NAFLD can progress to non-alcoholic steatohepatitis (NASH), a more serious condition in which the liver becomes damaged or scarred.22

Human studies show that supplementing with omega-3s has substantial benefits in patients with the condition.

For example, omega-3s have been found to significantly improve liver blood flow, decrease deposits of liver fat, reduce liver enzyme levels in the blood (a marker of liver-cell injury), and lead to significant increases in insulin sensitivity.23-27

Studies also show an over 98% reduction in the risk of having more severe liver disease after treatment with DHA, compared with a placebo group.27,28

One study also showed that omega-3 supplementation not only slowed the progression of NAFLD to NASH, but reversed some of the structural damage that had already occurred in the liver.29 This is a landmark finding, considering this type of liver damage is considered irreversible.

Finally, in a 2017 review of clinical trials in which NAFLD was treated with fish-oil supplementation, 12 separate trials reported decreased liver fat or other markers of NAFLD. The authors suggested that longer treatment duration and improved patient compliance may be important factors for success.30

NOT ALL FISH OIL PREPARATIONS ARE THE SAME
Not All Fish-Oil Preparations Are the Same

Quality counts with all supplements, but it is especially critical when considering fish oil.

The sources, processing, shipping, and final concentration of fish oil products are critical indicators of their quality—and many fall short.

Before choosing a fish oil supplement, you should consider two important categories:

  1. Concentration and value
  2. Freshness and sustainability

As an example, a readily-available commercial “natural fish oil” supplement sold at a major US pharmacy chain offers an enormous jar of softgels at an apparently reasonable price. But if you take a closer look, you’ll see that the recommended dose contains 3,600 mg of “total fish oil,” but only 1,080 mg of “total omega-3” fats—and there are no details about exactly how much EPA and DHA is present.

That means that just 30% of the daily dose may be composed of beneficial EPA/DHA.

To achieve desired intake, you would need to take six large softgels of the commercial product, risking fishy burps and other unpleasant side effects.

In addition, few major fish oil distributors reveal their geographical location, the amount of processing, or the environmental impact of their operations. Many processing plants are located far from the harbors where fresh fish are brought. And few fish oil operations are owned or operated by the fishermen who bring home the harvest, limiting their personal and ethical investments in the product.

A High-Quality Fish Oil

A partnership between a “lipid technology” expert and the two largest fishing companies in Chile (a major source of ocean fish worldwide) began active production in 2012.56

This partnership has a pilot processing plant on-site, where fishing boats arrive daily to unload the freshest possible catch. The operation has a tiny ecological footprint and is in compliance with the very latest sustainable fisheries recommendations and certifications.

Achieving a high concentration of the active EPA and DHA forms of omega-3 is a priority. At their new seaside plant, fish are harvested, and oil is extracted with a process called selective crystallization, which achieves final concentrations of EPA and DHA in the range of 60% to 85% of the product (compared with30% in most commercial products). This high concentration means smaller softgels are packed with more essential omega-3 fatty acids.

A daily dose of the new fish oil composition (two softgels, taken twice daily with meals), provides a total 3,580 mg of fish oil that supplies 1,500 mg EPA and 1,000 mg DHA. That means 70% of the daily dose is composed of the beneficial omega-3 fats.

Omega-3s are a virtual necessity for sustaining heart, brain, and overall body health. Choose fish oil as selectively as you would choose fish for the table—wholesome, sustainably harvested, and fresh.

Powerful Brain Protection

Omega-3s play vital roles in the brain’s very structure and function.31-34

The amount of omega-3 fats in the brain dwindles as we age.35 This leads to losses of brain plasticity, which is the ability to rapidly form new connections and retain new impressions and memories.33 It is also correlated with the diminished ability to use glucose as fuel—an energy deficit that has been linked to mental slowing and neurological impairment.34

The good news is that supplementing with omega-3s can favorably alter brain structure and function. And what’s more, supplementing with omega-3s improves age-related conditions associated with inflammatory changes, such as memory impairments and Alzheimer’s.36-38

Combat Cognitive Impairment

Cognitive impairment, dementia, and neurodegenerative diseases are now recognized as inflammatory conditions.

The inflammatory changes may begin years—perhaps decades—before symptoms occur,36-38 which reinforces the importance of supplementing with fish oil before major symptoms arise.

For example, in a study of adults with mild cognitive impairment (which often precedes dementia), a daily supplement of 720 mg EPA/480 mg DHA improved basic cognitive aptitude, speed of perception, and working memory compared with people receiving a placebo.39

In a study of healthy adults between 50 and 75 years old, supplementation with 1,320 mg EPA/880 mg DHAdaily for 26 weeks improved memory performance and ability to recall object locations.38

Defeat Depression

Defeat Depression

Depression comes in many different forms and can arise for any number of reasons. Studies consistently show that omega-3s have benefits against depression, regardless of the cause.

For example, one study evaluated the impact of omega-3s on women with major depression associated with menopause. After eight weeks of taking 930 mg EPA/750 mg DHA daily, the average standardized depression score fell by 56%.

Even more compelling data from this same study showed that 45% of participants reported feeling normal and experiencing no depression by the end of the trial.40 As an added benefit, the women experienced a reduction in the frequency of hot flashes with supplementation.

In a more recent study, young adults with symptoms of depression were randomly assigned to take either a placebo or 1,000 mg EPA/400 mg DHA daily.41 After just 21 days, scores on the depression inventory (a self-reported test that measures the severity of depression) fell significantly in supplemented subjects, but not in the placebo group. This study found that 67% of the patients taking omega-3s “no longer met the criteria for being depressed.”41

A human and an animal study both suggest that the antidepressant effects of fish oil/omega-3s may be a result of anti-inflammatory activity.42,43

Additional Omega-3 Benefits

Additional Omega-3 Benefits

The ability of omega-3 fats/fish oil to fight inflammation and induce favorable gene expressions in various tissues is now attracting the attention of researchers in virtually all fields of medicine.

Here are just a few highlights of some recent studies:

• Cancer is highly dependent on inflammatory changes for its promotion once a malignant cell has developed.44-46 Animal and human studies are revealing multiple ways in which omega-3 fats may quell cancer-associated inflammation, with far-reaching effects, in colorectal, breast, pancreatic, and blood system cancers.47-50

• Autoimmune diseases are a group of destructive disorders characterized by out-of-control inflammation and the immune system attacking one’s own tissues. These conditions are relatively common in the elderly. Current treatments are less than adequate, often requiring high doses of immunosuppressive drugs. A pair of studies has shown impressive results of fish oil/omega-3 supplementation in patients with rheumatoid arthritis, a notoriously painful autoimmune disease for which conventional treatments can be highly problematic.51-53

• Chronic kidney disease and its progression are closely linked with high levels of inflammation, making it an ideal target for omega-3 intervention. Two recent papers examined the role of omega-3 supplementation in chronic kidney disease. One showed that omega-3 fats were an effective solution for one of the most frustrating and even disabling symptoms of this disease, chronic itching, also known as pruritus. In another study, omega-3 supplementation resulted in longer telomeres, which are the longevity-associated chromosomal “clocks” that shorten as we age.54,55

These findings are almost certainly the tip of a very large iceberg, as researchers pursue potential benefits of omega-3s in a host of inflammation-related disorders.

LATE-BREAKING FINDINGS ON OMEGA-3 FATS
Late-Breaking Findings on Omega-3 Fats

New studies on omega-3 fats suggest still more mechanisms of action—and ultimately more roles for these versatile nutrients in preventing disease and promoting good health. Here is a summary of their findings:

  • The long-chain omega-6 and omega-3 fatty acids are molecular precursors of the endocannabinoid signaling compounds.57 The brain-signaling endocannabinoid system is involved in regulation of appetite, pain sensation, mood, and memory.58
  • Blood levels of total omega-3 and DHA fats are strongly correlated with diversity in the gut microbiome, the intestinal community of microbes that is intimately related to our health.59 Greater diversity is nearly always associated with greater disease resistance and better health.
  • In a further exploration of relationships between omega-3 fats and the microbiome, researchers leveraged omega-3’s anti-inflammatory powers, coupling them with a probiotic formulation to reduce the inflammation-induced side effects of chemotherapy.60 In a group of patients with colorectal cancer, this approach improved quality of life, relieved some chemotherapy side effects, and reduced key markers of inflammation.

Summary

Summary

Peer-reviewed published studies continue to document the anti-inflammatory value of omega-3 supplements in some of the most troubling symptoms and chronic diseases of aging.

Metabolic disorders such as obesity, diabetes, and fatty liver are yielding to treatment with omega-3s, as are numerous brain-related conditions including major depression and dementia.

Evidence is also accumulating about roles of omega-3s in inflammation-dependent conditions such as cancer, autoimmune disease, and chronic kidney disease.

Supplementing with fish oil ensures you remain on the higher end of the omega-3 scale that has been shown to reduce human mortality rates, along with many chronic conditions of older age.

If you have any questions on the content of this article, please call Joe Hammond at 1-786-370-8557 or email joe.hammond@HammondLifeExtension.com.

