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ANTI - AGING MEDICAL NEWS | SUMMER 2020
TABLE OF CONTENTS Product Announcements . . . . . . . . . .50 Exhibitor Listings . . . . . . . . . . . . . . 74
ARTICLES
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Fasting for Healthy Longevity New Directions for Women in MenopauseHealth and Inflammation
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By: Felice Gersh, M.D.
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What Bugs Your Heart? The Role of Microorganisms in Cardiovascular Health and the Application of Botanicals
Omega-3 Fatty Acids and Aging By: Kasey Hutchinson, RDN
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Methylation Pathways
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Anti-Aging Benefits: Resveratrol vs. Pterostilbene
By: Dr. Alison McAllister
By: Jocelyn Strand, ND
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The Gastrointestinal Microbiome: An Evolving Understanding By: Christine Stubbe, ND
A Comparison of Bioavailability and Health Benefits
By: Sara Cook, ND & Lisa Murray, RDN
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Discover the Regenerative Potential of Exosomes By: Jason Sanders, MD
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Beyond HDL:
New Insights into HDL Function in Cardiovascular Disease By: Mark Houston, MD & Sara Gottfried, MD
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Specialized Pro-Resolving Mediators: Novel Mechanisms for Supporting a Healthy Inflammatory Response By: Caitlin Higgins
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ANTI - AGING MEDICAL NEWS • SUMMER 2020
Fasting for Healthy Longevity New Directions for Women in Menopause By: Felice Gersh, M.D. The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
Menopause is a universal event for women. The exact age varies somewhat, but the eventual permanent loss of ovarian hormone production is inevitable. Although a natural and “normal” event, the menopausal transition and subsequent years in a menopausal state do not benefit women’s overall health. This is especially true for cardiovascular health. Cardiovascular disease is the number one killer of women in the United States and the risk of a cardiovascular event is directly related to decreasing levels of estrogen as women progress through the menopausal transition. Women who experience menopause early, before age 40, are twice as likely to suffer from a non-fatal heart attack, stroke, or angina before age 60 compared to women who go through menopause at ages 50 or 51, which is the U.S. average.1 They are also more likely to suffer from fatal cardiac events and have an overall lower life expectancy.2 In contrast, women who go through menopause after age 51 have lower rates of cardiovascular disease and enjoy longer life expectancy. Menopause, and the resulting state of permanent estrogen deficiency, is a powerful risk factor for cardiovascular disease that is greatly underappreciated. Loss of estrogen causes systemic vascular inflammation, immune dysregulation, loss of glucose homeostasis, and gut microbiome dysbiosis.3 These dysfunctions set the stage for metabolic disease and ever escalating cardiovascular risk.
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Typical therapies offered to women to reduce cardiovascular events are pharmaceuticals, such as blood pressure drugs, statins, and diabetes medications. Although pharmaceuticals can be warranted and valuable in certain situations, they don’t access the body’s innate mechanisms to maintain metabolic homeostasis and don’t address the multitude of dysfunctions developing in the menopausal female body. Hormone therapy is also available, but the FDA does not yet recognize or endorse the use of hormones in women to reduce cardiovascular risk. This is despite a substantial body of science supporting the beneficial impact of hormones on the cardiovascular system.4 However, even if the implementation of bio-identical hormones becomes routine for women transitioning into menopause and thereafter, the reality is that we cannot yet administer hormones in a way that replicates the complex hormonal levels and rhythms of a healthy 25-year old woman. Too many women, including those who use hormones, suffer from cardiometabolic diseases. Fasting has been an integral part of the human experience since the beginning of our species and plays a significant role in many religions and societies. Simply put, fasting is any time one is not eating. There are several variations that are associated with different health benefits.
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
Fasting for Healthy Longevity – New Directions for Women in Menopause
“Time-restricted eating” refers to an extended and habitual overnight fast lasting 12 or more hours. When a person fasts for 16 to 24 hours, that is called “intermittent fasting.” If a person fasts for a few days up to a week, that is labeled “periodic or prolonged fasting.” Women in the menopausal transition and up to around age 65 years can gain significant health benefits from all forms of fasting. Combining timerestricted eating with a regular program of periodic fasting is likely the most advantageous combination
Time-restricted eating is the easiest form of fasting because the majority of the fast coincides with time spent sleeping. This is, in fact, why it is so beneficial. Overnight fasting bolsters circadian rhythm in both pre-clinical studies and human observational studies. As with all creatures, humans are governed by time. We have a master clock in our brain that sits atop the optic nerve and senses light and dark, plus nutrients, to track the 24-hour day. Throughout our bodies, we have clock genes that govern most metabolic functions, and these peripheral clocks, in alignment with the master clock, keep all the organs of the body working in beautiful synergy. Unfortunately for menopausal women, estrogen plays a major role in the proper functioning of the master clock.5 As menopause progresses and estrogen production declines, women succumb to circadian rhythm dysfunction, essentially a state of perpetual jetlag that substantially increases risk for diabetes, heart attacks, weight gain, insomnia, cancers, and mood disorders. Time-restricted eating utilizes the power of the peripheral clock genes to reset the clocks in the organs and maintain the synergy that the master clock promotes. By eating at regular fixed times, the body can re-establish metabolic unity and harmony and prevent weight gain and metabolic disruption as seen in clinical and pre-clinical studies10,11 Time-restricted eating can be easily paired with caloric timing—eating more calories earlier in the day and fewer in the evening. Clinical studies have shown that the body is more receptive to food in the morning when insulin sensitivity is high. During a morning meal, glucose enters cells readily and insulin levels rise only minimally, which reduces weight gain, lowers the risk of diabetes, and contributes to metabolic synchrony.9
If a woman in menopause eats a large, healthy breakfast, a moderate lunch, and a very light, early dinner, and if she fasts every night for approximately 13 hours, she can avert circadian rhythm dysfunction. Intermittent fasting refers to 16 to 24h fast. In the common 5:2 intermittent fasting diet, participants fast or eat fewer than 500 calories for two non-consecutive days every week and eat normally on the other five days. Data shows that such fasting is especially helpful for weight loss. Not consuming any calories or eating fewer than 500 calories for two days a week is associated with significant weight loss over time, and for women carrying extra pounds, the benefits can be quite substantial.
Weight gain is extraordinarily common in peri- and postmenopausal women. When estrogen levels plummet, the body’s ability to transport glucose into cells declines and the capacity to burn fat for energy decreases. This causes the body to rely on inflammatory metabolic processes to store excess energy as visceral fat in the abdominal cavity. Visceral fat gives women the dreaded “apple shape” and is a sign of metabolic dysfunction. Because these abdominal fat deposits are themselves inflammatory, they also contribute to increasing metabolic in a vicious spiral of ever-increasing inflammation and weight gain. In addition to damaging health, these fat deposits can damage women’s confidence and sense of self. Women watch their bodies transform, seemingly without cause, from the sexy, curvy look of their reproductive years to the matronly look of the menopause years. Intermittent fasting effectively addresses this problem of fat accumulation. Unfortunately, such a diet plan is extremely challenging, and few women can maintain such a rigid fasting regimen over months and years. Periodic or prolonged fasting, a fast that lasts three to seven days, done about three times per year, offers comparable weight loss benefits to intermittent fasting without the demanding every-week schedule. Most people can’t, and really shouldn’t, undergo a multi-day water fast, but fortunately, there is a variation of periodic/ prolonged fasting that is safe and effective for most people—
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
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Fasting for Healthy Longevity – New Directions for Women in Menopause
the fasting mimicking diet. Certain foods, sometimes called stealth foods, can provide nutrition without triggering the body’s nutrient sensors. If a person eats small amounts of these stealth foods for several days, her body will think that she is fasting. She will get all of the amazing benefits of periodic fasting, but she won’t experience the physical stress and discomfort of actually fasting. Additionally, she won’t lose muscle mass, which is a risk of a true water fast and is very detrimental for menopausal women. The fasting mimicking diet is a five-day researched diet plan that mimics a four-day water fast. It was developed at the University of Southern California’s Longevity Institute under the directorship of Professor Valter Longo. I collaborated with Professor Longo at the time the diet was being formulated, and currently, I am on the speaker’s bureau for the company it spawned. The fasting mimicking diet is an innovative concept for menopausal women because data supports that periodic/prolonged fasting is a beneficial form of fasting for long term health and vitality. Certain cellular functions can only be activated by a longer fast. Pre-clinical studies have confirmed that healthy cells undergo a process called autophagy, a powerful form of cellular rejuvenation. These cells breakdown their internal components, called organelles, and reconfigure them into new organelles, thereby rejuvenating the organs they comprise.6 Studies show that when people follow the fasting mimicking diet once a month for three months, they lose body weight, trunk, and total body fat; lowered systolic BP; and reduced IGF-1. 8
Helping women lead optimally healthy lives after the onset of menopause requires accessing all the therapeutic tools we have. Happily, fasting can be incorporated into that toolbox to support a healthy longevity for the vast majority of our menopausal patients.
REFERENCES 1. Bernhardt et al. 2019. The Lancet; 4 (11) PE539-E540. 2. Ossewaarde et al. 2005. Epidemiology; 16. 556-62. 3. Choi et al. 2017. J Microbiol Biotechnol; 27(12): 2228-2236. 4. Naftolin et al. 2019. F1000Research; 8, 1576. 5. Hatcher et al. 2020. Eur J Neurosci; 51(1):217-228. 6. Alirezaei et al. 2011. Europ J of Neuroscience; 33(2): 197-204. 7. Bianchi et al. 2015. Impact Journals; Oncotarget; 6(14): 11806-11819. 8. Wei, et al. 2017. Sci Transl Med. 9(377). 9. Hamid R Farshchi, et al. 2005. The American Journal of Clinical Nutrition, Volume 81, Issue 2, February 2005, Pages 388–396 10. Corey, et al. Nutrients 2019, 11, 2442; doi:10.3390/nu11102442 11. Natali, et al 2017 Volume 77, pp. 199-215
AUTHOR BIOGRAPHY: Felice Gersh, M.D. holds dual board certifications in OB-GYN and Integrative Medicine. She is the founder and director of the Integrative Medical Group of Irvine. Follow her on Instagram Dr Gersh is an L-Nutra advisor. @dr.felicegersh.
Every woman must transition through and into menopause, a Contact info: state that may encompass a full half of her lifespan. Menopause, fgersh@integrativemgi.com marked by permanent estrogen deficiency, is complex and the (949) 753-7475 impacts on a woman are chronic and body-wide. Treatments must likewise be multifaceted and aimed at the root causes of a woman’s symptoms. Pharmaceuticals may have their place, but they don’t address underlying metabolic dysfunction. Bioidentical hormones are beneficial when given properly, but we cannot create the fluctuating hormonal rhythms and levels seen in naturally menstruating women. Lifestyle—sleep, diet, exercise, and mindfulness—is a critical component of any health plan. It’s time for fasting to take its place as an additional powerful therapeutic for menopausal wellness. In my practice, combining time-restricted eating with the fasting mimicking diet has helped my many menopausal patients maintain their health and vibrancy. When women can control their menopausal symptoms, lose weight, in addition to physical wellness, they gain optimism.
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ANTI-AGING MEDICAL NEWS
• SUMMER 2020
What Bugs Your Heart?