References

  1. Wan Y, Zheng J, Wang F, et al. Fish, long chain omega-3 polyunsaturated fatty acids consumption, and risk of all-cause mortality: a systematic review and dose-response meta-analysis from 23 independent prospective cohort studies. Asia Pac J Clin Nutr. 2017;26(5):939-56
  2. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58(20):2047-67
  3. Available at: https://health.gov/dietaryguidelines/2015/guideli... Accessed November 14, 2017
  4. Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans.2017;45(5):1105-15
  5. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-9
  6. Available at: https://www.nhlbi.nih.gov/health/health-topics/to... Accessed November 6, 2017
  7. Gao H, Geng T, Huang T, et al. Fish oil supplementation and insulin sensitivity: a systematic review and meta-analysis. Lipids Health Dis. 2017;16(1):131
  8. Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr. 2006;83(2):461s-5s
  9. Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2009;121(6):21-33
  10. Must A, McKeown NM. The Disease Burden Associated with Overweight and Obesity. In: De Groot LJ, Chrousos G, Dungan K, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000
  11. Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm.2010;2010
  12. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15(4):6184-223
  13. Howe P, Buckley J. Metabolic health benefits of long-chain omega-3 polyunsaturated fatty acids. Mil Med.2014;179(11 Suppl):138-43
  14. Kurt A, Andican G, Siva ZO, et al. The effects of n-3 long-chain polyunsaturated fatty acid supplementation on AGEs and sRAGE in type 2 diabetes mellitus. J Physiol Biochem. 2016;72(4):679-87
  15. Gonzalez-Acevedo O, Hernandez-Sierra JF, Salazar-Martinez A, et al. [Effect of Omega 3 fatty acids on body female obese composition]. Arch Latinoam Nutr. 2013;63(3):224-31
  16. Haghravan S, Keshavarz SA, Mazaheri R, et al. Effect of Omega-3 PUFAs Supplementation with Lifestyle Modification on Anthropometric Indices and Vo2 max in Overweight Women. Arch Iran Med. 2016;19(5):342-7
  17. Kaliannan K, Wang B, Li XY, et al. Omega-3 fatty acids prevent early-life antibiotic exposure-induced gut microbiota dysbiosis and later-life obesity. Int J Obes (Lond). 2016;40(6):1039-42
  18. Fisman EZ, Tenenbaum A. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol. 2014;13:103
  19. van Greevenbroek MM, Schalkwijk CG, Stehouwer CD. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth J Med. 2013;71(4):174-87
  20. Pohl M, Mayr P, Mertl-Roetzer M, et al. Glycemic control in patients with type 2 diabetes mellitus with a disease-specific enteral formula: stage II of a randomized, controlled multicenter trial. JPEN J Parenter Enteral Nutr. 2009;33(1):37-49
  21. Milic S, Lulic D, Stimac D. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations. World J Gastroenterol. 2014;20(28):9330-7
  22. Available at: http://www.merckmanuals.com/professional/hepatic-... Accessed November 14, 20147
  23. Scorletti E, Bhatia L, McCormick KG, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology. 2014;60(4):1211-21
  24. Sofi F, Giangrandi I, Cesari F, et al. Effects of a 1-year dietary intervention with n-3 polyunsaturated fatty acid-enriched olive oil on non-alcoholic fatty liver disease patients: a preliminary study. Int J Food Sci Nutr.2010;61(8):792-802
  25. Pacifico L, Bonci E, Di Martino M, et al. A double-blind, placebo-controlled randomized trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat and associated cardiovascular risk factors in overweight children with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2015;25(8):734-41
  26. Boyraz M, Pirgon O, Dundar B, et al. Long-Term Treatment with n-3 Polyunsaturated Fatty Acids as a Monotherapy in Children with Nonalcoholic Fatty Liver Disease. J Clin Res Pediatr Endocrinol.2015;7(2):121-7
  27. Nobili V, Bedogni G, Alisi A, et al. Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child. 2011;96(4):350-3
  28. Nobili V, Alisi A, Della Corte C, et al. Docosahexaenoic acid for the treatment of fatty liver: randomised controlled trial in children. Nutr Metab Cardiovasc Dis. 2013;23(11):1066-70
  29. Li YH, Yang LH, Sha KH, et al. Efficacy of poly-unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis. World J Gastroenterol. 2015;21(22):7008-13
  30. de Castro GS, Calder PC. Non-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids. Clin Nutr. 2017
  31. Yassine HN, Braskie MN, Mack WJ, et al. Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E epsilon4 Carriers: A Review. JAMA Neurol. 2017;74(3):339-47
  32. Bourre JM, Bonneil M, Clement M, et al. Function of dietary polyunsaturated fatty acids in the nervous system. Prostaglandins Leukot Essent Fatty Acids. 1993;48(1):5-15
  33. Dyall SC, Michael GJ, Whelpton R, et al. Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain.Neurobiol Aging. 2007;28(3):424-39
  34. Pifferi F, Dorieux O, Castellano CA, et al. Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur. J Lipid Res.2015;56(8):1511-8
  35. Giusto NM, Salvador GA, Castagnet PI, et al. Age-associated changes in central nervous system glycerolipid composition and metabolism. Neurochem Res. 2002;27(11):1513-23
  36. Thomas J, Thomas CJ, Radcliffe J, et al. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer’s Disease. Biomed Res Int. 2015;2015:172801
  37. Robinson JG, Ijioma N, Harris W. Omega-3 fatty acids and cognitive function in women. Womens Health (Lond). 2010;6(1):119-34
  38. Kulzow N, Witte AV, Kerti L, et al. Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. J Alzheimers Dis. 2016;51(3):713-25
  39. Bo Y, Zhang X, Wang Y, et al. The n-3 Polyunsaturated Fatty Acids Supplementation Improved the Cognitive Function in the Chinese Elderly with Mild Cognitive Impairment: A Double-Blind Randomized Controlled Trial. Nutrients. 2017;9(1)
  40. Freeman MP, Hibbeln JR, Silver M, et al. Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial. Menopause. 2011;18(3):279-84
  41. Ginty AT, Conklin SM. Short-term supplementation of acute long-chain omega-3 polyunsaturated fatty acids may alter depression status and decrease symptomology among young adults with depression: A preliminary randomized and placebo controlled trial. Psychiatry Res. 2015;229(1-2):485-9
  42. Rapaport MH, Nierenberg AA, Schettler PJ, et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016;21(1):71-9
  43. Dang R, Zhou X, Tang M, et al. Fish oil supplementation attenuates neuroinflammation and alleviates depressive-like behavior in rats submitted to repeated lipopolysaccharide. Eur J Nutr. 2017
  44. Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006;79(3-4):123-30
  45. Yum HW, Na HK, Surh YJ. Anti-inflammatory effects of docosahexaenoic acid: Implications for its cancer chemopreventive potential. Semin Cancer Biol. 2016;40-41:141-59
  46. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-99
  47. Molfino A, Amabile MI, Monti M, et al. The Role of Docosahexaenoic Acid (DHA) in the Control of Obesity and Metabolic Derangements in Breast Cancer. Int J Mol Sci. 2016;17(4):505
  48. Chagas TR, Borges DS, de Oliveira PF, et al. Oral fish oil positively influences nutritional-inflammatory risk in patients with haematological malignancies during chemotherapy with an impact on long-term survival: a randomised clinical trial. J Hum Nutr Diet. 2017
  49. Djuric Z, Aslam MN, Simon BR, et al. Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors. J Nutr Biochem. 2017;46:90-9
  50. Park M, Kim H. Anti-cancer Mechanism of Docosahexaenoic Acid in Pancreatic Carcinogenesis: A Mini-review. J Cancer Prev. 2017;22(1):1-5
  51. Dawczynski C, Dittrich M, Neumann T, et al. Docosahexaenoic acid in the treatment of rheumatoid arthritis: A double-blind, placebo-controlled, randomized cross-over study with microalgae vs. sunflower oil. Clin Nutr.2017
  52. Sorto-Gomez TE, Ortiz GG, Pacheco-Moises FP, et al. Effect of fish oil on glutathione redox system in multiple sclerosis. Am J Neurodegener Dis. 2016;5(2):145-51
  53. Veselinovic M, Vasiljevic D, Vucic V, et al. Clinical Benefits of n-3 PUFA and -Linolenic Acid in Patients with Rheumatoid Arthritis. Nutrients. 2017;9(4)
  54. Barden A, O’Callaghan N, Burke V, et al. n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease. Nutrients. 2016;8(3):175
  55. Panahi Y, Dashti-Khavidaki S, Farnood F, et al. Therapeutic Effects of Omega-3 Fatty Acids on Chronic Kidney Disease-Associated Pruritus: a Literature Review. Adv Pharm Bull. 2016;6(4):509-14
  56. Golden Omega. Golden Omega - Direct to the Source Corporate proprietary literature2016
  57. Dyall SC. Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair. Lipids. 2017;52(11):885-900
  58. Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-57
  59. Menni C, Zierer J, Pallister T, et al. Omega-3 fatty acids correlate with gut microbiome diversity and production of N-carbamylglutamate in middle aged and elderly women. Sci Rep. 2017;7(1):11079
  60. Golkhalkhali B, Rajandram R, Paliany AS, et al. Strain-specific probiotic (microbial cell preparation) and omega-3 fatty acid in modulating quality of life and inflammatory markers in colorectal cancer patients: A randomized controlled trial. Asia Pac J Clin Oncol. 2017

___________________________________________________________________________________________________


Restore Youthful Skin from Within

April 2019

By Michael Downey

Collagen and hyaluronic acid are natural skin components that maintain moisture, support elasticity and promote smoothness.1,2

Aging, along with sun exposure, reduces the skin's content of collagen and hyaluronic acid.

Loss of these components weakens skin structures, leading to age-related dryness and wrinkles.1,2

Clinical trials show that oral use of a collagen peptide improves skin elasticity by an average of 7%3 and reduces the depth of eye wrinkles by 20%.4

Hyaluronic acid regenerates the skin's underlying architecture by increasing moisture,5 stimulating collagen-elastin synthesis,6,7 promoting tissue repair,8-11 and combating ultraviolet radiation.12

Scientists have developed clinically-effective doses of these nutrients in great-tasting gummies. This enables aging individuals to replenish the collagen and hyaluronic acid found naturally in youthful skin.

What you need to know

  • Collagen, in the form of collagen peptides, improves skin elasticity and levels of essential structural proteins and reduces the depth of eye wrinkles by as much as 20%.
  • Hyaluronic acid supplementation has been shown to significantly reverse the loss of moisture content in your skin as you age, helping to restore a more youthful appearance, and to treat dry, itchy skin.
  • Clinical studies document that replenishing the age-related decline in the levels of these 2 skin components with oral supplements leads to more youthful-appearing and healthier skin.
  • A novel way to take these 2 essential nutrients has been developed in the form of great-tasting gummies that provide clinically effective doses and have less than 1 gram of sugar per serving.

Collagen Is Essential for Youthful Skin

Womans face with magnifying glasses

Collagen is the most abundant protein in the human body. It is the main component of most types of connective tissue, and is vital for healthy, vibrant skin.13

Collagen makes up 70% of the weight of the inner layer of skin.14 It provides flexibility and is integrated with elastin fibers, the protein that allows the skin to stretch and return to its original shape.

As we age, the number of collagen fibers in the dermis declines drastically. The cells that produce collagen fibers slow down, and the remaining fibers stiffen, break, and begin to lose shape. Elastin fibers also begin to fray and lose elasticity. This deterioration of collagen and elastin leads to skin that appears wrinkled and sagging.15

To solve this problem, scientists developed collagen peptides that provide the building blocks for collagen synthesis and stimulate the production of new collagen and elastin in the skin. This leads to increased suppleness and elasticity—and reduces skin wrinkles.4

Oral Collagen Peptides Block Skin Aging

Preclinical research has shown that hydrolyzed (partially broken-down) collagen peptides increase the expression of collagen, which helps to produce stronger, suppler skin. These collagen peptides also reducethe activity of a "protein-melting" enzyme (metalloproteinase 2) that degrades collagen and hastens skin aging.16

In a more recent breakthrough, scientists demonstrated in human trials that a collagen peptide oral supplement is clinically effective against the appearance of aging skin.

Researchers conducted a double-blind, placebo-controlled study to evaluate the effectiveness of orally-administered collagen peptides on skin elasticity. They gave volunteers either a placebo or the oral collagen supplement for 8 weeks. The test group took either 2.5 grams or 5 grams of the supplement.3

Both doses of the collagen peptides demonstrated the same result, which was an average of 7%improvement in skin elasticity. Even 4 weeks after the last dose, the supplemented group retained higher skin elasticity than the placebo group. The improvement in skin elasticity was greater in the subgroup of women over age 49.3

Next, scientists set up a double-blind, placebo-controlled study to evaluate the effects of collagen peptides on skin wrinkles. Study subjects consisted of 114 women, aged 45 to 65, who were given daily oral collagenpeptide supplements of 2.5 grams. Wrinkles were measured regularly during the 8-week trial.4

After 4 weeks, the volume of eye wrinkles for the supplemented group had decreased by 7.2%, compared with placebo recipients. And when the trial had run its full 8-week course, those taking the collagen peptide supplements had a stunning 20.1% reduction in the size of unsightly eye wrinkles.4

The researchers also studied the effects of collagen peptides on the synthesis of the dermal matrix, the structural framework responsible for skin renewal and vitality.

They did so by evaluating changes in the amount of structural proteins in the dermal matrix. The greater the content of these proteins, the healthier and suppler the skin appears.

Supplemented subjects in this study had a 65% increase in the accumulation of essential type-I pro-collagenand an 18% increase in elastin fibers.4

Loss of Hyaluronic Acid Causes Aging of the Skin

Collagen is one of the most well-known components of healthy, youthful-looking skin. But hyaluronic acid is just as essential.

Hyaluronic acid has the capacity to attract and retain up to 1,000 times its weight in water.17 Although it is found throughout most tissues in the body, more than 50% of the body's concentration of hyaluronic acid is located in the skin.1,18 There, it is an essential component of the extracellular matrix, a hydrated network that provides structural integrity and cohesion to skin.19

Hyaluronic acid is one of the most potent weapons for fighting skin aging and preserving youthful skin. But the body produces less of it as we age—a problem worsened by environmental stress, particularly chronic sun exposure.20-23

Together, these factors lead to skin wrinkling, dryness, and the sagging that is characteristic of aging skin.

Fortunately, scientists made a dramatic finding: Oral supplementation with hyaluronic acid can slow, and even reverse, these effects.

Oral Hyaluronic Acid Replenishes Skin Moisture

Dermatologist looking at skin

A team of scientists analyzed several studies on the skin-improving effects of orally ingested hyaluronic acid.1

Participants in most of the studies were diagnosed with "chronically rough and dry skin" prior to the trial. For people like them, moisturizers and other treatments did little to help. But hyaluronic acid made a radical difference. Compared to volunteers who received the placebo, the hyaluronic-acid-treated subjects had a significant increase in skin moisture after 4-6 weeks of oral supplementation.1

Furthermore, the moisturizing effects of oral hyaluronic acid were found to continue for a full 2 weeks after supplementation had been discontinued.1

The scientific team also reported another benefit: Not only did consuming hyaluronic acid significantly moisturize the skin, but it also reduced the itching that comes with dry skin.1

Their published review included the clear conclusion that "employing HA [hyaluronic acid] as a dietary supplement makes the skin healthy."1

A New Way to Take Oral Collagen Peptides and Hyaluronic Acid

Woman smiling

Oral supplementation with collagen peptides and hyaluronic acid has been shown clinically to reverse the harsh effects of declining levels of these essential skin components.

But scientists have gone a step further. They've developed a novel and convenient way to orally supplement with potent doses of these nutrients.

These two clinically-validated "beauty-from-within" skin components—collagen peptides and hyaluronic acid—are now available in a great-tasting, easy-to-chew and swallow gummy supplement.

This delivery system is different from other supplement gummies for 2 key reasons. First, taking 4 gummiesprovides a clinically effective dose of each of these skin-rejuvenating components. Many other gummies provide woefully insufficient doses of nutrients.

Second, while most gummies contain high amounts of sugar as the first ingredient, these gummies have less than 1 gram of sugar per serving —and taste great.

So it is easy to enjoy a few, delicious gummies each day to replenish the skin's decreasing supplies of collagen and hyaluronic acid, which have been clinically shown to:

  • Increase skin moisture,
  • Improve elasticity,
  • Decrease wrinkle depth,
  • Boost levels of structural proteins pro-collagen and elastin, and
  • Provide more youthful-appearing skin.

Summary

Collagen, when supplemented in the form of specialized peptides, is easily absorbed by the body.

These collagen peptides boost skin elasticity, reduce eye wrinkle depth up to 20%, and increase pro- collagen and elastin levels. This provides strength and resilience to the dermal matrix.

Hyaluronic acid protects and nourishes the skin by pumping up its moisture content, which addresses dry and itchy skin.

Impressive clinical studies have demonstrated that orally taking these two "beauty-from-within" skin components provides noticeable improvements in the appearance of aging skin.

Scientists have developed a novel way to take these 2 key nutrients together—in great-tasting gummies that deliver clinically effective doses.

If you have any questions on the content of this article, please call Joe Hammond at 1-786-370-8557 or email joe.hammond@HammondLifeExtension.com.

References

  1. Kawada C, Yoshida T, Yoshida H, et al. Ingested hyaluronan moisturizes dry skin. Nutr J. 2014 Jul 11;13:70.
  2. Rittie L, Fisher GJ. Natural and sun-induced aging of human skin. Cold Spring Harb Perspect Med. 2015Jan 5;5(1):a015370.
  3. Proksch E, Segger D, Degwert J, et al. Oral supplementation of specific collagen peptides has beneficial effects on human skin physiology: a double-blind, placebo-controlled study. Skin Pharmacol Physiol. 2014;27(1):47-55.
  4. Proksch E, Schunck M, Zague V, et al. Oral intake of specific bioactive collagen peptides reduces skin wrinkles and increases dermal matrix synthesis. Skin Pharmacol Physiol. 2014;27 (3):113-9.
  5. Masson F. Skin hydration and hyaluronic acid. Ann Dermatol Venereol. 2010 Apr;137 Suppl 1:S23-5.
  6. Beasley KL, Weiss MA, Weiss RA. Hyaluronic acid fillers: a comprehensive review. Facial Plast Surg. 2009May;25(2):86-94.
  7. McKee CM, Penno MB, Cowman M, et al. Hyaluronan (HA) fragments induce chemokine gene expression in alveolar macrophages. The role of HA size and CD44. J Clin Invest. 1996 Nov 15;98(10):2403-13.
  8. Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol. 2007;23:435-61.
  9. Noble PW. Hyaluronan and its catabolic products in tissue injury and repair. Matrix Biol. 2002 Jan;21(1):25-9.
  10. Teriete P, Banerji S, Noble M, et al. Structure of the regulatory hyaluronan binding domain in the inflammatory leukocyte homing receptor CD44. Mol Cell. 2004 Feb 27;13(4):483-96.
  11. Wang Y, Lauer ME, Anand S, et al. Hyaluronan synthase 2 protects skin fibroblasts against apoptosis induced by environmental stress. J Biol Chem. 2014 Nov 14;289(46):32253-65.
  12. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Clin Cosmet Investig Dermatol. 2013 Dec 12;6:295-316.
  13. Available at: https://www.ncbi.nlm.nih.gov/books/NBK507709/. Accessed January 8, 2019.
  14. Available at: https://emedicine.medscape.com/article/1294744-overview#showall. Accessed January 8, 2019.
  15. McLafferty E, Hendry C, Alistair F. The integumentary system: anatomy, physiology and function of skin. Nurs Stand. 2012 Sep 19-25;27(3):35-42.
  16. Zague V, de Freitas V, da Costa Rosa M, et al. Collagen hydrolysate intake increases skin collagen expression and suppresses matrix metalloproteinase 2 activity. J Med Food. 2011 Jun;14(6): 618-24.
  17. Mateo Orobia AJ, Saa J, Ollero Lorenzo A, et al. Combination of hyaluronic acid, carmellose, and osmoprotectants for the treatment of dry eye disease. Clin Ophthalmol. 2018;12:453-61.
  18. Laurent UB, Dahl LB, Reed RK. Catabolism of hyaluronan in rabbit skin takes place locally, in lymph nodes and liver. Exp Physiol. 1991 Sep;76(5):695-703.
  19. Nusgens BV. [Hyaluronic acid and extracellular matrix: a primitive molecule?]. Ann Dermatol Venereol. 2010Apr;137 Suppl 1:
    S3-8.
  20. Dai G, Freudenberger T, Zipper P, et al. Chronic ultraviolet B irradiation causes loss of hyaluronic acid from mouse dermis because of down-regulation of hyaluronic acid synthases. Am J Pathol. 2007Nov;171(5):1451-61.
  21. Ghersetich I, Lotti T, Campanile G, et al. Hyaluronic acid in cutaneous intrinsic aging. Int J Dermatol. 1994Feb;33(2):119-22.
  22. Matuoka K, Hasegawa N, Namba M, et al. A decrease in hyaluronic acid synthesis by aging human fibroblasts leading to heparan sulfate enrichment and growth reduction. Aging (Milano). 1989 Sep;1(1):47-54.
  23. Rock K, Grandoch M, Majora M, et al. Collagen fragments inhibit hyaluronan synthesis in skin fibroblasts in response to ultraviolet B (UVB): new insights into mechanisms of matrix remodeling. J Biol Chem. 2011 May 20;286(20):18268-76.
  24. Baumann L. Skin ageing and its treatment. J Pathol. 2007 Jan;211(2):241-51.

_________________________________________________________________________________________________


Power a Longer Life via NAD+ Restoration

February 2019

By Gene Richmond

In year 2001, Life Extension® researchers actively sought a method to boost levels of a coenzyme in aging people.

We knew this was critical to achieving healthy longevity.

Consumers had to wait until 2014 for a validated method to become available.

This coenzyme is called NAD+ and is vital for energizing cells and supporting youthful cellular processes.1-4

For resveratrol users, NAD+ is especially important.

That's because resveratrol promotes expression of cell proteins called sirtuins that protect against age-related decline.3-7

But sirtuins need NAD+ to function.

What you need to know

  • Every cell in the body relies on NAD+ both to maintain normal energy supply and to protect the cell.
  • Sirtuins, proteins critical for maintaining optimal health and longevity, are completely dependent on adequate levels of NAD+ to function optimally.
  • As we age, our NAD+ levels and sirtuin activity decline.
  • Interventions to boost NAD+ levels in cells have demonstrated promise in extending life and preventing loss of function.
  • Nicotinamide riboside is an NAD+ precursor that is readily absorbed from the gut and is effective at boosting levels of NAD+ in cells throughout the body.

And as we age, NAD+ levels drastically plummet. 6-8

The result is loss of cellular functions and potential accelerated aging.