The Role of Microorganisms in Cardiovascular Health and the Application of Botanicals By: Jocelyn Strand, ND The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
Cardiovascular disease (CVD) now affects 48% of adults in the US and is the leading cause of death. Within that category, coronary artery disease resulting in myocardial infarction is most prevalent, while stroke comes in second, and is the 5th leading cause of death overall. The good news is that 90% of stroke risk is due to modifiable risk factors. As providers, we can work alongside our patients to alter factors that increase risk of CVD. Hypertension (HTN), the most common form of CVD, is a major modifiable risk factor for many other CVDs, including acute coronary syndrome, cardiomyopathy, congestive heart failure, pulmonary hypertension, and stroke.1,2 Considering the prevalence of CVD and our ability to manage its risk, it is vital that we identify root causes and direct therapeutics accordingly. One potential target lies in the microbiome. The term microbiome describes the microbial composition of a given area on the body and varies depending on habitat. It is diverse, consisting of bacteria, archaea, fungi, protozoa, viruses and their trillions of genomes collectively.3 The oral and the gastrointestinal microbial communities exhibit the greatest diversity and are innately linked to one another. A flourishing, heterogeneous microbial community is essential both for oral and systemic health. 8 These communities are important for human physiology,immune system development, digestion, detoxification reactions and synthesis of micronutrients. In short, they assist us in maintaining health. Alterations in the balance (increased pathogen load, reduced
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commensals, or reduced diversity) of these microorganisms and their functions can result in microbial dysbiosis and has been linked to a host of local and systemic conditions, including cardiovascular disease.3,4,7
DYSBIOSIS CREATES INFLAMMATION A healthy gut epithelium provides a barrier for microorganisms and metabolites. When dysbiosis occurs, pathogens release mediators that disrupt the GI mucosa and its ability to function as a barrier to systemic circulation. One of these metabolites is lipopolysaccharide (LPS). LPS is generated in the cell wall of both commensal and pathological gram-negative bacteria. It binds to LPS binding protein, which is then recognized by innate immune cells (macrophages, neutrophils, and dendritic cells). This initiates activation of toll-like receptor 4 (TLR4) and consequently nuclear factor kappa B (NF-kB). NF-kB is a transcription factor that activates a cascade of events including the release of pro-inflammatory cytokines, chemokines, and adhesion molecules. These chemical messengers result in a chronic inflammatory response mediated by both the innate (macrophage activation) and adaptive (T cell activation) immune systems. The downstream effect is chronic inflammation, platelet aggregation, foam cell formation, and ultimately the production of atherosclerotic plaque.3,4
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
What Bugs Your Heart? The Role of Microorganisms in Cardiovascular Health and the Application of Botanicals
A two-to-three-fold increase in LPS is called metabolic endotoxemia (ME), which is commonly found in CVD patients. However, even modest increases in LPS have been shown to cause fat deposition, insulin resistance, chronic inflammation, damage to mitochondrial DNA in the heart, and increases pro-atherogenic endothelial adhesion molecules.4 “Microbiota and their metabolites profoundly modulate the progression of atherosclerosis, the most common cause of ACS, stroke and peripheral vascular disease.”3 The host-microbiome interaction influences the production of other metabolites including trimethylamine-N-oxidase (TMAO). Increases in Prevotella and decreased Bacteroides resulted in higher levels of TMAO in one study. TMAO is a bacterial metabolite that exerts harmful effects on the circulatory system, resulting in endothelial dysfunction. It increases chronic inflammation via increased expression of pro-inflammatory cytokines. There is mounting evidence that TMAO influences the progression of CVD, including a direct link to major adverse cardiovascular events. Its effects are so consistent and remarkable that TMAO is now considered a prognostic tool in patients with cardiomyopathy and possibly a marker for gut barrier permeability.3,4 In addition to the metabolic effects of dysbiosis, intestinal permeability allows the translocation of microorganisms from the GI into systemic circulation. Studies have detected the presence of microbial DNA in atherosclerotic plaque and in the fat around the heart. Research shows that these bacteria can be of oral or GI origin.4 Numerous studies have revealed the presence of bacterial biofilms within fatty deposits of damaged arteries (but rarely in healthy arteries), and have established a significant association between infection and coronary heart disease.3,4 Biofilms are a source of constant and spontaneous inoculation of pathogens and are resistant to immune activity and medications.
ORAL HEALTH AND CARDIOVASCULAR DISEASE The role of the microbiota is not limited to the GI tract. In the mouth, there is a complex interplay between microorganisms, the immune system, and “ecological niche” (prevailing properties of the local area) that require balance. We now understand that there are 700+ species of bacteria in the mouth, with a mean of 296. In one milliliter of saliva, there are 108 microorganisms, and as we swallow one liter or more of
saliva each day, it is critical to maintain optimal health in the oral microbiome. 8 Oral health requires balance in the immune-inflammatory state. When there is a dysregulation in the complex interplay between salivary components, immune activity, and existing microbes, dysbiosis occurs causing negative health implications, such as caries, periodontitis, endodontic infection, alveolar bone loss, and tonsillitis.5 Release of mediators from oral pathogens have a systemic effect (e.g. cytokines and prothrombin). People with untreated tooth infections are 2.7 times more likely to have cardiovascular problems, such as coronary artery disease, than patients who have had treatment of dental infections. 7 Proper oral hygiene has been shown to reduce risk of CVD, including HTN, and stool levels of opportunistic pathogens. Periodontal disease, which affects up to 77% of American 13 adults over 30, promotes the release of pro-inflammatory cytokines, and is well established as a risk factor for AS and other CVD. Furthermore, numerous bacteria associated with pathology in the gut are present in the mouth and can create pathology therein or translocate to the gut and contribute to GI dysbiosis. 7,13 Prevotella, which populates the mouth, is one example of a pathogen that is associated with the production of TMAO, a contributing factor in endothelial dysfunction. 4
BIOFILMS PLAY A SIGNIFICANT ROLE IN THE ORAL MICROBIOME AND CARDIOVASCULAR HEALTH The teeth provide a non-shedding surface for organisms to establish biofilm in the form of plaque. Neutrophils are the primary immune defense in the mouth but are not effective against biofilm-associated bacteria. As they attack biofilms, they set off an inflammatory cascade that develops into a gingivitis lesion and increased infiltration of T cells and macrophages. Gingivitis progresses into periodontitis, the characteristic periodontal pocket, and the destruction of surrounding tissue. Due to the anatomical proximity of the periodontal biofilm to the gingival bloodstream, pockets may act as reservoirs for pathogens and their metabolites, as well as inflammatory mediators and immunocomplexes that can disseminate systemically. 11 “Less than 1 minute after an oral procedure, organisms from the infected site may have reached the heart, lungs, and peripheral blood capillary system”. 12
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• SUMMER 2020
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What Bugs Your Heart? The Role of Microorganisms in Cardiovascular Health and the Application of Botanicals
Bacteria commonly live in biofilm communities that can sense each other using chemical signaling molecules, a mechanism known as quorum sensing. Biofilms are responsible for 80% of all infections and for most chronic infections. They are complex, dynamic structures that react to stimulus in coordinated behavior via intracellular communication. Biofilms are 10-5,000 times less susceptible to antimicrobials than a single bacterium. 8
BOTANICALS PROVIDE A SOLUTION FOR INFECTION Herbal medicines have been utilized by humans in the treatment of infection for thousands of years, and provide a safe and effective option for addressing biofilms and dysbiosis. A study with nearly 400 people found that herbal remedies were as effective as Rifaximin (the most studied antibiotic related to SIBO) at treating symptoms. An array of herbals and essential oils were used in that trial. The conclusion reads “Herbal therapies are at least as effective as rifaximin for resolution of SIBO by LBT (lactulose breath test). Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for rifaximin non-responders. Further prospective studies are needed to validate these findings and explore additional alternative therapies in patients with refractory SIBO.”14
Using the anti-pathogenic properties of more than one botanical in a combination or formula provides a broader spectrum of activity against pathogens. The resulting formulations, or “biocidal combinations”, are powerful allies that may be used to address infection.Testing has illustrated remarkable broad-spectrum antimicrobial activity (in vitro) with a combination containing Bilberry extract, Noni, Milk Thistle, Echinacea (purpurea & angustifolia), Goldenseal, Shiitake, White Willow, Garlic, Grapeseed extract, Black Walnut (hull and leaf ), Raspberry, Fumitory, Gentian, Tea Tree oil, Galbanum oil, Lavender oil, and Oregano oil. A & L Analytical Laboratories, performed USP Effectiveness Tests, in which this botanical combination was injected with large numbers of disease causing organisms and then cultured for 28 days. The results demonstrated the bacteria and yeast pathogens are completely eliminated in a matter of hours, and do not recur over a 28 day period of being cultured. “The advanced botanical combination appears to be effective at reducing the level of inoculates.” - John Toth, Bio-Services, A & L Laboratories.
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BOTANICALS ARE EFFECTIVE AGAINST BIOFILMS Botanicals accomplish control of biofilms through several methods. One method is by the inhibition of quorum sensing. Quorum sensing is cell signaling by bacteria and other organisms using autoinducers to determine gene expression, virulence, resistance, and development of biofilms. Botanicals shown to inhibit quorum sensing such as Garlic and Oregano are well known for their antimicrobial ability.This understanding of how they can combat biofilms highlights their clinical and historical significance.15
Another method of biofilm control is by the inhibition of efflux pumps within cells, called multi-drug resistance pumps. Plants containing tannins, berberine, and certain phenolics have useful effects as efflux pump inhibitors, demonstrating marked synergy when combined with conventional antibiotics against a variety of both Grampositive and Gram-negative organisms. Goldenseal, Black Walnut, White Willow, Raspberry Leaf, and Garlic are a few that have been studied.15, 16
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
What Bugs Your Heart? The Role of Microorganisms in Cardiovascular Health and the Application of Botanicals
Bacteriostatic
agents
inhibit
the
reproduction
of
and are useful additions to the biocidal combination for
biofilm organisms and so help to control the spread of
biofilm control. Grapeseed and Bilberry contain condensed
infection. Berberine has been proven bacteriostatic for S.
tannins, which prevent adherence of biofilms and may
epidermidis. One study showed that sub-minimal inhibitory
inhibit swarming.17,18,19,20 One study performed at the
concentrations blocked the formation of S. epidermidis
University of Binghamton shows the complete eradication
biofilms. Both Gentian and Goldenseal contain Berberine
of biofilms with exposure to a biocidal formula.
Use of Botanicals in Oral Infections Botanicals have a long history of use in oral health. A recent study illustrates the potential of a liposomal botanical formula to significantly reduce the pathogen load. In this study, 35 pathogens were detected, followed by an 8 week treatment with the biocidal formula. Post testing, pathogenic bacteria was reduced to 4 remaining organisms. The study showed clearance of bacterial, viral, amoeba, and fungal pathogens.
A Novel Approach The wealth of data available on botanicals demonstrates the usefulness of herbals and nutrients as a safe and effective strategy addressing bacterial, viral, and fungal infections. Furthermore, thereisampleevidencetosuggestthatmanybiofilm-encapsulated infections will also respond to use of these antimicrobial botanicals. Used correctly, the wealth of the plant kingdom is one of our greatest allies in optimizing our health and provides a strong defense against infectious diseases. Botanicals offer a novel approach, and deserve consideration where CVD is concerned.
REFERENCES
AUTHOR BIOGRAPHY:
1. https://www.acc.org/latest-in-cardiology/ten-points-toremember/2019/02/15/14/39/aha-2019-heart-disease-and-stroke-statistics
2. https://www.heart.org/en/news/2019/01/31/cardiovascular-diseases-affect-nearlyhalf-of-american-adults-statistics-show
While in private practice as a Primary Care Provider, Jocelyn
4. https://onlinelibrary.wiley.com/doi/full/10.1111/1440-1681.13250
and autoimmune conditions. In 2019, Dr. Strand became the
3. https://www.ncbi.nlm.nih.gov/pubmed/31469291
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746314/pdf/nihms929622.pdf 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057715/ (1) 7. https://www.nature.com/articles/sj.bdj.2016.865 (2)
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5274568/ (3)
9. https://www.jstage.jst.go.jp/article/internalmedicine/advpub/0/advpub_2908-19/_ article – HPV (4)
Strand, ND, specialized in GI system disorders, Lyme disease, Director of Clinical Education for Bio-Botanical Research, Inc.