A patented supplement called nicotinamide riboside replenishes cellular NAD+.

Studies reveal how restoring NAD+ may slow or halt certain aging processes, boost brain function, and reduce risk for age-related disorders.3,7,9

NAD+ and Brain Function

Longer life means little without an enhanced healthspan as well. Fortunately, boosting levels of NAD+ in later life maximizes healthy function and can prevent degenerative disorders.

A major cause of diminishing life quality in older age is loss of cognitive function and dementia.

Research has found that supporting healthy levels of NAD+ has neuroprotective effects, guarding against age-related loss of brain function including traumatic injury and stroke.10-23

Two recent studies utilized experimental mouse models of Alzheimer's disease, the most common cause of dementia in older adults.10,12 These mice display changes in the brain similar to those observed in elderly humans, and could be expected to result in significant deficits in cognition.

IMPACT OF SEVERE NAD+ DEFICIT
Shaded DNA strand becoming a human
  • Tremors
  • Depression
  • Arterial Stiffness
  • Circadian Rhythm Imbalance
  • Pro-youth Genes Turned Off
  • Restless Leg Syndrome
  • Cellular Senescence
  • Sarcopenia
  • Death

In both studies, giving the mice nicotinamide riboside supplements stopped the decline of NAD+ levels in the brains—and greatly reduced cognitive deterioration.

The studies also showed reduced evidence of DNA damage in brain cells, reduced inflammation, and signs that synaptic plasticity was restored. Synaptic plasticity (the ability of the brain to adapt and maintain healthy connections) is typically impaired in older age and in cognitive disorders like dementia.

Another remarkable two-pronged study showed that nicotinamide riboside helps protect against the effects of Parkinson's disease.17

In the first part of the study, using a fly model of Parkinson's, nicotinamide riboside prevented the death of nerve cells in the brain and preserved motor function. In the second part, using human brain cells harvested from Parkinson's disease patients, the supplement raised levels of NAD+ and caused improvements in mitochondrial
function.17

The study researchers concluded that nicotinamide riboside is a promising approach to protecting against Parkinson's disease and likely other degenerative diseases of the nervous system.

Obesity, Metabolism, and Cardiovascular Function

Magnifying glass overlooking cellular strands

Obesity, diabetes, and metabolic syndrome are common age-related issues. Along with other factors, these conditions put people at risk for cardiovascular disease, cancer, and kidney failure.

NAD+ is crucial to basic metabolic functions and cellular integrity. Several studies confirm that raising levels of NAD+ increases metabolism and may help prevent andtreat obesity, fatty liver disease, diabetes, and metabolic syndrome.24-28

That's where nicotinamide riboside comes in. By stimulating levels of NAD+, nicotinamide riboside enhances metabolism. In mice, it increases metabolic rate, raising body temperature slightly and reducing deposits of abdominal fat, which is tied to high risk for cardiovascular disease.29

Even in rats fed a high-fat diet, nicotinamide riboside boosts metabolism and prevents obesity.25,30

In mice suffering from prediabetes and diabetes, it improves control of blood sugar and reduces weight while protecting against tissue injury such as liver damage and nerve disease.27

The potential benefits for humans are extraordinary. Both by improving metabolic health and by its direct effects on the heart muscle and blood vessels, nicotinamide riboside shows promise in preventing cardiovascular disease.31

That's remarkable enough. But nicotinamide riboside supplements have also shown promise as a treatmentfor heart disease by raising levels of NAD+, known to be vital for normal heart function and recovery following an injury.32-34

In one study, mice with cardiac disease and heart failure were protected by nicotinamide riboside.32 While untreated animals rapidly developed dilation of the heart, thinning of the heart muscle, and decreased cardiac output—often seen in human heart disease—animals given supplements of nicotinamide riboside maintained cardiac muscle integrity and function.

NAD+ and Longevity

IMAGE DESCRIPTION HERE

There are a number of known behaviors one can make to extend a healthy lifespan.

These include a wholesome diet, avoidance of toxins, intake of inflammation-suppressing nutrients, and regular exercise.

Recent studies show promise for a more targeted approach to increasing longevity.

Sirtuin activity is a crucial component to living a longer life.

As NAD+ levels fall and sirtuinactivity wanes, aging becomes more evident as follows:

  • Diminished brain function,35,36 leading to cognitive decline and risk for dementia.
  • Inflammation in blood vessels that contributes to atherosclerosis and cardiovascular disease.37,38
  • Fatty changes in the liver that leads to non-alcoholic fatty liver disease (NAFLD).39-41
  • Increased fat storage,42,43 that leads to overweight and obesity. When fat is stored around the liver and other organs, it increases systemic inflammation and contributes to metabolic and cardiovascular disease.
  • Insulin resistance, impairing the metabolism of glucose and leading to metabolic syndrome and diabetes.38,44,45
  • Muscle changes, including loss of muscle strength, fat deposits in muscles, and fatigue. 46

Studies show that enhancing sirtuin activity promotes longevity.5-7,9,38,47,48 Sirtuin activity is vitally dependent on NAD+, so boosting the body's NAD+ levels as we age may help prolong life.

This has been demonstrated in a wide variety of living organisms.49,50

Yeast grown with nicotinamide riboside have an increase in lifespan.51 In one study, worms given nicotinamide riboside lived 16% longer.52

Even in already elderly mice, a study by an international team of scientists published in Science showed that nicotinamide riboside extends lifespan by nearly 5%.53 This is at an age where other treatments attempting to prolong life fail. Scientists also observed several biochemical changes in these animals, indicating rejuvenation of cell function.

NAD+ MAY IMPROVE HEART FUNCTION

"Stabilizing the intracellular NAD+ level represents a promising therapeutic strategy to improve myocardial bioebergetics and cardiac function."

"In this issue of Circulation, Diguet, et al report exciting data suggesting that supplementation with NAD+ precursor, nicotinamide riboside, reduces cardiac dysfunction in preclinical models of heart failure."

— May 22, 2018 http://circ.ahajournals.org/content/137/21/2274

NAD+ and DNA Repair

The DNA in our cells suffers considerable damage every day. The only reason this does not kill us is that cells are very efficient at repairing this damage, which comes in the form of single- and double-strand DNA breaks.

As NAD+ levels decline with age, we are less able to repair cellular DNA.

For example, sirtuins protect DNA from damage that can lead to potentially harmful mutations. Threats to DNA increase significantly with age. Protective sirtuin proteins must operate at full strength in order to properly safeguard DNA, shielding against age-related loss of function and risk for cancer.

In fact, research has demonstrated that dwindling sirtuin activity is associated with more rapid aging—and that boosting sirtuin activity is protective, prolonging lifespan and guarding against disease.9

But sirtuins require NAD+ to function. An ample and continuously renewing supply of NAD+ is needed by the cell to keep operating normally.

Since NAD+ levels diminish with advancing age, replenishing our NAD+ supply is essential to any plan to forestall aging and degenerative disease.9

NAD+ NEEDED FOR DNA REPAIR
artistic image of DNA strand
  • Each cell in your body suffers 10 DNA breaks every day.*
  • Unrepaired DNA damage is a major degenerative aging factor.
  • NAD+ depletion with aging turns off DNA repair enzymes.

* Lieber, MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79:1281-211.

Nicotinamide Riboside Boosts NAD+

A proven method of boosting NAD+ levels in the body is to supply cells with precursor compounds that naturally convert to NAD +.

One way to do this is with nicotinamide riboside. This naturally occurring form of vitamin B3 is only found in trace amounts in the diet. Therefore, the only way to significantly raise its intake is through supplementation.

Research shows that when taken by mouth, nicotinamide riboside is highly bioavailable, and has been shown to boost NAD+ levels in the body.54

One study showed that compared to baseline, daily supplementation with 250 mg or 500 mg of nicotinamide riboside for 4 weeks increased NAD+ blood levels by approximate 40% and 90% respectively.55

NAD+ SHARPLY PLUMMETS WITH AGE
Life Extension Magazine cover September 2017
  • At age 50, we have 40% less NAD+ than at age 20.
  • By age 80, NAD+ levels drop as much as 98%.

* The Plasma NAD+ Metabolome is Dysregulated in "Normal" Aging. Rejuvenation Research. 2018 Oct 23, and unpublished clinical observations.

Summary

NAD+ is a vital cofactor for energy metabolism and hundreds of longevity-promoting processes in every cell of the body.

Aging is associated with reduced NAD+ levels. This decline is a major contributor to the aging process and puts cells and tissues at risk for age-related injury and loss of function.

Nicotinamide riboside is a readily absorbed compound that helps cells maximize their supply of NAD+ to help maintain DNA repair.

Human studies show that nicotinamide riboside is highly bioavailable and rapidly increases NAD+ in cells.

Boosting NAD+ to more youthful levels with nicotinamide riboside has been demonstrated to prolong life and reverse loss of function in animal models.

WHAT ARE SIRTUINS AND WHY ARE THEY SO POWERFUL AS AN ANTI-AGING TARGET?

Sirtuins are regulatory proteins in all cells that play a critical role in the response to stress and injuries that cause damage, particularly DNA damage.6,7

Over a lifetime, cells accumulate damage, which can lead to loss of function and risk for disease.

Without mechanisms to defend against and repair this damage, cells rapidly age and become dysfunctional. That is where sirtuins come in.

Activated sirtuins help initiate repair of DNA, preventing the development of dysfunctional genes and mutations.

Sirtuins are also involved in the body's internal clock, the circadian rhythm, which is crucial to maintaining a healthy metabolism. Defects in this clock have been associated with premature aging and disease.

Therefore, maintaining optimal sirtuin activity is one the body's best defenses against the ailments and illnesses associated with aging. But sirtuins require NAD+ to function normally.

Advancing age leads to accumulating DNA damage. As sirtuins use NAD+ to fight this damage, the body's supply of NAD+ is depleted. The resulting low NAD+ levels then impair the ability of sirtuins to continue functioning normally, leading to further DNA damage.

A powerful way to break this cycle is to replenish the body's levels of NAD+.

If you have any questions on the content of this article, please call Joe Hammond at 1-786-370-8557 or email joe.hammond@HammondLifeExtension.com.