drstrand@biocidin.com www.biocidin.com
10. https://www.mdpi.com/2304-6767/6/2/10/htm (5)
11. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0757.1994. tb00019.x?sid=nlm%3Apubmed(6) 12. https://www.ncbi.nlm.nih.gov/pubmed/29563402(7)
13. https://www.nature.com/articles/s41440-019-0260-4.pdf ?draft=collection 14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030608/ 15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119553/ 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486105/ 17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840435/
18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101405/pdf/zac3043.pdf 19. https://www.sciencedirect.com/science/article/abs/pii/S0956713514006586
20. https://www.researchgate.net/profile/Mengfei_Peng/publication/307156613_ Bioactive_extracts_from_berry_byproducts_on_the_pathogenicity_of_Salmonella_ Typhimurium/links/5a295fd1aca2728e05dab087/Bioactive-extracts-from-berrybyproducts-on-the-pathogenicity-of-Salmonella-Typhimurium.pdf
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
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The Gastrointestinal Microbiome: An Evolving Understanding By: Christine Stubbe, ND The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
In this era of discovering the microbiome’s role in human health, we are only at the beginning of having a full understanding of the intricacies. What stories can the microbiome tell us about our health? Can measurement of these organisms serve as a gauge of how well we’re doing? Research continues to rapidly accumulate; however, it is challenging to piece together the entire puzzle with all the available information to tell a complete story. In the last decade, the amount of publications on the microbiome in general, and on the gastrointestinal microbiome has spiked significantly. The gastrointestinal microbiome is a complex and dynamic ecosystem that has both inter- and intrapersonal variation, and is influenced by age, ethnicity, geographic location, diet, lifestyle, medications, and environmental factors.1 It is unique, like a fingerprint.2 If there are no two microbiomes alike, then how is it possible to draw conclusions? Translating the data to clinical application can be challenging; it takes time to arrive at meaningful conclusions. Pattern analysis is an essential part of having a greater understanding of how the microbiome affects human health – and vice versa. Microbes inhabit various places on and in the human body, with the vast majority concentrated in the gastrointestinal tract. They
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influence our health directly and indirectly via the production of postbiotic metabolites. The microbiome is responsible for immune and inflammation regulation, barrier function, short chain fatty acid production, vitamin synthesis, protection against pathogenic organisms and many other vital functions.3-5 A sick microbiome can accelerate the aging and disease process. Some organisms are involved in the production of potentially harmful metabolites such as lipopolysaccharide (LPS) associated with liver disease, neurological degeneration, diabetes, and chronic gut inflammation,6 and trimethylamine N-oxide (TMAO) involved in cardiovascular disease, diabetes, and obesity.7,8 Additionally, there are also links to age-related changes such as loss of bone and muscle mass, as well as skin wrinkling.9 Researchers are even discovering links between the microbiome and more abstract topics such as circadian rhythm.10 We are discovering that the microbiome’s impact on human health is far more intricate than we’ve ever understood. Since the inception of the Human Microbiome Project in 2007, research has come a long way with conducting a census and mapping the normal bacteria that live in and on the human body.10 But, what is the ideal reference population for setting the optimal
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
The Gastrointestinal Microbiome: An Evolving Understanding
healthy benchmark? The microbiome census shows us that microbiomes vary regionally, so what’s considered normal in one part of the world may be different from another part of the world. And is normal healthy? An unhealthy microbiome may precede chronic disease manifestation by years.11-14 The distinction between normal/healthy versus diseased/unhealthy microbiome reference ranges is better determined in clinical studies of healthy versus diseased cohorts. Additionally, longitudinal studies help to determine what makes for an optimal microbiome. Certain key commensal bacteria are known for their proor anti-inflammatory effects. Most are familiar with the probiotics Lactobacillus and Bifidobacterium as having a beneficial impact on human health. Since the study of microbiome began, other beneficial key influencers have emerged such as Faecalibacterium prausnitzii or Akkermansia muciniphila as having anti-inflammatory and gut membrane protective properties.15 Other commensal species such as Fusobacterium spp. or Veillonella spp. are associated with inflammation.16 However, the presence of these bacteria alone is not enough to determine whether a patient’s microbiome is inflammatory or not. While it is well-known that a single pathogen can promote infectious colitis; commensal bacteria do not necessarily regulate inflammation on their own. They function in the context of a community. One paper discusses the concept of pathogenic communities: “In addition to the classic pathogenic species, we propose that another kind of pathogenicity exists in the gut: one in which the whole community is ‘pathogenic’ when its emergent properties contribute to disease. In a ‘pathogenic community,’no single microbe is pathogenic alone. Instead, the community assemblage is an environmental risk factor that contributes to a disease state. A microbial community will be pathogenic within the context of other risk factors, such as host genotype, diet, and behavior.”17 It is important to identify pathogenic communities and patterns, versus placing importance on single organisms.
enterotypes. Enterotypes are clusters of organisms that form a community and people tend to be dominant in one of three enterotypes. Enterotypes are found in different regions of the world among different cultures with different diets and each enterotype has its own clinical relevance. However, the concept has been challenged in the literature due to lack of standardization.18 Other attempts at finding microbiome patterns include analyzing ratios as they relate to health conditions. There are phylum level assessments including the Firmicutes/Bacteroidetes and other phylum level ratios, as well as individual organism ratios. Literature suggests that a high Firmicutes/Bacteroidetes (F/B) ratio may be associated with a greater risk of metabolic syndrome, diabetes, and obesity.19-21 However, the literature is mixed on this subject. Additionally, not all sources calculate the ratio using the same methodology. The term microbiome includes the organisms (microbiota) and their genes. Whole genome sequencing helps to determine the individual organism’s functional roles, however, it is important to remember that not all genes are expressed. Assessing the direct metabolites shows their phenotypic expression versus only looking at genotypic potential. Commercial laboratories measuring commensal bacteria are uniquely positioned to analyze data on a large scale, using their unique set of measured organisms. Certain types of analysis can provide meaningful data for the clinician that can help understand the patient’s microbiome patterns, assisting in treatment decisions. Abundance The total commensal abundance is a sum-total of the reported commensal bacteria compared to a healthy cohort. Low levels of commensal bacteria are often observed after antimicrobial therapy, or in diets lacking fiber and/ or prebiotic-rich foods and may indicate the need for microbiome support. Conversely, higher total commensal abundance may indicate potential bacterial overgrowth or probiotic supplementation.
ASSESSING THE MICROBIOME
Balance
There are many attempts at finding microbiome patterns in the literature, one of which includes looking at
Assessing overall balance is important to know how a patient’s composition of flora compares to a healthy cohort. In general, it is widely accepted that diversity of
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The Gastrointestinal Microbiome: An Evolving Understanding
the microbiome is considered a marker of health. Decreased diversity has been associated with disease.12,22 The presence of pathogens or potential pathogens can indicate imbalance and may require treatment.
A NOVEL INFLAMMATION - ASSOCIATED DYSBIOSIS SCORE An Inflammation-Associated Dysbiosis (IAD) score was introduced in a recently published paper.16 The score differentiates patients with Inflammatory Bowel Disease (IBD) from those with other diagnoses including irritable bowel syndrome (IBS), celiac disease, and healthy patients. The score is based on a specific pattern seen upon analysis of 24 commensal bacteria. The strength of this data set and score is that it is based on 173,221 stool tests. The score is unique because it was derived from the microbiome’s association with inflammatory test biomarkers including fecal calprotectin, eosinophil protein X, and secretory IgA. Additionally, it was validated in two separate studies that distinguish IBD from healthy and other diseases. This score is the first of its kind that incorporates stool biomarkers with microbiome markers.
This group also created another dysbiosis condition score that is opposite the IAD score (unpublished data). The creation of these types of scores provides the clinician with a meaningful synthesis of the data that guides treatment.
THERAPEUTIC OPTIONS
Chen L, Reynolds C, David R, Peace Brewer A. Development of an Index Score for Intestinal Inflammation-Associated Dysbiosis Using Real-World Stool Test Results. Digestive diseases and sciences. 2019.
It is not known whether dysbiosis is a cause or consequence of intestinal inflammation. It is likely a vicious cycle.23 The IAD score shows an association – not necessarily causation, although the authors do discuss root cause. Another interesting aspect of this study was that it reinforced the pathogenic community concept discussed earlier. When the 24 individual organisms were assessed individually, a correlation with IBD could not be made – the score takes the community into account.
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The creation of these types of scores are helpful because they can cause a clinician to change their treatment plan based on results. There is no consensus in the literature on targeted strategies for correcting a certain pattern of dysbiosis. More outcome studies are needed. A unique aspect of the IAD score was a negative association with total commensal abundance. Theoretically, if the IAD score is elevated and abundance is low, antibiotics may be detrimental to the already reduced abundance. However, if the IAD score is high and abundance is high, if antibiotics are warranted, it would likely be a safer option than if the abundance were low. More studies are needed to confirm this.
Rather than focusing on targeting individual organisms, it is important to treat the microbiome and human host as a system. Simply identifying organisms and reporting their amounts presents a challenge for the clinician’s clinical utility. What does it mean when some are high, and some are low? Does each one require treatment? It is not possible to target only one commensal organism with a therapeutic since they function as a community.
It is important to remove the factors that are damaging or destabilizing to the microbiome while supplying the commensal bacteria with what they need to thrive. Antibiotics, stress, environmental toxins, and a Western diet can all contribute to dysbiosis. Conversely, a fiber-rich plant-based diet, prebiotics, probiotics, physical activity, and stress management can promote a healthy microbiome.22 It is not surprising that the accumulating data that links healthy diet and lifestyle to longevity and health also happens to be the factors that make for a healthy microbiome.
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CONCLUSION It is valuable for clinical laboratories to develop test-specific algorithms that synthesize the clinical, as well as other biomarker data to provide a clinically meaningful microbiome evaluation. As data is assessed in this manner, we come closer to personalized treatment recommendations. 1.
Rinninella E, Raoul P, Cintoni M, et al. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases. Microorganisms. 2019;7(1):14.
2.
Franzosa EA, Huang K, Meadow JF, et al. Identifying personal microbiomes using metagenomic codes. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(22):E2930-2938.
3.
Clemente JC, Manasson J, Scher JU. The role of the gut microbiome in systemic inflammatory disease. BMJ. 2018;360:j5145.
4.
Fava F, Danese S. Intestinal microbiota in inflammatory bowel disease: friend of foe? World journal of gastroenterology. 2011;17(5):557-566.
5.
Rowland I, Gibson G, Heinken A, et al. Gut microbiota functions: metabolism of nutrients and other food components. European journal of nutrition. 2018;57(1):1-24.
6.
Wassenaar TM, Zimmermann K. Lipopolysaccharides in Food, Food Supplements, and Probiotics: Should We be Worried? European journal of microbiology & immunology. 2018;8(3):63-69.
7.
Dehghan P, Farhangi MA, Nikniaz L, Nikniaz Z, Asghari-Jafarabadi M. Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) potentially increases the risk of obesity in adults: An exploratory systematic review and dose-response meta- analysis. Obesity reviews : an official journal of the International Association for the Study of Obesity. 2020.
8.
Yang S, Li X, Yang F, et al. Gut Microbiota-Dependent Marker TMAO in Promoting Cardiovascular Disease: Inflammation Mechanism, Clinical Prognostic, and Potential as a Therapeutic Target. Frontiers in pharmacology. 2019;10:1360.
9.
Finlay BB, Finlay JM. The Whole-Body Microbiome: How to Harness Microbes—Inside and Out—for Lifelong Health. The Experiment; 2019.
10. Human Microbiome Project’s Health Relevance. Human Microbiome Project 2019; https://commonfund.nih.gov/hmp/public, 2020. 11. Ding S, Chi MM, Scull BP, et al. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PloS one. 2010;5(8):e12191. 12. Wilkins LJ, Monga M, Miller AW. Defining Dysbiosis for a Cluster of Chronic Diseases. Scientific reports. 2019;9(1):12918.
13. Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The intestinal microbiome in early life: health and disease. Frontiers in immunology. 2014;5:427. 14. Dutta SK, Verma S, Jain V, et al. Parkinson’s Disease: The Emerging Role of Gut Dysbiosis, Antibiotics, Probiotics, and Fecal Microbiota Transplantation. Journal of neurogastroenterology and motility. 2019;25(3):363-376. 15. Hiippala K, Jouhten H, Ronkainen A, et al. The Potential of Gut Commensals in Reinforcing Intestinal Barrier Function and Alleviating Inflammation. Nutrients. 2018;10(8). 16. Chen L, Reynolds C, David R, Peace Brewer A. Development of an Index Score for Intestinal Inflammation-Associated Dysbiosis Using Real-World Stool Test Results. Digestive diseases and sciences. 2019. 17. Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006;124(4):837-848. 18. Costea PI, Hildebrand F, Arumugam M, et al. Enterotypes in the landscape of gut microbial community composition. Nature microbiology. 2018;3(1):8-16. 19. Koliada A, Syzenko G, Moseiko V, et al. Association between body mass index and Firmicutes/Bacteroidetes ratio in an adult Ukrainian population. BMC Microbiol. 2017;17(1):120. 20. Indiani C, Rizzardi KF, Castelo PM, Ferraz LFC, Darrieux M, Parisotto TM. Childhood Obesity and Firmicutes/Bacteroidetes Ratio in the Gut Microbiota: A Systematic Review. Childhood obesity (Print). 2018;14(8):501509. 21. Lyu M, Wang YF, Fan GW, Wang XY, Xu SY, Zhu Y. Balancing Herbal Medicine and Functional Food for Prevention and Treatment of Cardiometabolic Diseases through Modulating Gut Microbiota. Front Microbiol. 2017;8:2146. 22. Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ (Clinical research ed). 2018;361:k2179. 23. Butto LF, Haller D. Dysbiosis in intestinal inflammation: Cause or consequence. International journal of medical microbiology : IJMM. 2016;306(5):302-309.
Christine Stubbe, ND
is a Medical Education specialist, GI product line specialist, and content writer for
Genova Diagnostics. She participates in many teaching and speaking events, and has written for peer-reviewed journals and other publications.
cstubbe@gdx.net 800.522.4762
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Discover the Regenerative Potential of Exosomes By: Jason Sanders, MD The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
Regenerative medicine is an innovative, medical subspecialty that strives to treat or prevent injury and disease by naturally repairing, restoring and regenerating damaged or diseased organs and tissues. This field has exploded in recent years to meet the needs of patients with both complex and common medical problems. Some regenerative medical therapies aim to slow or stop degenerative or pathophysiologic processes that ultimately present themselves as symptomatic conditions. Other regenerative therapies activate the body’s native repair system by influencing the behavior of somatic and progenitor cells to stop degenerating and start regenerating. Stem cell therapy is decades-old regenerative medical technology that has shown the ability to supercharge the body’s ability to repair itself and to combat disease and injury. Recent scientific evidence indicates that the core mechanism of stem cell therapy, which has been very successful in the treatment of different medical conditions, lies in exosomes. Stem cell therapy most commonly employs the mesenchymal stem cell – a natural precursor cell involved in the development of connective tissues that has the capacity to transform into other cell types with more specific functions. Mesenchymal stem cells also have the ability to support normal growth, development
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and tissue repair. For regenerative medicine applications, health care providers have used both young mesenchymal stem cells, which may originate from perinatal tissue such as the umbilical cord, and adult mesenchymal stem cells, which may originate from bone marrow or fat. Originally, scientists and physicians believed that these stem cells exerted their effects by engrafting and differentiating into different cell types to replace diseased or damaged tissues. More recent evidence clearly demonstrates that these stem cells do not engraft, but work by a paracrine mechanism, meaning that they influence the behavior of other cells within the same tissue environment. In the case of allogeneic cells, those harvested from another person, these cells survive less than 3 days after transplantation. In the case of autologous cells, those harvested from tissues in the same person, these cells survive for about 7 days. In either case, the function of these cells during that time is to produce and release exosomes. The nature of these exosomes depends on the parent cell type and the tissue environment, but these exosomes mediate the paracrine effect of the stem cells. So, what are exosomes? Exosomes are sophisticated, nano-scale, biologic signals that are contained within extracellular vesicles.
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These membrane-enclosed capsules ranging in size from about 20 to 200 nanometers are filled with cellular signaling information. Virtually every type of cell produces exosomes as a means of intercellular communication, so exosomes are the essence of the message of the parent cell. That message may tell other cells to reduce inflammation, repair damaged tissues or even reverse aging. Proteins constitute one part of the message of exosomes.The most familiar type of proteins contained within exosomes may be referred to as growth factors. These proteins trigger cellular signaling pathways that initiate specific behaviors in the target cells that internalize the exosomes. Some of the proteins contained within exosomes are growth factor receptors, which may cause growth factors to influence the behavior or the target cells, in different ways than the growth factor would alone. Binding proteins, also contained within exosomes, may have a similar effect. Enzymes contained within exosomes may augment normal enzymatic pathways or restore lost or deficient enzymatic processes exogenously. Finally, immune modulators are signaling proteins that influence inflammation and the activity of the immune system. Messenger RNA comprises another important part of the message contained within exosomes. mRNA is the blueprint for protein production, and proteins govern the structure and function of cells.The mRNA contained within exosomes induces target cells to translate numerous copies of each of the proteins that correspond to each exosomal mRNA. In this way, exosomes can directly hijack the natural protein production machinery of the target cells. Each strand of mRNA remains viable for about 30 days, which may contribute, in part, to the sustained effect exosomes exert on target cells. The persistent effects of exosomes that extend beyond that 30 days may result from the effect of the exosomes on the signaling of the target cells. Cells have the capacity to selectively load exosomes with specific contents, and if the parent cell exosomes influence the loading of the target cell exosomes, the target cell exosomes will perpetuate the message of the parent cells, as they are internalized by secondary or tertiary target cells. These cascading effects may allow the original exosomes to cause lasting effects on cells and tissues that persist much longer than the original contents of the exosomes. Micro RNA represents another important part of the message of exosomes, which scientists have only very
recently begun to understand. These short, non-coding strands of RNA bind to complementary strands of mRNA. When microRNA binds to mRNA, it has two effects. One, microRNA obstructs the binding of ribosomes to mRNA, preventing the translation of specific mRNA. The other effect results from micro RNA destabilizing the mRNA strands, causing them to degrade more quickly. The combined effects of microRNA on endogenous mRNA act as an off-switch for specific protein production, making micro RNA just as important, if not more important, a signaling mediator as the proteins and mRNA contained within the exosomes. All of the contents of exosomes are contained within a lipid bilayer membrane very similar to the parent cell membrane. The exosome membrane, while similar to the parent cell membrane, is not identical, as the membrane proteins and the phospholipid composition may vary. These variances may have some significance related to exosome homing or internalization. The primary function of the exosome membrane is to protect the contents of the exosome from degradation by circulating proteases or RNAses. The exosome membrane also serves to facilitate internalization of the exosomes into the target cells. Perinatal MSC exosomes contain the proteins, mRNA and microRNA packaged by mesenchymal stem cells, the youngest progenitor cells of the connective tissue lineage. These cells naturally support the development of connective tissues like skin, hair, bone, muscle and cartilage. Mesenchymal stem cells also possess beneficial biologic properties that could have applications in regenerative medicine, and these biologic effects are mediated by the exosomes that the MSCs produce. The most important property of perinatal MSC exosomes is that they are produced by very young stem cells, less than a day old, that have the greatest regenerative potential. Numerous studies have demonstrated that perinatal MSC exosomes have multiple innate biologic properties that could have profound effects in regenerative medicine. These exosomes reduce inflammation, which is now understood to be a core mechanism of many diseases and traumatic processes. Excessive activity of immune cells also plays a role in many autoimmune and degenerative conditions, and perinatal MSC exosomes have demonstrated efficacy in modulating the activity of immune cells. These exosomes also promote the development of connective tissues and
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Discover the Regenerative Potential of Exosomes
blood vessels. Perinatal MSC exosomes have also demonstrated efficacy in preserving the viability of damaged cells, which has the effect of preventing apoptosis and necrosis. In severely damaged tissues that do not survive, these exosomes reduce the extent of fibrosis and scarring in the healing tissues. Perinatal MSC exosomes have also shown suppression of tumor growth in pre-clinical models that have been studied. It is important to note that these biologic properties may be related to one or more of the proteins, as well as the micro RNAs contained within these exosomes. One of the most important points to understand, when considering the biologic properties of perinatal MSC exosomes, is that their effects are not the result of any single protein, mRNA or micro RNA that is contained within the exosomes. Instead, the biologic properties of these exosomes result from the combined effects of hundreds of proteins, mRNAs and micro RNAs acting in concert on multiple signaling pathways and having direct effects within the target cell. The composite effect of these exosomal signaling factors sometimes causes predictable effects based on the exosome constituents. At other times exosomes may exhibit paradoxical effects that cannot be easily explained by the well understood biologic activity of their individual contents. In the case of perinatal MSC exosomes, they appear to have positive net biologic effects across the models of injury and disease that have been studied in vitro and in vivo. One explanation for the beneficial biologic properties of perinatal MSC exosomes exert may be related to their role in nature. The natural function of perinatal MSC exosomes is to support the development of the fetus. A central function in this regard is to promote the rapid, controlled cell proliferation that underlies growth. These exosomes also play a role in suppressing inflammation in utero to allow the pregnancy to be carried to term, and modulating the maternal immune system to prevent rejection of the fetus. Supporting the development of connective tissues and their blood supply are also important roles of perinatal MSC exosomes. Finally, these exosomes participate in the suppression of oncogenesis by controlling the growth of the rapidly dividing cells. The biologic properties of perinatal MSC exosomes differ from those of adult MSC exosomes. The closest analog to mesenchymal stem cells in the adult are progenitor cells that may be harvested from bone marrow or fat. These adipose-derived
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or bone marrow-derived stromal cells behave differently and produce exosomes with different contents than perinatal MSCs because of the age-associated decline in the numbers and level of function of these senescent progenitor cells. For example, at birth there are about 1 in 10,000 MSCs in bone marrow, while at age 20, there are about 1 in 100,000 MSCs in bone marrow. These senescent progenitor cells also express different proteins and miRNA than perinatal MSCs. One familiar example of this loss of protein expression may be illustrated by the reduction in lactase expression in adults, which results in lactose intolerance in many adults. Another clinically relevant example of the loss of protein expression in adult cells is the reduced expression of tumor suppressor proteins, which explains why many cancers are frequently diagnosed later in life. Finally, recent cataloguing of micro RNA present in circulating microvesicles indicates that the levels of specific micro RNAs change with aging or in specific disease states. Tissue-derived exosomes also differ from isolated, perinatal MSC exosomes for several reasons, one of which is that sampling tissues for exosomes yields a multitude of different exosomes produced by different cell types, which differ significantly in their contents and corresponding biologic properties. MSC exosomes constitute only a very small fraction of the population of exosomes and other biologic material in both adult and perinatal tissues. In order to concentrate MSC exosomes from composite perinatal tissue, different methods may be employed. One such method is sterile filtration, which can remove cells and other larger particulate material from the samples, but unfortunately leaves nano-particulate debris with similar size and density to the exosomes along with the entire fraction of exosomes produced by different cell types. One example of particulate contamination that may persist after this type of filtration may be ABO blood type incompatibility antibodies, which could cause lifethreatening complications, if unknowingly administered along with exosomes. Another method for MSC exosome isolation is antibody-coated bead extraction, which uses antibodies that bind to MSC exosome membrane proteins to separate these exosomes from the other biologic material in tissues. Unfortunately, the antibody remains attached to the exosome after this separation, creating the potential to trigger an immune response. Compared with both of these methods,isolated MSC exosomes can be much more safely and effectively harvested from isolated MSC cultures, which virtually eliminates the potential for contamination with particulate biologic material and infectious agents.
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The results of nano-tracking analysis demonstrate a clear difference between the exosomes harvested from isolated MSC cultures, illustrated above, and exosomes derived from processing tissue samples. Nano-tracking analysis can determine the size and number of nano-particles reflecting light in a sample. In the upper row, the size distribution shows a single peak indicating a consistent population of nano-particles, as opposed to the multiple peaks in the lower row, which indicate significant particulate contamination. Also, the scatter plot in the upper right shows dense clustering of particles by size indicating the consistency of the sample of isolated MSC exosomes. In the lower right, there is significant scattering of the results representing a very inconsistent sample consistent with particulate biologic contamination. Optimal methods for isolation of MSC exosomes begin with rigorous screening of tissue donors, and subsequently, the donated tissues that exceeds the standards required by the American Academy of Tissue Banks. After successfully screening the donors and tissues, isolated mesenchymal stem cells may be harvested and cultured on chemically defined synthetic growth media, which contains no animal or human products. Over a period of about 4 weeks, the cultured MSCs will produce significant numbers of exosomes and release them into the growth media. This conditioned media can be sterilefiltered to remove the cells and any material that is not the same size and density as an exosome. Unlike processed, composite tissue samples, conditioned media produced by isolated MSC cultures does not contain any biologic nano-particulates that might contaminate the exosomes fraction after filtration process. Despite the intrinsic purity of exosomes isolated in this fashion, the product of filtration should still undergo sterility and endotoxin testing to confirm the absence of any infectious agents. Specialized protein and RNA sequencing identifies the specific contents of the exosome sample. Finally, STORM super resolution fluorescence microscopy is able to confirm that these protein and RNA contents are contained within MSC exosomes. STORM super resolution fluorescence microscopy is able to quantify single molecule fluorescence and identify individual proteins on the surface of exosomes. CD 9, 63 and 81 are membrane proteins that are characteristic of mesenchymal stem cells. Detection of these proteins by STORM microscopy in a configuration that resembles the size and three-dimensional
structure of the exosomes, as illustrated on the lower right, allows direct visualization of the exosomes and confirms that these exosomes originated from mesenchymal stem cells.Unlike nano-tracking analysis, which can only detect size and number without identifying nano-particles, STORM microscopy can also directly count the MSC exosomes in a sample and can visualize exosome movement and internalization into cells in real time.
YOU MAY BE WONDERING WHY ANY OF THIS MATTERS‌
Consider why the science and clinical potential of exosomes might matter to a cancer patient. If physicians could use advanced exosome characterization modalities to detect abnormal exosomes produced by cancer cells long before the cancer could be detected by physical exam or traditional diagnostic tests, treatment could begin sooner with potentially better outcomes. Perhaps physicians could utilize the innate perinatal MSC exosome property of tumor suppression to slow or stop the growth of tumors, or prevent the development of cancer before it begins. The intrinsic biologic properties of perinatal MSC exosomes may also provide some benefit in the preservation of normal tissues damaged by the chemotherapy or radiation commonly used in the treatment of cancer. Ultimately targeted exosome-based therapies could be developed for destruction of specific cancer cells without the collateral damage to normal tissues. All of these exosome-based diagnostic and therapeutic modalities could eventually help to improve the survival of cancer patients. Consider the impact that therapeutic MSC exosomes could have on the life of a spinal cord injury patient. Currently, the only real tool in the armamentarium for an acute spinal cord injury patient is high dose corticosteroids, and this is part of the initial treatment protocol for spinal cord injury in trauma centers. The objective of this type of treatment is to reduce the inflammation, which is what causes the swelling and ischemia that lead to neuronal cell death and motor and sensory deficits below the level of the direct mechanical injury.