References

  1. Ansari HR, Raghava GP. Identification of NAD interacting residues in proteins. BMC Bioinformatics. 2010Mar 30;11:160.
  2. Braidy N, Berg J, Clement J, et al. Role of Nicotinamide Adenine Dinucleotide and Related Precursors as Therapeutic Targets for Age-Related Degenerative Diseases: Rationale, Biochemistry, Pharmacokinetics, and Outcomes. Antioxid Redox Signal. 2018 May 11.
  3. Kulikova VA, Gromyko DV, Nikiforov AA. The Regulatory Role of NAD in Human and Animal Cells. Biochemistry (Mosc). 2018 Jul;83(7):800-12.
  4. Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015 Dec 4;350(6265):1208-13.
  5. Watroba M, Dudek I, Skoda M, et al. Sirtuins, epigenetics and longevity. Ageing Res Rev. 2017 Nov;40:11-9.
  6. Johnson S, Imai SI. NAD (+) biosynthesis, aging, and disease. F1000Res. 2018;7:132.
  7. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014 Aug;24(8):464-71.
  8. Zhou CC, Yang X, Hua X, et al. Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol. 2016 Aug;173(15):2352-68.
  9. Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab. 2018 Mar 6;27(3):529-47.
  10. Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging. 2013 Jun;34(6):1581-8.
  11. Hamity MV, White SR, Walder RY, et al. Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats. Pain. 2017 May;158(5):962-72.
  12. Hou Y, Lautrup S, Cordonnier S, et al. NAD(+) supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1876-E85.
  13. Klaidman L, Morales M, Kem S, et al. Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology. 2003 Nov;69(3):150-7.
  14. Lin JB, Kubota S, Ban N, et al. NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice. Cell Rep. 2016 Sep 27;17(1):69-85.
  15. Long AN, Owens K, Schlappal AE, et al. Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer's disease-relevant murine model. BMC Neurol. 2015 Mar 1;15:19.
  16. Sadanaga-Akiyoshi F, Yao H, Tanuma S, et al. Nicotinamide attenuates focal ischemic brain injury in rats: with special reference to changes in nicotinamide and NAD+ levels in ischemic core and penumbra. Neurochem Res. 2003 Aug;28(8):1227-34.
  17. Schondorf DC, Ivanyuk D, Baden P, et al. The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson's Disease. Cell Rep. 2018Jun 5;23(10):2976-88.
  18. Sorrentino V, Romani M, Mouchiroud L, et al. Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature. 2017 Dec 14;552(7684):187-93.
  19. Vaur P, Brugg B, Mericskay M, et al. Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration. FASEB J. 2017 Dec;31(12):5440-52.
  20. Wang X, Hu X, Yang Y, et al. Nicotinamide mononucleotide protects against beta-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016 Jul 15;1643:1-9.
  21. Wei CC, Kong YY, Hua X, et al. NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia. Br J Pharmacol. 2017 Nov;174(21):3823-36.
  22. Zhou M, Ottenberg G, Sferrazza GF, et al. Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment. Brain. 2015 Apr;138(Pt 4):992-1008.
  23. Won SJ, Choi BY, Yoo BH, et al. Prevention of traumatic brain injury-induced neuron death by intranasal delivery of nicotinamide adenine dinucleotide. J Neurotrauma. 2012 May 1;29(7):1401-9.
  24. Bai P, Canto C, Oudart H, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011 Apr 6;13(4):461-8.
  25. Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47.
  26. Kraus D, Yang Q, Kong D, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014 Apr 10;508(7495):258-62.
  27. Trammell SA, Weidemann BJ, Chadda A, et al. Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice. Sci Rep. 2016 May 27;6:26933.
  28. Yoshino J, Mills KF, Yoon MJ, et al. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011 Oct 5;14(4):528-36.
  29. Crisol BM, Veiga CB, Lenhare L, et al. Nicotinamide riboside induces a thermogenic response in lean mice. Life Sci. 2018 Oct 15;211:1-7.
  30. Serrano A, Asnani-Kishnani M, Rodriguez AM, et al. Programming of the Beige Phenotype in White Adipose Tissue of Adult Mice by Mild Resveratrol and Nicotinamide Riboside Supplementations in Early Postnatal Life. Mol Nutr Food Res. 2018 Nov;62(21):e1800463.
  31. Matasic DS, Brenner C, London B. Emerging potential benefits of modulating NAD(+) metabolism in cardiovascular disease. Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H839-H52.
  32. Diguet N, Trammell SAJ, Tannous C, et al. Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy. Circulation. 2018 May 22;137(21):2256-73.
  33. Ryu D, Zhang H, Ropelle ER, et al. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation. Sci Transl Med. 2016 Oct 19;8(361):361ra139.
  34. Xu W, Barrientos T, Mao L, et al. Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart. Cell Rep. 2015 Oct 20;13(3):533-45.
  35. Imai S. Dissecting systemic control of metabolism and aging in the NAD World: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis. FEBS Lett. 2011 Jun 6;585(11):1657-62.
  36. Imai S, Yoshino J. The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes Obes Metab. 2013 Sep;15 Suppl 3:26-33.
  37. Sebastian C, Satterstrom FK, Haigis MC, et al. From sirtuin biology to human diseases: an update. J Biol Chem. 2012 Dec 14;287(51):42444-52.
  38. Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95.
  39. Schug TT, Li X. Sirtuin 1 in lipid metabolism and obesity. Ann Med. 2011 May;43(3):198-211.
  40. Tao R, Wei D, Gao H, et al. Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene. J Biol Chem. 2011 Apr 22;286(16):14681-90.
  41. Kemper JK, Choi SE, Kim DH. Sirtuin 1 deacetylase: a key regulator of hepatic lipid metabolism. Vitam Horm. 2013;91:385-404.
  42. Ahn J, Lee H, Jung CH, et al. MicroRNA-146b promotes adipogenesis by suppressing the SIRT1-FOXO1 cascade. EMBO Mol Med. 2013 Oct;5(10):1602-12.
  43. Pang W, Wang Y, Wei N, et al. Sirt1 inhibits akt2-mediated porcine adipogenesis potentially by direct protein-protein interaction. PLoS One. 2013;8(8):e71576.
  44. Sasaki T, Kim HJ, Kobayashi M, et al. Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. Endocrinology. 2010 Jun;151(6):2556-66.
  45. Frojdo S, Durand C, Molin L, et al. Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. Mol Cell Endocrinol. 2011 Mar 30;335(2):166-76.
  46. Feige JN, Lagouge M, Canto C, et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 2008 Nov;8(5):347-58.
  47. Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013 Oct 1;27(19):2072-85.
  48. Satoh A, Stein L, Imai S. The role of mammalian sirtuins in the regulation of metabolism, aging, and longevity. Handb Exp Pharmacol. 2011;206:125-62.
  49. North BJ, Rosenberg MA, Jeganathan KB, et al. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 2014 Jul 1;33(13):1438-53.
  50. Fang EF, Scheibye-Knudsen M, Brace LE, et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell. 2014 May 8;157(4):882-96.
  51. Belenky P, Racette FG, Bogan KL, et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell. 2007 May 4;129(3):473-84.
  52. Mouchiroud L, Houtkooper RH, Moullan N, et al. The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell. 2013 Jul 18;154(2):430-41.
  53. Zhang H, Ryu D, Wu Y, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43.
  54. Trammell SA, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016 Oct 10;7:12948.
  55. Dellinger RW, Santos SR, Morris M, et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD(+) levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study. NPJ Aging Mech Dis. 2017 2017/11/24;3(1):17.

________________________________________________________________________________________________


Fall Asleep Faster and Stay Asleep Longer

August 2019

By Katherine De Mateo

The Centers for Disease Control and Prevention estimates that about 35% of adults get less sleep than they should.1

That’s part of the reason sleeping pills are so popular. But they come with serious drawbacks, including risk for physical dependence, accidents, and eventual tolerance that renders them ineffective.

Several plant-derived extracts have been found to safely help promote healthy sleep.

Scientists have created a combination of three such extracts: lemon balm, honokiol (a compound found in the magnolia tree), and apigenin (an ingredient found in chamomile).

Together, they work on multiple sleep centers in the brain to help restore healthy sleep patterns.

One study of people with mild-to-moderate anxiety disorders and sleep disturbances showed 85% of subjects that supplemented with lemon balm extract achieved full remission for insomnia and 70% of the subjects had complete relief of anxiety symptoms.2

Preclinical and clinical studies and gene expression analysis show that these ingredients can help people fall asleep more easily and improve sleep quality, leading to restorative and health-promoting rest.2-5

The Problem with Sleeping Pills

Woman in bed taking pills

Based on studies in sleep research, the CDC and other experts recommend that adults get seven or more hours of sleep a night.1,6

Using this standard, they found that more than 1 in 3 adults get suboptimal sleep on a regular basis. Frequently getting insufficient sleep has been linked to increased risk of obesity, depression, dementia, and chronic health issues like type II diabetes and heart disease.7-10

The failure to get enough sleep can be influenced by many factors, including caffeine consumption, stress, anxiety, and sleep disorders. The problem worsens with age, with around 40% of all elderly adults suffering from some form of sleep complaint.11,12 Changes in hormones as we grow older have been linked to insomnia and poor sleep quality,13,14 and some medications prescribed to older individuals can disrupt sleep.15

Pharmaceutical sleep aids are extremely popular, but they come with an array of problems. One group of drugs, the benzodiazepines , works by enhancing the effect of a calming neurotransmitter called gamma-aminobutyric acid (GABA). This causes reduction in anxiety, relaxation of muscles, and sedation. Common drugs in this class include Valium®, Xanax®, and Klonopin®.

But these drugs can cause too much sedation, leading to a “hangover” effect in the morning. Even worse, users can become addicted with regular use. And as doses increase, overdose becomes a possibility.16

Newer sleeping pills, such as Ambien® and Lunesta®, work by interacting with GABA receptors in the brain to produce sedative, anti-anxiety effects. Though they have a slightly lower risk for addiction, regular use can still lead to dependence. And many users of these drugs complain about a “zombie” effect the following day, which can cause poor mental performance, and risk for injuries such as falls.17,18

The newest class of sleep aids, orexin receptor antagonists, takes a different approach than the above-mentioned drugs that enhance GABA signaling. The orexin system in the brain controls wakefulness. Therefore, orexin receptor antagonists enhance sleep. Users of orexin receptor antagonists are subject to a “hangover” effect and the potential for physical dependence, like they are with most potent sleep aids.19

A Healthier Alternative

Lemon balm is an herb in the mint family that enhances GABA neurotransmitter activity in the brain, but by a different mechanism than benzodiazepines and other sleeping pills. The compounds in lemon balm, including rosmarinic acid, have been found to inhibit the enzyme that normally degrades GABA.4 This keeps GABA levels higher, to support a sleep-promoting and anxiety-reducing effect.

The magnolia tree is the source of a compound called honokiol. Research has shown that honokiol interacts with the receptor for GABA. Through this interaction, it boosts the activity of GABA to aid sleep.5

The flowering herb chamomile has long been used as a natural sleep aid. Part of this effect may also be attributed to its GABA-enhancing activity. But chamomile and its active components, particularly the nutrient apigenin, may act by additional mechanisms to further promote sleep.20

Computer-based gene expression analysis found that apigenin’s profile resembles an orexin receptor antagonist, and therefore may be working in a similar fashion.3 Orexin, made in the wake centers of the brain, is a compound that promotes wakefulness. A blocker of orexin, which apigenin may be, reduces wakefulness and promotes sleep.21,22

Medical Research on Herbal Sleep Aids

Scientists have uncovered evidence that lemon balm, honokiol, and chamomile can improve sleep.