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Specialized Pro-Resolving Mediators:
Novel Mechanisms for Supporting a Healthy Inflammatory Response By: Caitlin Higgins The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
WHAT ARE PRO - RESOLVING LIPID MEDIATORS?
Specialized pro-resolving mediators (SPMs) are produced in human blood, milk, and brain tissue from naturally-occurring omega-3 and omega-6 polyunsaturated fatty acids that help support the body’s innate immune response during the “resolution phase” of acute inflammation, clearance of pathogenic microbes, support a normal pain response and promote tissue regeneration.1 Researchers have discovered that these SPMs include a superfamily of endogenous lipid-based chemical mediators known as resolvins, maresins,protectins,and lipoxins.These unique metabolites actively down-regulate the inflammatory response without compromising a healthy immune system response.2 SPMs themselves do not block the initial phases of acute inflammation, which is a vital response to injury, infection, and illness, but rather have been shown in research to evoke novel anti-inflammatory and pro-resolving mechanisms that aid in the process of resolving acute inflammation, accelerating the return to homeostatic balance within the body.3 This active resolution process
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controlled by SPMs is done so via targeting immune cells to stop actively responding to pro-inflammatory chemical mediators, thus limiting overall inflammation. More specifically, SPMs promote resolution by binding to G-protein coupled receptors that can modify cellular behaviors such as mediating pro-inflammatory chemokine, cytokine, and adipokine regulation, microRNA transcription and translocation, and cell traffic.4 At the site of inflammation, SPMs promote clearance of damaging byproducts, microbes, and debris by enhancing macrophage phagocytosis.5
RESOLUTION FOR PAIN MANAGEMENT, TISSUE REPAIR, & INFLAMMATION
SPMs may help support a normal pain response caused by inflammation and injury. Evidence from research studies shows that SPM biosynthesis and concentrations are much lower in circulation among patients with chronic inflammatory conditions.6 An RCT observing a population who suffer from chronic headaches showed that increasing omega-3 fatty acid intake while reducing omega-6s raised serum SPM levels which significantly
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Specialized Pro-resolving Mediators: Novel Mechanisms for Supporting a Healthy Inflammatory Response
attenuated headache pain through increasing production of antinociceptive mediators and improving the overall quality of life.7 In an animal model of rheumatoid arthritis with significantly lower levels of resolvin D3 mediators (members of the SPM family), when mice were given resolvin mediators, they experienced significantly improved joint pain, stiffness, and inflammation due to lower levels of leukocytes and inflammatory eicosanoid infiltration.8 In an in vitro animal model of peritonitis,upon administration of maresin lipid mediators, neutrophilic phagocytosis of E. coli and bacteria at the site of infection increased significantly, reducing the resolution interval by 10 hours.9 Furthermore, in a clinical trial of obese women, those who supplemented with omega-3 fatty acids had statistically significantly higher concentrations of DHA-derived resolvins which activated specific genetic pathways that are responsible for up-regulating antioxidant enzymes and lipid metabolism in those subjects.10
WHY SPMS?
Unlike common anti-inflammatory drugs and medications, SPMs have favorable profiles and fortunately do not suppress immune system function as they are naturally-produced and involved in the biological process of inflammatory resolution. Direct supplementation may help in facilitating the body’s natural response to inflammatory challenges caused by aging, physical traumas, inflammatory-rich/ nutrient-poor diets, chronic stress, infections, and other insults. Research suggests that supplementation with proresolving mediators may also be beneficial for those who have single nucleotide polymorphisms (SNPs) for enzymes involved in SPM biosyntheses, such as the ALX/FPR2 SNPs, dysfunctioning SPM receptors, and inflammatory autoimmune conditions, as well as for those whose diets are low in omega-3 essential fatty acids (e.g., wild-caught fatty fish, flaxseed, walnuts).11 A diet enriched in omega3s, coupled with high-quality, highly-concentrated supplemental SPMs, is shown to have favorable effects in reducing overall inflammation.12
REFERENCES 1. Chiang, N., & Serhan, C. N. (2017). Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Molecular Aspects of Medicine, 58, 114–129. doi:10.1016/j.mam.2017.03.005 2. Colas, R. A., Shinohara, M., Dalli, J., Chiang, N., & Serhan, C. N. (2014). Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Cell Physiology, 307(1), C39-C54. doi: https://doi. org/10.1152/ajpcell.00024.2014 3. Serhan, C. N. (2014). Pro-resolving mediators are leads for resolution physiology. Nature, 510, 92-101. doi: https://doi.org/10.1038/nature13479 4. Cooray SN, Gobbetti T, Montero-Melendez T, et al. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc Natl Acad Sci U S A. 2013;110(45):18232–18237. doi:10.1073/pnas.1308253110 5. Serhan, C. N., Chiang, N., & Dalli, J. (2015). The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Seminars in Immunology, 27(3), 200–215. doi:10.1016/j.smim.2015.03.004 6. Norris, P. C., Skulas-Ray, A C., Riley, I., Richter, C. K., Kris-Etherton, P. M., Jensen, G. L., … Maddipati, K. R. (2018). Identification of specialized proresolving mediator clusters from healthy adults after intravenous low-dose endotoxin and omega-3 supplementation: a methodological validation. Scientific Reports, 8, 18050. Retrieved from https://www.nature.com/articles/s41598018-36679-4 7. Ramsden, C. E., Faurot, K., Zamora, D., Suchindran, C., MacIntosh, B., Gaylord, S., … Mann, D. (2013). Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: A randomized trial. Pain, 154(11), 2441– 2451. doi: 10.1016/j.pain.2013.07.028 8. Arnardottir, H. H., Dalli, J., Norling, L. V., Colas, R. A., Perretti, M., & Serhan, C. N. (2016). Resolvin D3 is dysregulated in arthritis and reduces arthritic inflammation. The Journal of Immunology, 197(6), 2362-2368. doi: https://doi. org/10.4049/jimmunol.1502268 9. Dalli, J., Chiang, N., & Serhan, C. N. (2014). Identification of 14-series sulfidoconjugated mediators that promote resolution of infection and organ protection. Proceedings of the National Academy of Sciences of the United States of America, 111(44), E4753–E4761. doi:10.1073/pnas.1415006111 10. Polus, A., Zapala, B., Razny, U., Gielicz, A., Kiec-Wilk, B., Malczewska-Malec, M., … Dembinska-Kiec, A. (2016). Omega-3 fatty acid supplementation influences the whole blood transcriptome in women with obesity, associated with pro-resolving lipid mediator production. Biochim Biophys Acta, 1861(11), 17461755. doi: 10.1016/j.bbalip.2016.08.005 11. Recchiuti, A., Mattoscio, D. & Isopi, E. (2019). Roles, actions, and therapeutic potential of specialized pro-resolving mediators for the treatment of inflammation in cystic fibrosis. Frontiers in Pharmacology: Inflammation Pharmacology, 10(252). doi: https://doi.org/10.3389/fphar.2019.00252 12. Norling, L. V., Ly, L., & Dalli, J. (2017). Resolving inflammation by using nutrition therapy: roles for specialized pro-resolving mediators. Current Opinion in Clinical Nutrition and Metabolic Care, 20(2), 145–152. doi:10.1097/ MCO.0000000000000353
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Omega-3 Fatty Acids and Aging By: Kasey Hutchinson, RDN The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
Dietary patterns among humans have continued to transform throughout history, but genetic and nutritional needs remain constant. Researchers estimate that during Paleolithic times, people consumed a balanced 1:1 ratio of omega-3 to omega-6 fatty acids.1 However, in modern, westernized cultures, people consume nearly 20 times more omega-6’s than omega3’s. Not surprisingly, this imbalance is associated with a rise in various age-related and inflammatory diseases.1,3 However, key dietary interventions may be able to intercept premature aging and related conditions. Research shows that increasing the consumption of omega-3’s may improve human longevity and quality of life in older adults.
OMEGA - 3’S IN A NUTSHELL Omega-3 fatty acids include alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and others. ALA is mainly plant-derived and can be found in foods such as chia, hemp, and flax seed. EPA, DHA, and DPA, on the other hand, are
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predominantly found in the fatty tissues of fish, such as lake trout, sardines, and salmon. Contrarily, the main sources of omega-6 fatty acids in the diet come predominantly from processed foods and animals products, whose consumption is increasing throughout the world and leading to an imbalance of omega-3:omega-6 fatty acid intake.3 ALA must be converted to EPA, DHA, or others, in order for it to complete its functional role in the human body.4 This process is extremely inefficient in humans with conversion rates of about 15%.4 Excess ALA is typically stored or used for energy, like other dietary fats. Thus, the need for marine sources of omega3’s in the human diet is apparent. This can be accomplished either through increased consumption of seafood or fish oil supplementation.4 A recently published, 25-year prospective cohort study found an inverse relationship between serum levels of omega-3 fatty acids and incidence of age-related diseases.5 More specifically, researchers measured blood levels of DPA, DHA, and EPA
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concentrations in this cohort of 2,622 people. Individuals with the highest omega-3 serum content (6% of total fatty acids) had an 18% decreased risk of unhealthy aging and cognitive decline, and improved quality of life compared to people with lower omega-3 serum concentrations. Based on these results, researchers state that increasing dietary requirements of marine-based omega-3 fatty acids in older adults is highly recommended.
AA:EPA RATIOS AND AGE In order to get a more complete sense of the inflammatory tone of the body, it is important to evaluate serum levels of EPA, DHA, and DPA against serum levels of the omega-6 fatty acid arachidonic acid (AA). In fact, the AA:EPA ratio is quickly growing in popularity for its use as a biomarker in age-related diseases, such as cancer, heart disease, chronic kidney disease, and more. Indeed, the connection between inflammation and the progression of aging has been cited so frequently throughout scientific literature that researchers eventually coined the term ‘inflammaging’ to describe this relationship.6 While inflammation has a useful purpose in the body, such as pathogen elimination, it must be brought to a close in a process known as inflammation resolution.This process is mediated by omega-3 derivatives called pro-resolving mediators (PRMs), which help regenerate damaged tissue.7 Insufficient stores of EPA, DHA, and DPA in the tissue can prevent PRM biosynthesis. In fact, low concentrations of PRMs have been found in patients with age-related diseases such as chronic kidney disease, Alzheimer’s disease, and atherosclerosis. Since the tissue status of PRMs and serum status of AA:EPA are largely affected by dietary intake, nutrition interventions hold a promising solution to combat inflammaging.7-9
FISH OIL, SERUM FATTY ACIDS, AND QUALITY OF LIFE IN ELDERLY ADULTS Fish oil supplementation is a proven approach for reducing AA:EPA ratios. This concurrently improves quality of life and reduces risk of disease among elderly adults. A recent double-blind, placebo-controlled study assessed the impact of omega-3 supplementation on symptoms of depression in a
group of elderly, depressed women.8 Results indicated that 2.5 g/day of omega-3 fatty acids, at a ratio of 2:1 EPA to DHA, significantly improved depressive symptoms in as little as 8 weeks. There was also a significant reduction in AA:EPA ratios in depressed patients following treatment with fish oil. AA:EPA ratios were reduced from 37 to a ratio of 22 – just above the average healthy adult ratio of 15-20.8 Similar studies suggest that reducing AA:EPA ratios protects against coronary artery disease (CAD) and cancer proliferation among older individuals.9,10 While the effects of omega-3 fatty acids on brain and heart health are welldocumented, researchers are beginning to uncover more ways in which these essential fatty acids promote healthy aging.
OMEGA - 3, GUT HEALTH AND HUMAN LONGEVITY The gut associated lymphoid tissue (GALT) is the largest immune organ in the human body.11 Gut microbes play a vital role in GALT formation and maintenance. The gut microbiome also protects the body against pathogens and is involved in disease prevention.11 However, as humans enter their later stages of life, significant changes occur to the gut microbial composition. Namely, there is a substantial decrease in beneficial bacteria such as Bacteroidetes, Prevotella, Lactobacillus, Streptococcus, and Faecalibacterium prausnitzii and an increase in levels of Ruminococcus and Enterobacterium.12 This microbial trend correlates with an increase in both infectious and non-infectious disease, frailty, and inflammatory conditions. Numerous studies suggest that increasing omega-3 (DHA and EPA) intake, either through diet or supplementation, can ameliorate age-related gut dysbiosis.13-15 In fact, fish oil supplementation has been shown to increase the abundance of Clostridiaceae, Akkermansiaceae, and Bifidobacterium, while reducing the abundance of pathogenic gut microbes.15 Furthermore,it appears that such interventions increase shortchain fatty acid (SCFA) production and decrease systemic inflammation associated with metabolic endotoxemia.15 Short-chain fatty acids are crucial metabolites generated by the gut microbiome for strengthening immunity and combating inflammation. Yet, production of these beneficial molecules is sharply reduced in advanced age. Consequently,
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Omega-3 Fatty Acids and Aging
lower levels of intestinal SCFA in elderly adults is associated with aging-related maladies such as constipation, appetite disturbances, frailty, weight loss, cognitive decline, high blood pressure, vitamin D deficiency, diabetes, arthritis, sarcopenia, and more.16 Boosting SCFA levels in the gut offers a significant contribution towards graceful aging. However, this isn’t the only omega-3-related mechanism tied to longevity. It appears that marine-based fatty acids are directly related to telomere length.