Since they act by overlapping and unique mechanisms, a formulation combining all three can help restore healthy sleep patterns.

WHAT YOU NEED TO KNOW

Promoting Restful Sleep

  • It’s estimated that more than 1 in 3 adults get inadequate sleep.
  • Lack of sleep is associated with risk for many chronic diseases, including obesity, type II diabetes, heart disease, depression, and more.
  • Medication used to induce sleep can lead to dependence and can have many potential side effects.
  • Several plant-derived compounds have similar sleep-supporting effects, but without the worrisome side effects.
  • A combination supplement of lemon balm, honokiol, and chamomile provides sleep-promoting effects to achieve a full night of restorative, health-protecting sleep.

Lemon Balm Extract

Lemon Balm

In one study, investigators recruited people with mild-to-moderate anxiety disorders and sleep disturbances.2 Subjects were given a lemon balm extract for 15 days, then assessed by rating scales for anxiety and depression that included sleep quality.

At the end of the study, all the subjects were considered to have had a positive response to the supplementation, with 85% seeing a full remission of their insomnia and the remaining 15% being much improved.

In terms of anxiety symptoms, 70% of subjects who responded to the product were considered in complete remission and another 25% experienced significant improvement.

Another study of lemon balm evaluated patients with heart disease who had trouble sleeping, along with high levels of depression, anxiety, and stress.23 These subjects were randomized to receive either a lemon balmsupplement or a placebo for eight weeks.

The patients taking lemon balm had significantly reduced scores for depression, anxiety, and stress. They also took less time to fall asleep and had an increase in total sleep duration.

Honokiol

woman waking up well rested

In mouse models, honokiol reduced the time it took to fall asleep and increased the amount of sleep.24 In another animal study, honokiol was directly compared to diazepam (Valium®).25 It was found to reduce symptoms of anxiety to a similar level as the drug.

But while diazepam decreased muscle motor activity and tone, and impaired memory, honokiol did not. Mice experienced withdrawal symptoms when diazepam was stopped. The animals taking honokiol did not, indicating its use is not likely to lead to physical dependence.

INSUFFICIENT SLEEP IMPACTS HEALTH

Lack of sleep isn’t just an annoyance. It leads to serious problems for health and quality of life.

Inadequate sleep can have a harsh impact on cognitive function, causing slowed thinking, impaired attention, and inaccuracies that lead to loss of productivity during the day. It can also be downright dangerous. One study found that sleep deprivation led to poorer performance on cognitive and motor tasks comparable to a level of alcohol intoxication that would make it illegal to drive.29

Another study found that construction workers suffering from poor sleep were at greater risk for injuries at the workplace.30 And it’s been estimated that as many as 6,000 deaths due to car accidents per year have drowsy driving to blame.31

Sleep disorders affect long-term brain function as well. Repeated nights of inadequate sleep are associated with risk for mild cognitive impairment and dementia.11

Studies have also linked suboptimal sleep to obesity.32,33 Lack of sleep was found to cause abnormalities in levels of the hormones leptin and ghrelin, which are critically important to normal body fat balance.33These abnormalities can contribute to weight gain and, eventually, obesity—which, in turn, increases the risk for many diseases.34-37

In fact, poor sleep quality has been implicated in risk for type II diabetes and heart disease.10,38 Even death from cancer appears more likely with inadequate sleep. One large study showed that patients with colorectal cancer who get less than five hours of sleep per day have a 54% increase in cancer mortality, compared to those getting seven to eight hours of sleep.39

All told, sleep can have a dramatic impact on mental and physical functioning and overall health.

Chamomile Extract

Chamomille

Chamomile is a popular herb often used as a tea to promote sleep and relaxation.26

In a rat study, chamomile was shown to improve sleep onset and had a mild hypnotic effect (much like benzodiazepines).27 In one clinical study, chamomile showed encouraging beneficial effects on daytime functioning in people with sleep problems.28

Researchers believe that the active components present in chamomile, apigenin in particular, are responsible for its effects.

NEW TOOL IN DRUG DISCOVERY

The newest frontier in drug discovery utilizes a bioinformatics approach called connectivity mapping to uncover previously unrecognized connections between compounds.

Whenever a compound or drug is applied to cells a unique gene expression signature is created. When two signatures are highly similar, this might represent useful and previously unrecognized connections between seemingly unrelated compounds.

This advanced tool, the Connectivity Map (CMap) library, was developed by the Broad Institute and is available for researchers to use.

Recently, scientists leveraged this tool to help identify natural compounds that produce a similar signature to an orexin receptor antagonist, a new class of sleep drugs. One such compound they identified was apigenin.

Although further investigation into this new potential mechanism is warranted, these interesting preliminary findings could help explain the complex nature of apigenin pharmacology in the brain.

Summary

Getting enough quality sleep is critical to health. Inadequate sleep increases risk for many chronic illnesses.

A large percentage of adults do not get enough sleep on a regular basis, and sleep problems increase with advancing age.

Many people rely on pharmaceutical drugs to aid sleep, but these medications cause several potential adverse effects, including risk for addiction and tolerance (which means they stop working).

A combination of plant-derived nutrients may provide support for healthy sleep, without the risk for significant side effects.

Lemon balm, honokiol, and chamomile (which contains apigenin) work on slumber centers in the brain to induce and maintain sleep, but without the sedating or addictive properties of those pharmaceutical medications.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Available at: https://www.cdc.gov/sleep/data_statistics.html. Accessed May 9, 2019.
  2. Cases J, Ibarra A, Feuillere N, et al. Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Med J Nutrition Metab. 2011 Dec;4(3):211-8.
  3. In-house connectivity mapping. LINCS-Broad Institute Database. Data on File. 2019.
  4. Awad R, Muhammad A, Durst T, et al. Bioassay-guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity. Phytother Res. 2009 Aug;23(8):1075-81.
  5. Alexeev M, Grosenbaugh DK, Mott DD, et al. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology. 2012 Jun;62(8):2507-14.
  6. Watson NF, Badr MS, Belenky G, et al. Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015 Jun 1;38(6):843-4.
  7. Riemann D, Krone LB, Wulff K, et al. Sleep, insomnia, and depression. Neuropsychopharmacology. 2019May 9.
  8. von Ruesten A, Weikert C, Fietze I, et al. Association of sleep duration with chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. PLoS One. 2012;7(1):e30972.
  9. Cooper CB, Neufeld EV, Dolezal BA, et al. Sleep deprivation and obesity in adults: a brief narrative review. BMJ Open Sport Exerc Med. 2018;4(1):e000392.
  10. Lao XQ, Liu X, Deng HB, et al. Sleep Quality, Sleep Duration, and the Risk of Coronary Heart Disease: A Prospective Cohort Study With 60,586 Adults. J Clin Sleep Med. 2018 Jan 15;14(1):109-17.
  11. Zhang F, Zhong R, Li S, et al. The missing link between sleep disorders and age-related dementia: recent evidence and plausible mechanisms. J Neural Transm (Vienna). 2017 May;124(5):559-68.
  12. Adib-Hajbaghery M, Mousavi SN. The effects of chamomile extract on sleep quality among elderly people: A clinical trial. Complement Ther Med. 2017 Dec;35:109-14.
  13. Geyer C. In Search of a Good Night’s Sleep: Hormones, Mind, Movement, and Breath. Am J Lifestyle Med. 2018 Mar-Apr;12(2):120-3.
  14. Baker FC, de Zambotti M, Colrain IM, et al. Sleep problems during the menopausal transition: prevalence, impact, and management challenges. Nat Sci Sleep. 2018;10:73-95.
  15. Sutton EL. Insomnia. Med Clin North Am. 2014 May;98(3):565-81.
  16. Available at: https://www.drugs.com/article/benzodiazepines.html. Accessed May 13, 2019.
  17. Frey DJ, Ortega JD, Wiseman C, et al. Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening: a randomized placebo-controlled trial. J Am Geriatr Soc. 2011 Jan;59(1):73-81.
  18. Chung SD, Lin CC, Wang LH, et al. Zolpidem Use and the Risk of Injury: A Population-Based Follow-Up Study. PLoS One. 2013;8(6):e67459.
  19. Available at: https://www.sleepfoundation.org/articles/orexin-receptor-antagonists-new-class-sleeping-pill. Accessed May 13, 2019.
  20. Awad R, Levac D, Cybulska P, et al. Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system. Can J Physiol Pharmacol. 2007 Sep;85(9):933-42.
  21. Brisbare-Roch C, Dingemanse J, Koberstein R, et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 2007 Feb;13(2):150-5.
  22. Dubey AK, Handu SS, Mediratta PK. Suvorexant: The first orexin receptor antagonist to treat insomnia. J Pharmacol Pharmacother. 2015 Apr-Jun;6(2):118-21.
  23. Haybar H, Javid AZ, Haghighizadeh MH, et al. The effects of Melissa officinalis supplementation on depression, anxiety, stress, and sleep disorder in patients with chronic stable angina. Clin Nutr ESPEN. 2018 Aug;26:47-52.
  24. Qu WM, Yue XF, Sun Y, et al. Honokiol promotes non-rapid eye movement sleep via the benzodiazepine site of the GABA(A) receptor in mice. Br J Pharmacol. 2012 Oct;167(3):587-98.
  25. Kuribara H, Stavinoha WB, Maruyama Y. Honokiol, a putative anxiolytic agent extracted from magnolia bark, has no diazepam-like side-effects in mice. J Pharm Pharmacol. 1999 Jan;51(1):97-103.
  26. Sanchez-Ortuno MM, Belanger L, Ivers H, et al. The use of natural products for sleep: A common practice? Sleep Med. 2009 Oct;10(9):982-7.
  27. Shinomiya K, Inoue T, Utsu Y, et al. Hypnotic activities of chamomile and passiflora extracts in sleep-disturbed rats. Biol Pharm Bull. 2005 May;28(5):808-10.
  28. Zick SM, Wright BD, Sen A, et al. Preliminary examination of the efficacy and safety of a standardized chamomile extract for chronic primary insomnia: a randomized placebo-controlled pilot study. BMC Complement Altern Med. 2011 Sep 22;11:78.
  29. Williamson AM, Feyer AM. Moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally prescribed levels of alcohol intoxication. Occup Environ Med. 2000Oct;57(10):649-55.
  30. Brossoit RM, Crain TL, Leslie JJ, et al. The effects of sleep on workplace cognitive failure and safety. J Occup Health Psychol. 2018 Nov 29.
  31. Available at: https://www.cdc.gov/features/dsdrowsydriving/index.html. Accessed May 13, 2019.
  32. Gangwisch JE, Malaspina D, Boden-Albala B, et al. Inadequate sleep as a risk factor for obesity: analyses of the NHANES I. Sleep. 2005 Oct;28(10):1289-96.
  33. Taheri S, Lin L, Austin D, et al. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004 Dec;1(3):e62.
  34. Foley D, Ancoli-Israel S, Britz P, et al. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res. 2004 May;56(5):497-502.
  35. Gislason T, Almqvist M. Somatic diseases and sleep complaints. An epidemiological study of 3,201 Swedish men. Acta Med Scand. 1987;221(5):475-81.
  36. Liu Y, Croft JB, Wheaton AG, et al. Association between perceived insufficient sleep, frequent mental distress, obesity and chronic diseases among US adults, 2009 behavioral risk factor surveillance system. BMC Public Health. 2013 Jan 29;13:84.
  37. Liu Y, Wheaton AG, Chapman DP, et al. Sleep duration and chronic diseases among U.S. adults age 45 years and older: evidence from the 2010 Behavioral Risk Factor Surveillance System. Sleep. 2013 Oct 1;36(10):1421-7.
  38. Spiegel K, Knutson K, Leproult R, et al. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol (1985). 2005 Nov;99(5):2008-19.
  39. Xiao Q, Arem H, Pfeiffer R, et al. Prediagnosis Sleep Duration, Napping, and Mortality Among Colorectal Cancer Survivors in a Large US Cohort. Sleep. 2017 Apr 1;40(4).