TELOMERES AND OMEGA - 3 FATTY ACIDS Telomeres are structures at the end of each strand of DNA that protect chromosomes. With each cellular replication cycle, telomeres shorten, triggering senescence (aging) and apoptosis (cell death), which may be enhanced by stress and inflammation.17 As telomeres shorten, physical signs of aging appear and the risk of age-related diseases, such as cancer, Parkinson’s disease, osteoporosis, osteoarthritis, and coronary artery disease, increases. The rate of shortening is affected by genetics, diet, environment, inflammation, and lifestyle. Telomere length is thus a fundamental indicator of biological age, which means that reducing telomere shortening is central to human longevity research. A prospective cohort study of 608 patients with coronary artery disease investigated serum omega-3 fatty acid levels in relation to telomere length.18 Fasting blood samples were taken from volunteers at a baseline examination and in a 5-year follow up visit. Average telomere length was measured from the DNA from blood samples. Results indicated that higher baseline omega-3 blood levels were associated with an increase in telomere length, regardless of other lifestyle factors. In fact, for each standard deviation increase in baseline omega-3 levels, there was a 32% decrease in telomere shortening.18 Similarly, in a double-blind, randomized trial, researchers assessed changes in telomere length in relation to omega-3 supplementation.19 This 4-month study involved 106 healthy, overweight individuals who were randomly divided into three groups. The high dose group (2.5 g/ day omega-3), low dose group (1.25 g/day omega-3) and a placebo group, who received corn oil supplements. At the end of the study the low dose group showed an
44
increase in telomere length of 21 base pairs (bps), while the high dose group showed a 51 bps increase. The control group experienced a 43 bps decrease in telomere length. While these differences were not considered significant, researchers came to a fascinating conclusion. Omega-3 supplementation changed fatty acid ratios, specifically the omega-6:omega-3 ratios in the serum. For every unit decrease in n-6:n-3 PUFA ratio, there was a 20 bps increase in telomere length (p = 0.02), indicating that metabolism and intestinal absorption may affect how well these fats become incorporated into body tissues.19 This research, along with others, point to an important connection between inflammation, oxidative stress, and immune cell aging.
OMEGA - 3’S ENHANCE LONGEVITY AND PROMOTE GRACEFUL AGING: BIOCHEMICAL MECHANISMS In vivo and animal models help to elucidate the specific mechanisms by which omega-3 fatty acids affect telomere length. Researchers discovered that marine-based fatty acids affect aging due to their effect on the redox-telomereantioncogene axis.20 In a recent study, published in the journal Oncotarget, D-galactose was administered to mice in order to produce advanced glycation end-products (AGEs) in vivo. This protocol is favored among researchers because it mimics the aging process and represents a well-known free radical theory of aging. Mice were then divided into groups to receive either fish oil, polyunsaturated fats, or corn oil. Blood samples were taken to assess the effects of various dietary fats on telomere length, telomerase activity, superoxidase activity, cerebral monoamine oxidase, redox activity, and activation of the antioncogene, a gene which suppresses tumor growth. Similar to the concept of “inflammaging”, the free radical theory implies that organisms age due to oxidation of tissue and accumulation of free radicals. This is accompanied by the loss of telomere length and the increase in physical signs of aging.20 Free radicals, such as superoxide, also impair the activity of telomerase, the enzyme involved in telomere lengthening. Superoxidase activity is typically diminished in people of advanced age and the resulting surge in free radicals damages telomeres, causing senescence and cellular aging. Results from this study indicate that fish oil supplementation
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improves redox state, increases hepatic and cardiac superoxide dismutase (SOD) activity, reduces cerebral monoamine oxidase activity, and leads to increased length of telomeres as compared to the corn oil group. Furthermore, DHA significantly improved activation of testicular antioncogene, which suggests that it can protect against testicular cancer. Fish oil may therefore improve longevity and reduce the risk of age-related cognitive decline and disease through these biochemical mechanisms.
correlated with a long, happy life, yet only in recent years has this been validated with experimental studies.21 Cold water fish
are a rich source of bioavailable omega-3 fatty acids, such as
EPA, DHA, and DPA. As these molecules are absorbed into the body and incorporated into blood cells and tissues, they begin to elicit a powerful, preventative impact on aging and
age-related diseases. Similarly, supplementation with omega-
3’s and SPMs that are extracted and purified from marine
sources can provide significant health benefits by improving
the quality of life in older adults and boosting longevity. In
CONCLUSION
conclusion, the consumption of wild-caught, cold water fish and the supplementation of high quality fish oil from reputable
The connection between diet and longevity has long been recognized. Scientists have observed that seafood intake is
sources can go a long way toward improving health outcomes and human longevity.
REFERENCES 1.
Scaioli E, et al. The Imbalance between n-6/n-3 Polyunsaturated Fatty Acids and Inflammatory Bowel Disease: A Comprehensive Review and Future Therapeutic Perspectives. Int J Mol Sci. 2017;18(12):2619.
10.
Garassino, et al. A new biomarker in cancer patients: The arachidonic acid/ eicosapentaenoic acid (AA/EPA) ratio. Clinical Cancer Research. 2006; 12(19).
2.
Lawrenson JG, et al. Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration. Cochrane Database of Systematic Reviews. 2012.
11.
Shi N, et al. Interaction between the gut microbiome and mucosal immune system. Mil Med Res. 2017;4:14.
3.
Table 3. Food sources of linoleic acid (PFA 18:2), listed in descending order by percentages of their contribution to intake, based on data from the National Health and Nutrition Examination Survey 2005-2006. Food sources of linoleic acid (PFA 18:2), listed in descending order by percentages of their contribution to intake, based on data from the National Health and Nutrition Examination Survey 2005-2006. https:// epi.grants.cancer.gov/diet/foodsources/fatty_acids/table3.html. Accessed February 6, 2020.
12.
Vemuri R, et al. Gut Microbial Changes, Interactions, and Their Implications on Human Lifecycle: An Ageing Perspective. BioMed Research International. 2018;2018:1-13.
13.
Marlow G, Ellett S, Ferguson IR, et al. Transcriptomics to study the effect of a Mediterranean-inspired diet on inflammation in Crohn’s disease patients. Hum Genomics. 2013;7(1):24. Published 2013 Nov 27. doi:10.1186/1479-7364-7-24
14.
Parolini C. Effects of Fish n-3 PUFAs on Intestinal Microbiota and Immune System. Mar Drugs. 2019;17(6):374. Published 2019 Jun 22. doi:10.3390/md17060374
15.
Costantini L, et al. Impact of Omega-3 Fatty Acids on the Gut Microbiota. Int J Mol Sci. 2017;18(12):2645.
16.
Nagpal R, et al. Gut microbiome and aging: Physiological and mechanistic insights. Nutr Healthy Aging. 2018;4(4):267–285.
17.
Barden, et al. n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease. Nutrients. 2016; 8(3): 175.
18.
Farzaneh-Far R, et al. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010;303(3):250–257.
19.
Kiecolt-Glaser JK, et al. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun. 2013;28:16–24.
20.
Chen J, et al. Polyunsaturated fatty acids ameliorate aging via redoxtelomere-antioncogene axis. Oncotarget. 2017;8(5):7301–7314.
21.
Cassidy A, et al. Associations between diet, lifestyle factors, and telomere length in women. Am J Clin Nutr. 2010;91(5):1273–1280.
4.
Office of Dietary Supplements - Omega-3 Fatty Acids. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/ Omega3FattyAcids-HealthProfessional/. Accessed February 6, 2020.
5.
Lai H. Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study. Bmj. 2018;363:k4067.
6.
Franceschi C, Campisi J. Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2014;69(Suppl 1). doi:10.1093/gerona/glu057.
7.
Doyle, R., et al. Pro-resolving lipid mediators: Agents of antiageing? Seminars in Immunology. 2018; 40: 36-48. doi:10.1016/j. smim.2018.09.002
8.
Rizzo AM, Corsetto PA, Montorfano G, et al. Comparison between the AA/EPA ratio in depressed and non depressed elderly females: omega-3 fatty acid supplementation correlates with improved symptoms but does not change immunological parameters. Nutr J. 2012;11:82. Published 2012 Oct 10.
9.
Serikawa, et al. The ratio of eicosapentaenoic acid to arachidonic acid is a critical risk factor for acute coronary syndrome in middle-aged older patients as well as younger adult patients. 2014; 63(1): 35-40.
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Sulforofan Extra Mitochondrial Rescue | Ph: (561) 767-0721 | www.mitochondrialrescue.com 伀琀栀攀爀 椀渀最爀攀搀椀攀渀琀猀㨀 洀椀挀爀漀挀爀礀猀琀愀氀氀椀渀攀 挀攀氀氀甀氀漀猀攀Ⰰ 洀愀最渀攀猀椀甀洀 猀琀攀愀爀愀琀攀Ⰰ 最愀猀琀爀漀ⴀ爀攀猀椀猀琀愀渀琀 挀愀瀀猀甀氀攀 ⠀栀礀搀爀漀砀礀瀀爀漀瀀礀氀洀攀琀栀礀氀挀攀氀氀甀ⴀ 氀漀猀攀Ⰰ 最攀氀氀愀渀 最甀洀⤀ 一漀 最氀甀琀攀渀Ⰰ 礀攀愀猀琀Ⰰ 眀栀攀愀琀Ⰰ 挀漀爀渀Ⰰ 攀最最Ⰰ 愀搀搀攀搀 猀甀最愀爀Ⰰ 猀琀愀爀挀栀Ⰰ 瀀爀攀猀攀爀瘀愀愀瘀攀猀Ⰰ 瀀攀愀渀甀琀猀⼀渀甀琀猀 漀爀 ǻ猀栀⼀猀栀攀氀氀ǻ猀栀 圀攀椀最栀 漀昀 挀漀渀琀攀渀琀㨀 ㈀㌀Ⰰ㤀最
匀甀氀昀漀爀愀昀愀渀 䔀堀吀刀䄀 匀甀氀昀漀爀愀昀愀渀 䔀砀琀爀愀 挀漀渀瘀攀爀琀猀 琀漀 猀甀氀昀漀爀愀瀀栀愀渀攀 椀渀 琀栀攀 戀漀搀礀⸀ 匀甀氀昀漀爀愀瀀栀愀渀攀 椀猀 愀 挀漀洀瀀漀甀渀搀 椀渀 戀爀漀挀挀漀氀椀 猀攀攀搀猀 琀栀愀琀 攀渀挀漀甀爀愀最攀猀 愀渀渀漀砀椀搀愀渀琀 瀀爀漀琀攀挀挀漀渀Ⰰ 瀀爀漀洀漀琀攀猀 挀攀氀氀甀氀愀爀 愀渀搀 椀洀洀甀渀攀 栀攀愀氀琀栀⸀
匀琀漀爀愀最攀㨀 匀琀漀爀攀 椀渀 愀 挀漀漀氀 愀渀搀 搀爀礀 瀀氀愀挀攀Ⰰ 甀渀搀攀爀 ㈀㔀뀀䌀 䬀攀攀瀀 漀甀琀 漀昀 琀栀攀 爀攀愀挀栀 漀昀 挀栀椀氀搀爀攀渀⸀ 吀栀攀猀攀 猀琀愀琀攀洀攀渀琀猀 栀愀瘀攀 渀漀琀 戀攀攀渀 攀瘀愀氀甀愀琀攀搀 戀礀 琀栀攀 䘀漀漀搀 ☀ 䐀爀甀最 䄀搀洀椀渀椀猀琀爀愀愀漀渀⸀ 吀栀椀猀 瀀爀漀搀ⴀ 甀挀琀 椀猀 渀漀琀 椀渀琀攀渀搀攀搀 琀漀 搀椀愀最渀漀猀攀Ⰰ 琀爀攀愀琀Ⰰ 挀甀爀攀Ⰰ 漀爀 瀀爀攀瘀攀渀琀 愀渀礀 搀椀猀攀愀猀攀⸀
匀甀最最攀猀琀攀搀 甀猀攀㨀 挀愀瀀猀甀氀攀 搀愀椀氀礀 眀椀琀栀 愀 洀攀愀氀 漀爀 愀猀 搀椀ⴀ 爀攀挀琀攀搀 戀礀 愀 栀攀愀氀琀栀挀愀爀攀 瀀爀漀昀攀猀猀椀漀渀愀氀⸀ 䌀愀甀甀漀渀㨀 吀栀攀 瀀爀漀搀甀挀琀 猀栀漀甀氀搀 渀漀琀 戀攀 甀猀攀搀 戀礀 瀀攀爀猀漀渀猀 愀氀氀攀爀最椀挀 琀漀 愀渀礀 椀渀最爀攀搀椀攀渀琀 挀漀渀琀愀椀渀攀搀 椀渀 琀栀攀 挀漀洀瀀漀猀椀ⴀ ⴀ漀渀⸀ 吀栀攀 瀀爀漀搀甀挀琀 猀栀漀甀氀搀 渀漀琀 戀攀 甀猀攀搀 戀礀 瀀爀攀最渀愀渀琀 愀渀搀 戀爀攀愀猀猀攀攀搀椀渀最 眀漀洀攀渀⸀ 䤀渀最爀攀搀椀攀渀琀 䈀爀漀挀挀漀爀愀瀀栀愀渀椀渀글 䄀挀挀瘀愀琀攀搀Ⰰ 戀爀漀挀挀漀氀椀 爀愀ϻ渀愀琀攀 昀爀漀洀 䈀爀愀猀猀椀挀愀 漀氀攀爀愀挀攀愀 椀琀愀氀椀ⴀ 挀愀 猀攀攀搀 猀琀愀渀搀愀爀搀椀稀攀搀 漀渀 最氀礀挀漀猀椀ⴀ 渀漀氀愀琀攀猀 愀渀搀 洀礀爀漀猀椀渀愀猀攀⸀
䴀愀渀甀昀愀挀琀甀爀攀爀㨀 䘀漀爀 䌀愀爀渀漀洀攀搀 搀漀漀Ⰰ 䔀氀攀瀀栀愀渀琀 䌀漀Ⰰ 倀愀渀挀攀瘀愀挀欀椀 瀀甀琀 㐀㈀ⴀ㐀㐀Ⰰ 䈀攀氀最爀愀搀攀Ⰰ 匀攀爀戀椀愀Ⰰ 甀渀搀攀爀 䤀匀伀 㤀 㨀㈀ 㠀 愀渀搀 䠀䄀䌀䌀倀 猀琀愀渀搀愀爀搀猀
䄀洀漀甀渀琀 瀀攀爀 猀攀爀瘀椀渀最 ㈀ 洀最⨀
⨀ 䐀愀椀氀礀 嘀愀氀甀攀猀 渀漀琀 攀猀琀愀戀氀椀猀栀攀搀
㘀 挀愀瀀猀甀氀攀猀
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DUE TO COVID-19
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The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
Methylation Methylation is the act of adding a methylPathways group from one substance to another. Methylating a substance activate or deactivates it, Dr. Alison McAllister
impacting genes and body functions. Methylation plays a role in many body processes including neurotransmitter synthesis, detoxification of chemicals and hormones especially estrogen, and production of energy.