______________________________________________________________________________________________


Restore Youthful Cognitive Function

January 2019

By Harry Fulton

Starting around age 30, we begin to notice short-term memory deficits.

This may happen when after taking a drug, we have no immediate recall if we actually swallowed the pill.

As people advance past 60 years, they often rely on "pill organizers" to ensure medications are taken on schedule.

Short-term memory decline is a troubling aspect of brain aging.

A clinical study evaluated a standardized sage extract compared to placebo in adults over age 64.1

Within hours of ingesting this sage extract, memory performance increased nearly 60%, along with an approximate 2.5-fold improvement in attention.

When this sage extract was tested in the C. elegans model of aging, there was a 12% increase in lifespan,2attributable in part to increased expression of insulin signaling genes that have been tied to enhanced longevity.3

Meticulous research has now identified how this sage extract enhances cognitive function in humans and increases lifespan in a validated model of aging.

What you need to know

  • Sage has been recognized for its numerous health benefits for centuries.
  • Numerous beneficial compounds in sage enhance and protect brain function by several complementary mechanisms.
  • Low levels of the neurotransmitter acetylcholine are associated with age-related cognitive dysfunction and dementia. Like medications used to treat dementia, sage boosts levels of this important neurotransmitter in the brain.
  • A proprietary sage extract with unique properties that have not been identified in other sage formulations18has demonstrated beneficial effects on cognitive performance and cerebral blood flow in humans, as well as boosting longevity related genes in a C. elegans animal model.
  • Sage can work together with other brain healthy nutrients to maximize brain function and prevent age-related cognitive decline.

Sage Extracts Protect the Brain

Foods considered as a part of the Mediteranian diet

Age-related mental decline, including mild cognitive impairment, is a normal part of brain aging.

Many factors lead to dwindling cognitive functions.

Readers of this magazine take steps to circumvent mind-robbing pathologies, such as maintaining cerebral circulation and keeping homocysteine in safe ranges.

Clinical data on a novel sage extract indicates additional protective effects.

Role of Acetylcholine on Short-Term Memory

Neurotransmitters are compounds brain cells use to communicate with one another.

Acetylcholine is a neurotransmitter critical for memory, attention, and reasoning. With aging and neurodegenerative disorders, acetylcholine levels can be depleted.4

This decrease in acetylcholine is responsible for many age-related deficits, including poor memory and the inability to pay attention to tasks.5

Currently available drugs can improve dementia symptoms by boosting brain levels of acetylcholine. This has been demonstrated to reduce the cognitive deficits in the short term.6,7

In a recent review of several trials in Alzheimer's patients, treatments that boost acetylcholine are associated with more than 20% lower overall mortality.7

These treatments work to increase acetylcholine in the brain by blocking activity of an enzyme that degrades it. This enzyme is called acetylcholinesterase .

Sage extracts inhibit this same enzyme and boost acetylcholine levels. Significant improvements in cognitive functions have been demonstrated in human studies.1,8-11

BOOSTING BRAIN PERFORMANCE

Acetylcholine is one of the most common neurotransmitters and its functions are critical for normal cognition, including memory, attention, and reasoning.

Unfortunately, acetylcholine is one of the hardest hit in aging and Alzheimer's disease.4 Brain cells that use acetylcholine are some of the most profoundly affected.

Most modern medical treatments for dementia attempt to improve symptoms by boosting levels of acetylcholine, which has demonstrated the ability to reduce the cognitive deficits and enhance brain function in the short term.6,7

These drugs increase levels of acetylcholine by blocking the activity of the enzyme that degrades it, called acetylcholinesterase.

Many studies have now confirmed that sage also exhibits this ability, boosting levels of acetylcholine in addition to all of its preventative properties.1,3,8-11

This may explain why sage can cause almost immediate augmentation of brain function.

Pharmaceutical approaches to treating dementia mostly address acetylcholine. The multiple mechanisms of sage in the brain can help boost current cognitive function as well as prevent future progression of age-related dysfunction.

Growing New Brain Cells

Foods considered as a part of the Mediteranian diet

Neurotrophins are proteins produced in the body that help maintain brain function. They support survival of brain cells and encourage neurogenesis, a process that replenishes and repairs brain cells.12

Normal aging leads to lower neurotrophins levels, which is implicated in the progression of cognitive impairment and Alzheimer's disease.13

Sage helps to support healthy levels of neurotrophins, boosting their levels even in the presence of cellular stress and injury.10

The ability of sage extract to support neurotrophins can help protect against future loss of functionality and dementia.

MEASURING SUPERIOR BIOLOGICAL ACTIVITY

Intensive chemical analysis of this novel sage extract demonstrates that it has a unique chemical fingerprint compared to other sources of sage.18

Furthermore, this proprietary sage extract has superior biological activity compared with other sage sources and cognitive drugs when tested by Chronoscreen™ assay in C. elegans.2,19

Chronoscreen™ is a patented technology that can evaluate the effect of nutrients and drugs on lifespan in a whole organism.

Life Extension has closely collaborated with scientists at a group called Sibelius to uncover the specific mechanisms of action of this proprietary sage extract. The goal has been to more precisely identify how this particular sage extract enhances memory and attention in humans.

This Chronoscreen™ assay revealed the surprising finding of a 12% lifespan increase in the C. elegansmodel, an effect not found with other sage extracts.2

Oxidative Stress and Inflammation

Female scientist reading

Most age-related diseases are at least partially tied to oxidative stress and inflammation. Age-related deterioration of brain function is no exception.

Sage contains compounds that scavenge harmful free radicals and reduce the deleterious effects of inflammation.10

In a rat model of diabetes, one study showed that sage limited oxidative damage and boosted oxidant-reducing defense systems. This resulted in reversal of learning and memory deficits.14

COMPLEMENTARY NUTRIENTS FOR BRAIN HEALTH
Mitochondrial cell

While sage provides protection and enhancement of brain health by several means, there are other nutrients which can help maximize nervous system function, complementing the action of sage extract.

Phosphatidylserine

Phosphatidylserine is a phospholipid, one of the structural components of the membranes that surrounds all cells in the body. This is particularly critical for nerve cells in the brain because it is their cell membrane that carries nerve impulses throughout the nervous system.23 The myelinthat surrounds nerve fibers and aids signal conduction also relies on phosphatidylserine for normal structure and function.

Aging is associated with structural deterioration in the nervous system, which may be reduced by phosphatidylserine, preserving cognitive function.

Phosphatidylserine is particularly notable as a brain health supplement in that it is the only supplement that has been given "qualified health claim" status for its potential to reduce the risk of cognitive decline and dementia in the elderly by the U.S. Food and Drug Administration. 24

Blueberry

Blueberries are packed full of anthocyanins, powerful oxidant-reducing compounds that help protect the plant from oxidative stress. These compounds have been explored in the medical literature for years for their potential health benefits to humans.

Several recent trials in humans have demonstrated that enhancement of cognitive function can be added to the list of blueberry's benefits. Not only has blueberry been found to enhance memory and other cognitive performance in older subjects, it improves mood and cognition in children and young adults as well.25-29

Vinpocetine

Vinpocetine is a compound derived from the periwinkle plant.

It has been reported to have benefits for cognition and degenerative disorders of the brain such as Alzheimer's and Parkinson's disease due to multiple nervous system effects.30 It acts as a dilator of blood vessels to the brain, improving blood flow, as well as stimulating brain metabolism.

Pregnenolone

Pregnenolone is a hormone and hormone-precursor. It and its derivatives formed in the brain have modulatory effects on nervous system function.

Several studies in animals and humans have reported beneficial effects for the brain.31 It appears to be a neuroprotectant, defending the brain from various forms of injury. It has also been found to have positive effects on mood, memory, and other aspects of cognition.

Ashwagandha

Ashwagandha is an Indian herb also referred to as "Indian Ginseng". It has been used in traditional Indian medicine as a nerve tonic for millennia.

In modern research, ashwagandha has demonstrated neuroprotective effects and improvements in mood and cognition.32,33

For example, a recent study in patients suffering from mild cognitive impairment found that ashwagandha led to improvements in memory and other markers of cognitive functioning such as attention and decision-making executive function.32

Uridine 5'-monophosphate

Uridine 5'-monophosphate is a nucleic acid, a precursor necessary for the synthesis of RNA and proteins. In addition, it contributes to the production of components of synapses, the region where brain cells communicate with each other.34

Loss of functional synapses contributes to the decline in brain function with age and various degenerative diseases. Therefore, by aiding nerve cell functions related to synapses uridine is believed to help preserve brain function and protect it from degeneration.34

Readers of this magazine have been using some or all these nutrients for many decades to protect and enhance cognitive functionality.

Initial Human Studies

Sage extracts were tested in a series of trials in younger people.8,9,15,16

In each of these trials, scientists found that sage induced beneficial effects on mood and cognition.

Within hours of consuming the sage supplements, these younger subjects benefited from improved mood, reduced anxiety, enhanced long-term memory/attention, and reduced mental fatigue.