Methylation is the act of adding a methyl group from one substance to another. Methylating a substance activate or deactivates it, impacting genes and body functions. Methylation plays a role in many body processes including
neurotransmitter synthesis, chemicals and nutrients hormones especially estrogen,can andclinically productionhelp of energy. Knowing the methylation pathways anddetoxification how they ofinteract with and hormones guide treatment decision the methylation pathways and how they interact nutrients and hormones canmay clinically guidehomocysteine and impacts making, as well asKnowing understanding the risk of disease. Patients withwith MTHF genetic variants havehelp higher treatment decision making, as well as understanding the risk of disease. Patients with MTHF genetic variants may
on cardiovascular disease and brain function. Patients with COMT SNPs may methylate their 2-OH estrogens differently than the 4 have higher homocysteine and impacts on cardiovascular disease and brain function. Patients with COMT SNPs
OH estrogens. Assessing as many end products as possible allows theestrogens. clinicianAssessing to build as a picture ofproducts health around methylation and allow may methylate their 2-OH estrogens differently than the 4 OH many end as possible allows the clinician to build a picture of health around methylation and allow therapeutic or nutritional
therapeutic or nutritional interventions at the appropriate enzymes involved in the pathways. interventions at the appropriate enzymes involved in the pathways.
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Anti-Aging Benefits: Resveratrol vs. Pterostilbene
A Comparison of Bioavailability and Health Benefits By: Sara Cook, ND & Lisa Murray, RDN The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
Nearly two decades ago, it was discovered that resveratrol slowed the process of cellular aging in yeast. Harvard Medical School Professor David Sinclair, PhD, found in 2003 that resveratrol activated a longevity gene called SIRT1 and the resultant class of sirtuin proteins. Then, the same mechanism was found to be true in mice. And researchers were off and running to determine what miracles this molecule might have in store for humans. Investigations into resveratrol skyrocketed. Resveratrol was found to support cardiovascular health, antioxidant defenses, glucose metabolism, inflammatory pathways, and more. As results of these studies were reported, people became more interested in drinking resveratrol-rich red wine and taking resveratrol supplements. But not all studies have validated resveratrol’s benefits. For example, a study published in July 2014 in JAMA Internal Medicine found no association between higher intakes of resveratrol and rates of heart disease, cancer, or death in nearly 800 older Italian men and women. Some of the biggest hurdles for reaping the benefits of resveratrol in humans appear to be its limited bioavailability and rapid elimination from the body. But those hurdles might be overcome by a compound that has more recently gained traction. About 10 years after the discovery that resveratrol activated a longevity gene, researchers began to take interest in its molecular cousin, pterostilbene. Although it’s present
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in a higher concentration in blueberries than in red wine, pterostilbene is nearly identical in chemical structure to resveratrol. The first human-safety study of pterostilbene was published in 2013, and investigations have intensified since then. Pterostilbene is now championed as a more potent form of resveratrol. It’s said to offer all of the previously known benefits of resveratrol but with superior bioavailability. Are these claims true? Here’s a detailed comparison of these two cousin compounds.
STRUCTURAL DIFFERENCES Resveratrol and pterostilbene are both naturally occurring plant compounds. Resveratrol is concentrated in grape skins and red wine, but has also been isolated from the roots of Japanese knotweed. Pterostilbene is concentrated primarily in blueberries, but has also been found in peanuts and grapevines. Resveratrol and pterostilbene fall into a class of compounds called stilbenes. These phenolic compounds consist of two aromatic rings with hydroxyl groups (-OH). Resveratrol and pterostilbene are very similar in structure, but with one minute—yet critical—difference. Resveratrol has three hydroxyl groups, whereas pterostilbene has only one. The other two hydroxyl groups are replaced by methoxy groups (O-CH3) in pterostilbene. The difference in the number of hydroxyl groups is crucial because it influences how quickly the compound is metabolized and eliminated from the body. The three hydroxyl groups in
ANTI-AGING MEDICAL NEWS
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Anti-Aging Benefits: Resveratrol vs. Pterostilbene | A Comparison of Bioavailability and Health Benefits
resveratrol hasten the molecule’s removal. That makes it challenging to reach and maintain appreciable levels of resveratrol in the bloodstream. With only one hydroxyl group per molecule, pterostilbene is able to persist in circulation for a longer time. The slight difference in structure also makes pterostilbene more lipophilic. Pterostilbene can more readily pass through cell membranes—making it more available to support cellular pathways. Both resveratrol and pterostilbene are naturally occurring in two forms: cis and trans. The trans forms are more stable and more abundant in nature. Studies suggest that for both resveratrol and pterostilbene, the trans forms are superior to the cis forms in terms of biological activity.
BIOAVAILABILITY AND HALF - LIFE The good news about resveratrol and pterostilbene is that they’re both readily absorbed after oral intake, and are even capable of crossing the blood-brain barrier. The bad news is that they’re rapidly metabolized. Their time in circulation is fleeting. The absorption rate of resveratrol from the intestinal lumen is about 75 percent, but its rapid metabolism in the liver results in oral bioavailability of only about 1 percent. That’s because the liver produces resveratrol conjugates— primarily glucuronides and sulfates. In a human bioavailability study, 15 healthy volunteers each took a 500 mg capsule of trans-resveratrol. Blood samples taken after dosing showed that free resveratrol only represented 0.28 percent of total resveratrol in circulation, with the rest consisting of conjugated glucuronides or sulfates. The study also showed that resveratrol was short-lived— its concentration peaked at only about one hour after intake. That result was similar to an earlier study, which found that the half-life of trans-resveratrol was one to three hours following a single dose. When a compound has such low bioavailability and such a short half-life, it’s difficult to maintain a concentration in circulation. One study found that even when people
took 150 mg of trans-resveratrol six times per day, they still had low plasma concentrations. One of the most commonly cited comparisons of resveratrol and pterostilbene is that the oral bioavailability of resveratrol is only 20 percent, while pterostilbene reaches 80 percent. But it’s important to note that these percentages refer to the combined total of resveratrol plus resveratrol sulfate, and pterostilbene plus pterostilbene sulfate. It’s even more important to note that these percentages came from a study that was conducted in rats rather than humans. The other oft-cited comparison is that the half-life of pterostilbene is seven times longer than that of resveratrol. This statistic comes from two studies: One reported that resveratrol had a half-life of 14 minutes, and the other reported that pterostilbene had a half-life of 105 minutes. Again, these were preclinical studies that were conducted not in humans, but in rabbits, rats, and mice. Several unanswered questions remain. We don’t know whether the conjugated metabolites of resveratrol and pterostilbene have biological activity at the tissue level (there is some evidence of activity, albeit less than free resveratrol). Also, it’s unknown whether the bioavailability data on pterostilbene from animal studies can be translated to humans. Many researchers and clinicians are taking the limited data we have so far about the bioavailability of pterostilbene and running with it. Based on the studies mentioned above, pterostilbene has gained a reputation for being a more potent and bioavailable form of resveratrol.
COMPARISON OF HEALTH BENEFITS Resveratrol has been extensively researched. Experimental studies show that resveratrol modulates innumerable molecular mechanisms at the cellular level. It interacts, for example, with cellular pathways related to inflammation, apoptosis, and autophagy. It also interacts with pathways associated with aging and longevity, such as telomeres and cell senescence. Despite its low bioavailability, there is abundant evidence for resveratrol’s ability to promote health in humans.
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Anti-Aging Benefits: Resveratrol vs. Pterostilbene | A Comparison of Bioavailability and Health Benefits
Randomized, controlled trials have shown that resveratrol supplementation supports healthy weight management, blood-sugar metabolism, cardiovascular function, mood, and biomarkers of inflammation and oxidative stress. Resveratrol’s health benefits have also been confirmed in many other studies, and even meta-analyses. When it comes to pterostilbene, the evidence is much sparser. Aside from a safety study published in 2013, there have been very few trials conducted in humans. There was one study, conducted at the University of Mississippi in 80 adults, which found that pterostilbene supported healthy blood pressure and lipid metabolism. The vast majority of research on pterostilbene is in the experimental and preclinical phase. Researchers have found that pterostilbene supports many of the same cellular pathways as resveratrol—including supporting antioxidant defenses and modulating pathways involved in inflammation, apoptosis, and autophagy. Most experts agree that the molecular mechanisms of pterostilbene should be considered equivalent to those of resveratrol.
SELECTED REFERENCES 1. Almeida L, et al. Mol Nutr Food Res 53 Suppl 1 (2009): S7–15. 2. Asensi M, et al. Free Radic Biol Med 33, no. 3 (2002): 387–98. 3. Farzaei MH, et al. Pharmacol Res 128 (2018): 338–44. 4. Fogacci F, et al. Crit Rev Food Sci Nutr 59, no. 10 (2019): 1605–18. 5. Haghighatdoost F and Hariri M. Eur J Clin Nutr 73, no. 3 (2019): 345–55. 6. Hoshino J, et al. J Med Chem 53, no. 13 (2010): 5033–43. 7. Kapetanovic IM, et al. Cancer Chemother Pharmacol 68, no. 3 (2011): 593–601. 8. Li YR, Li S, and Lin CC. Biofactors 44, no. 1 (2018): 69–82. 9. Liu K, et al. Am J Clin Nutr 99, no. 6 (2014): 1510–19. 10. McCormack D and McFadden D. Oxid Med Cell Longev 2013 (2013): 575482
WHICH SHOULD YOU CHOOSE? PubMed has indexed more than 12,000 research studies on resveratrol, but only 500 on pterostilbene. However, the sheer number of scientific studies on a compound doesn’t necessarily mean the compound is superior. It’s also important to note that pterostilbene research lags about 10 years behind resveratrol research. The slight difference in molecular structure between resveratrol and pterostilbene provides a sound rationale for the superiority of pterostilbene. Pterostilbene should be more stable and bioavailable in theory, and preclinical studies validate the assumption. We look forward to more research on pterostilbene in the years to come. For now, many experts believe that what we’ve already learned about resveratrol regarding its ability to support cardiovascular health, cellular health, and metabolism is also true for pterostilbene. Researchers are hedging their bets that pterostilbene will prove to be all the things resveratrol is— but in a more potent form..