Sage extracts have also been studied in older individuals with Alzheimer's disease.11,17 In a preliminary study of Alzheimer's patients, sage extract improved neuropsychiatric symptoms and attention.11

In a randomized clinical trial of patients with mild-to-moderate Alzheimer's dementia, one arm of the study received a sage extract and the other a placebo.17 The researchers used a scoring system designed to evaluate cognitive functions in Alzheimer's patients.

Results of this study showed that over the course of four months, cognitive scores of people who received placebo deteriorated by about 22%. The study subjects supplemented with sage extract improved by about 26%.

Considering that these people presented with clinical indicators of mild-to-moderate dementia, the improvement seen after four months in the sage supplemented group is quite remarkable.

MILD COGNITIVE IMPAIRMENT & ALZHEIMER'S DISEASE

One of the most prevalent health concerns for the brain is age-related cognitive decline.

Early deterioration in brain function beyond that expected for one's age is referred to as mild cognitive impairment, affecting memory, attention, and other mental processes. Dementia refers to more severe loss of cognitive function. The most common cause of dementia by far is Alzheimer's disease. These two diagnoses are characterized by lower levels of acetylcholine.

Both of these disorders are very common, affecting millions of adults in the U.S. alone.

New Standardized Sage Extract

Findings from the human studies described thus far led to a search for compounds in sage responsible for these improvements in cognitive function.

An intensive investigation using advanced analytic techniques identified a sage plant that has superior biological activity.2

The result of this research is a standardized sage extract that has demonstrated improved mechanistic properties in microarray gene expression studies.3

To test this new sage extract in the real world, a rigorous study of cognition in aging humans was conducted.

Enhancement of Cognition in Aging Humans

Foods considered as a part of the Mediteranian diet

Using this standardized sage extract, a clinical study evaluated the effect on cognition in adults over age 64.1

The subjects underwent a battery of brain function tests before and after receiving this novel sage extract or placebo.

Here are the results:

  • Compared with placebo, memory performance in people receiving the sage extract was boosted by roughly 60%.
  • Compared to placebo, measures of attention were enhanced approximately 2.5-fold in sage-supplemented subjects.
  • These effects occurred rapidly, improving brain function within hours of intake of this new sage extract.

Cognitive function tends to decrease over the course of a day, resulting in worsening memory performance and accuracy of attention. Supplementation with sage extract enhanced both of these aspects of brain function in these subjects.

Potential Lifespan Increase

Pathologic aging is partially characterized by disruption of genes involved in insulin signaling and lipidmetabolism.

These effects are revealed in blood tests showing increases in glucose, cholesterol, and triglycerides as people grow older.

In a laboratory model of aging, this new sage extract was studied on the C. elegans roundworm. This kind of testing is used to identify the impact of compounds on human longevity potential.2

This particular sage extract was found to increase expression of lipid metabolism and insulin signaling genes, which have been tied to enhanced longevity.3

The result was a 12% lifespan increase in C. elegans that were fed this novel sage extract. Other sources of sage tested did not demonstrate extended life.2

Improved Neurotransmitter Signaling

As it relates to short-term memory loss, acetylcholine is one of the most studied neurotransmitters in the aging brain. By inhibiting the enzyme that degrades acetylcholine, extracts from sage have consistently been shown to improve cognitive performance.

In addition to acetylcholine, several other neurotransmitters are adversely affected by aging.

This novel sage extract has been shown to favorably modulate gene expression of other neurotransmitters crucial for cognitive function, such as GABA and glutamate.3

These findings explain the profound benefits observed in human studies that extend beyond boosting acetylcholine brain levels.

Improved Blood Flow to the Brain

Aging is associated with a reduction of blood flow to the brain, which contributes to adverse changes in cognitive function.20

A significant body of evidence points to diminished cerebral circulation as a precursor to both vascular and Alzheimer's dementia.

As we reported in the March 2014 issue of this magazine, loss of blood flow to the brain is a greater problem than most people realize. Here is one quote from what we published:21

"According to a study conducted at the Mayo Clinic, a surprising number of aging people
suffer a condition in which tiny areas of their brain become oxygen deprived. This cerebral
vascular deficit sharply increases risk of stroke, dementia, and cognitive impairment.
Healthy lifestyle choices can prevent and may help reverse it."22

This new sage extract may guard against this circulatory reduction as it has been found to have vasodilator properties, opening blood vessels that supply the brain.3

Summary

Foods considered as a part of the Mediteranian diet

The herb sage is uniquely suited to protecting brain function from deterioration associated with aging and dementia by several complementary mechanisms.

It also augments current cognitive function by enhancing levels of the neurotransmitter acetylcholine in the brain.

Scientists in England identified a proprietary standardized sage extract that protects and enhances cognitive function.

This extract has been found to have a unique chemical makeup18 and additional biological effects not previously identified in other sage preparations.2

This new sage extract has uniquely demonstrated the ability to extend lifespan in laboratory models and to improve cognition in elderly human subjects.

Coupled with other nutrients such as phosphatidylserine, blueberry, vinpocetine, and others, sage can be an important component of a comprehensive formula for the brain.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Scholey AB, Tildesley NT, Ballard CG, et al. An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology (Berl). 2008May;198(1):127-39.
  2. Sibelius. Internal Report. ChronoscreenTM Analysis: Cognition Enhancing Drugs & Natural Extracts. 2018.
  3. Confidential S. Sage Gene Expression Analysis. 2018.
  4. Francis PT. The interplay of neurotransmitters in Alzheimer’s disease. CNS Spectr. 2005Nov;10(11 Suppl 18):6-9.
  5. Klinkenberg I, Sambeth A, Blokland A. Acetylcholine and attention. Behav Brain Res. 2011Aug 10;221(2):430-42.
  6. Garcia-Ayllon MS, Small DH, Avila J, et al. Revisiting the Role of Acetylcholinesterase in Alzheimer’s Disease: Cross-Talk with P-tau and beta-Amyloid. Front Mol Neurosci. 2011;4:22.
  7. Mueller C, Perera G, Hayes RD, et al. Associations of acetylcholinesterase inhibitor treatment with reduced mortality in Alzheimer’s disease: a retrospective survival analysis. Age Ageing. 2018Jan 1;47(1):88-94.
  8. Kennedy DO, Dodd FL, Robertson BC, et al. Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults. J Psychopharmacol. 2011Aug;25(8):1088-100.
  9. Kennedy DO, Pace S, Haskell C, et al. Effects of cholinesterase inhibiting sage (Salvia officinalis) on mood, anxiety and performance on a psychological stressor battery. Neuropsychopharmacology. 2006Apr;31(4):845-52.
  10. Lopresti AL. Salvia (Sage): A Review of its Potential Cognitive-Enhancing and Protective Effects. Drugs R D. 2017Mar;17(1):
    53-64.
  11. Perry NS, Bollen C, Perry EK, et al. Salvia for dementia therapy: review of pharmacological activity and pilot tolerability clinical trial. Pharmacol Biochem Behav. 2003Jun;75(3):651-9.
  12. Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci. 2001;24:677-736.
  13. Erickson KI, Prakash RS, Voss MW, et al. Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci. 2010Apr 14;30(15):5368-75.
  14. Hasanein P, Felehgari Z, Emamjomeh A. Preventive effects of Salvia officinalis L. against learning and memory deficit induced by diabetes in rats: Possible hypoglycaemic and antioxidant mechanisms. Neurosci Lett. 2016May 27;622:72-7.
  15. Tildesley NT, Kennedy DO, Perry EK, et al. Salvia lavandulaefolia (Spanish sage) enhances memory in healthy young volunteers. Pharmacol Biochem Behav. 2003Jun;75(3):669-74.
  16. Tildesley NT, Kennedy DO, Perry EK, et al. Positive modulation of mood and cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers. Physiol Behav. 2005Jan 17;83(5):699-709.
  17. Akhondzadeh S, Noroozian M, Mohammadi M, et al. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer’s disease: a double blind, randomized and placebo-controlled trial. J Clin Pharm Ther. 2003Feb;28(1):53-9.
  18. Sibelius cognition enhancement product presentation. 2018.
  19. Available at: https://www.nutraceuticalsnow.com/articles/2018/0... Accessed September 14, 2018.
  20. Chen JJ, Rosas HD, Salat DH. Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage. 2011Mar 15;55(2):468-78.
  21. Available at: https://www.lifeextension.com/Magazine/2014/3/Leu... Accessed November 1, 2018.
  22. Available at: https://www.medicalnewstoday.com/articles/249005.... Accessed November 1, 2018.
  23. Glade MJ, Smith K. Phosphatidylserine and the human brain. Nutrition. 2015Jun;31(6):781-6.
  24. Taylor CL. Qualified health claim: final decision letter - phosphatidylserine and cognitive dysfunction and dementia. U.S. Food & Drug Administration;2003.
  25. Whyte AR, Cheng N, Fromentin E, et al. A Randomized, Double-Blinded, Placebo-Controlled Study to Compare the Safety and Efficacy of Low Dose Enhanced Wild Blueberry Powder and Wild Blueberry Extract (ThinkBlue) in Maintenance of Episodic and Working Memory in Older Adults. Nutrients. 2018May 23;10(6).
  26. McNamara RK, Kalt W, Shidler MD, et al. Cognitive response to fish oil, blueberry, and combined supplementation in older adults with subjective cognitive impairment. Neurobiol Aging. 2018Apr;64:147-56.
  27. Whyte AR, Schafer G, Williams CM. Cognitive effects following acute wild blueberry supplementation in 7- to 10-year-old children. Eur J Nutr. 2016Sep;55(6):2151-62.
  28. Miller MG, Hamilton DA, Joseph JA, et al. Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial. Eur J Nutr. 2018Apr;57(3):1169-80.
  29. Khalid S, Barfoot KL, May G, et al. Effects of Acute Blueberry Flavonoids on Mood in Children and Young Adults. Nutrients. 2017Feb 20;9(2).
  30. Zhang YS, Li JD, Yan C. An update on vinpocetine: New discoveries and clinical implications. Eur J Pharmacol. 2018Jan 15;819:30-4.
  31. Vallee M. Neurosteroids and potential therapeutics: Focus on pregnenolone. J Steroid Biochem Mol Biol. 2016Jun;160:78-87.
  32. Choudhary D, Bhattacharyya S, Bose S. Efficacy and Safety of Ashwagandha (Withania somnifera (L.) Dunal) Root Extract in Improving Memory and Cognitive Functions. J Diet Suppl. 2017Nov 2;14(6):599-612.
  33. Singh N, Bhalla M, de Jager P, et al. An overview on ashwagandha: a Rasayana (rejuvenator) of Ayurveda. Afr J Tradit Complement Altern Med. 2011;8(5 Suppl):208-13.
  34. Wurtman RJ. Synapse formation in the brain can be enhanced by co-administering three specific nutrients. Eur J Pharmacol. 2017Dec 15;817:20-1.