BIOS: Lisa Murray, RDN is the Medical Education Manager for
Emerson Ecologics and Wellevate, and Medical Editor for Element magazine, an Emerson Ecologics publication. lmurray@emersonecologics.com
Sara Cook, ND, Medical Copywriter and founder of NDpen is Senior Writer for Element Magazine. sarah@ndpen.com
11. Mousavi SM, et al. Obes Rev 20, no. 3 (2019): 487–98. 12. Remsberg CM, et al. Phytother Res 22, no. 2 (2008): 169–79. 13. Riche DM, et al. J Toxicol 2013 (2013): 463595. 14. Riche DM, et al. Evid Based Complement Alternat Med 2014 (2014): 459165 15. Semba RD, et al. JAMA Intern Med 174, no. 7 (2014): 1077–84. 16. Sergides C, et al. Exp Ther Med 11, no. 1 (2016): 164–70. 17. Tabrizi R, et al. Food Funct 9, no. 12 (2018): 6116–28. 18. Tsai HY, Ho CT, and Chen YK. J Food Drug Anal 25, no. 1 (2017): 134–47. 19. Walle T. Ann N Y Acad Sci 1215 (2011): 9–15.
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• SUMMER 2020
by Emerson Ecologics
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Beyond HDL:
New Insights into HDL Function in Cardiovascular Disease By: Mark Houston, MD and Sara Gottfried, MD The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article.
INTRODUCTION
High-density lipoprotein (HDL) plays a vital role in lipid biology and coronary heart disease (CHD) pathophysiology. However, a major paradigm shift is happening in the medical community regarding the role of HDL-cholesterol (HDL-C) in dyslipidemia and dyslipidemia-induced cardiovascular disease, especially CHD and myocardial infarction (MI). HDL are complex nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. HDL is best known for its ability to scavenge for and ferry low-density lipoprotein cholesterol (LDL-C) away from the arteries and back to the liver for redistribution, metabolism, and elimination, as well as for its anti-inflammatory, antithrombotic, anti-immune and antioxidative activity. The prevailing dogma for the past 30 years was that high total HDL-C (a lab measure reflecting the amount of cholesterol carried by the HDL particles) was cardioprotective, because it reflected better clearance of cholesterol. However, the emerging narrative is that the HDL particle is far more heterogeneous than previously understood. In order for HDL
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to be cardioprotective, it must be functional.1 Furthermore, there are genomic, proteomic, and other compositional considerations. The main takeaway is that because of the heterogeneity of HDL, measurement of HDL-C alone does not provide a complete picture of the protective qualities of HDL vis-à-vis cardiovascular disease.
HDL: THE PARADIGM SHIFT ABOUT THE ROLE OF HDL LDL is essentially a “garbage” type of particle that deposits cholesterol in cells all over the body, while HDL is like a garbage collector. It literally takes excess cholesterol out of tissue to remove it from the body, usually through the liver. Epidemiological studies, ranging from the Framingham Study and continuing through to the Atherosclerosis Risk in Communities (ARIC) Study, demonstrated that HDL-C is inversely associated with CHD and MI.2,3 Specifically, as the calculation was extended, CHD risk increases by 3% in men and 2% in women for every 1 mg/dL decrement in HDL-C.4 Put
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
Beyond HDL: New Insights into HDL Function in Cardiovascular Disease
another way, patients were told that if you have good HDL-C, then you’ll have good “reverse cholesterol transport (RCT),” i.e., the body’s ability to bring cholesterol back to the liver for removal. In the past, it was believed that as long as HDL-C levels were above a certain threshold, a patient was protected from having CHD and/or MI. New research has updated that perception. Several threads of evidence point to a more nuanced model. Pharmacological interventions in randomized trials that raise HDL-C by twoto three-fold have failed to produce the anticipated reduction in cardiovascular risk.5-9 Additionally, the level of the apolipoprotein A-I (apoA-I), the primary HDL-associated apolipoprotein, in HDL subtypes is a better predictor of cardiovascular risk than HDL-C concentration.10 Further studies showed that the antiatherogenic capacity of HDL seems to be mediated by function, in this case, cholesterol efflux capacity (CEC), which is a superior predictor of risk than total HDL-C concentration,11 though not all data are concordant. Further, data from genomewide association studies (GWAS) have shown that lower HDL-C may not cause CHD, a high HDL-C may not be protective from CHD, and heterogeneity of HDL structure and function may be more to blame.12,13
We only had what were called “indicative markers of HDL function,” such as myeloperoxidase (MPO) and some inflammatory and oxidative stress markers, but these were not the direct assessors of HDL function. However, a new test, currently in beta mode, may soon be available that has the ability to measure RCT and CEC. This lab test may allow practitioners to determine HDL function simply. Investigators have demonstrated that assessment of CEC is one metric of HDL function and may in fact be a predictor of atherosclerosis and cardiovascular disease risk.14 New research is painting a broader picture that HDL function may be impaired in other situations of systemic inflammation or oxidative stress (Figure 1) and, such as autoimmunity, suggesting that improvement in HDL function may help beyond cardiovascular risk.15
In other words, if HDL is the garbage collector, there’s a range of options in the fleet. Some garbage trucks look good but don’t perform. Some have flat tires. But some of the garbage trucks are top of line, some have large carrying capacity and others have small carrying capacity, and others are highly dependable and perform beyond expectations. That’s the spectrum of HDL function.
Figure 1. The cardioprotective properties of HDL particles can become dysfunctional under oxidative stress and inflammatory burden.
We can no longer rely on high HDL-C alone for heart health protection, because experts are now questioning the composition and function of the various types of HDL.
WHAT IS HDL FUNCTION?
HDL MAPPING OF VARIOUS SUBSPECIES OF HDL
Static measurement of HDL-C fails to reflect the dynamics of the HDL particle, its remodeling process, the HDL cargo load, HDL interconversions in the lipid pathway, the hepatic unloading, and resulting function. Up until recently, HDL function could not be measured.
There are five different forms of HDL particles. The test used to measure these different forms is called “HDL mapping,” which includes α-1, α-2, α-3, α-4, and pre- HDL. All of these forms are important; however, in the past the emphasis had been on the large HDL, which was α-1 in particular with
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
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Beyond HDL: New Insights into HDL Function in Cardiovascular Disease
a little bit of α-2.The concept has since changed. Some of the small particles, which are necessary to dock on the LDL tissue receptors and remove it, may be just as important in transforming to a larger HDL—which can handle more LDL, take it out, and deposit it in the liver. While the HDL size is important, it may be all types of HDL that play a role in this process.
• Pomegranate has been shown to change some of the enzymes such as paraoxonase 1 (PON-1) in the HDL particle and allow HDL to better transport cholesterol and to improve HDL’s antioxidant capacity.17,18
But even size doesn’t matter without proper function. For example, a patient may have a normal level of all HDL sizes with the HDL mapping, but the HDL function may be abnormal. Think of it like a garbage truck with four flat tires. Although the garbage truck is large and potentially powerful, it won’t make it to its destination to complete its job (i.e., cleaning up LDL). That’s why function is the biggest key factor.
• Lycopene-rich diet or lycopene has been shown to increase apoA-I and other proteins associated with HDL function.21,22
THE IMPORTANCE OF HDL PARTICLE NUMBER
The benefits of HDL also depend on the number of HDL particles. This is called HDL particle number, or HDL-P. Based on recent research, the higher the HDL particle number, the more protected you are from CHD and MI.16 That’s why many researchers agree that HDL function and particle number are the two most important factors when measuring HDL. In fact, in many studies the HDL-P and HDL function measurements are equally predictive of CHD and MI. If we’re able to determine both of these parameters together, we can better predict the role of HDL in providing protection from CHD and MI.
TESTING 1, 2, 3 For any patient with a history of HDL-related problems, the first and most important step is to complete an advanced lipid profile, which will guide treatment options such as nutritional support, exercise, weight loss, and nutraceutical supplementation. This requires specialized labs—now available all over the United States—that determine all the previously mentioned parameters.
DESIGNING A NUTRITIONAL MEDICINE TREATMENT PROTOCOL Supplementation can play a key role in HDL management. Keep in mind, there are very few pharmaceutical agents that modify HDL. In fact, most won‘t affect the lab parameters we’ve covered. However, various nutraceutical supplement and nutritional changes can modify at least one of these key factors.
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• Niacin shows promise for HDL-P and HDL support by improving function,19 though data are mixed.20
• Green tea extract, or EGCG, can also change the protein or lipid content of HDL so that the composition is not damaged by things like oxidative stress or inflammation,thereby reducing the risk of HDL dysfunction.23 • Increased intake of virgin olive oil, nuts, legumes, whole grains, and fish improves HDL function.24 Specifically, olive oil and whole-grain consumption raise CEC. More nut and legume intake improves PON-1 activity. Legume intake increases are also related to decreases in cholesteryl ester transfer protein activity. Fish consumption increments are associated with increases in PON-1 activity and declines in cholesteryl ester transfer protein activity, HDL-C concentrations, and functions related to HDL (CEC). • Flavonoids such as anthocyanin positively change serum biomarkers related to HDL function in several patient populations, including dyslipidemia, hypertension, and diabetes, resulting in not only increased HDL cholesterol levels, but also HDL antioxidant and CEC.25 • HDL function may be improved by quercetin,26 glutathione,27 resveratrol,28 and phosphatidyl serine,29 though several of the studies are underpowered,and more functional data are needed.30
TRACK PATIENT PROGRESS
As HDL-C provides almost no information on HDL function, other measurements will be needed to help tract whether interventions are improving HDL function. Biomarkers of low-grade inflammation (e.g., hs-CRP) and oxidative stress (myeloperoxidase) give information on whether HDL particles are at risk of becoming dysfunctional. Advanced lipid panel (e.g., HDL-P) and HDL mapping help provide additional information on the health of HDL particles. When you complete an HDL map, you’ll find that some components may be in the red zone (not good), some in the yellow zone (borderline), or some in the green zone, which is great. Once you receive a patient’s results,
ANTI-AGING MEDICAL NEWS
• SUMMER 2020
Beyond HDL: New Insights into HDL Function in Cardiovascular Disease
you can institute or alter an existing supplement and lifestyle protocol to positively modify HDL and repeat testing in two to four months to track patient progress. Keeping a close watch and conducting follow-up tests is key and may require you to alter your recommendations as you see fit. Once a patient has achieved optimal levels of all three components, there should be
a reduction in the event rate for CHD and MI.
CONCLUSION: SUPPORT PATIENTS ON THE PATH TO HEART HEALTH The latest discoveries on the key parameters of HDL efficiency have led to promising new treatment methods for
better patient outcomes. Recognizing and measuring HDL type and size, function, and particle number are key factors in protecting patients from CHD and MIs. Through proper nutrition and lifestyle protocols, we can better protect our patient populations from the perils of heart-related health concerns.
BIO Mark Houston, MD, is a highly recognized cardiovascular and hypertension specialist, serving as a physician at St.Thomas West Hospital in Nashville, where he holds several leadership positions including Director of the Hypertension Institute and Vascular Biology, Medical Director of Clinical Research, and Section Chief for the Division of Nutrition. Sara Gottfried, MD, the President of Metagenics Institute,is a board-certified gynecologist and physician scientist.She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. SaraGottfried@metagenics.com
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Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006;58:342-74.
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Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-14.
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Sharrett AR, Ballantyne CM, Coady SA, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108-13.
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Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.
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Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
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Investigators A-H, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
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Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99.
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Group HTC, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.
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Ferri N, Corsini A, Sirtori CR, Ruscica M. Present therapeutic role of cholesteryl ester transfer protein inhibitors. Pharmacol Res 2018;128:29-41.
10. Walldius G, Jungner I. Apolipoprotein A-I versus HDL cholesterol in the prediction of risk for myocardial infarction and stroke. Curr Opin Cardiol 2007;22:359-67. 11. Qiu C, Zhao X, Zhou Q, Zhang Z. High-density lipoprotein cholesterol efflux capacity is inversely associated with cardiovascular risk: a systematic review and meta-analysis. Lipids in Health and Disease 2017;16:212. 12. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:572-80. 13. Vitali C, Khetarpal SA, Rader DJ. HDL Cholesterol Metabolism and the Risk of CHD: New Insights from Human Genetics. Curr Cardiol Rep 2017;19:132. 14. Favari E, Thomas MJ, Sorci-Thomas MG. High-Density Lipoprotein Functionality as a New Pharmacological Target on Cardiovascular Disease: Unifying Mechanism That Explains High-Density Lipoprotein Protection Toward the Progression of Atherosclerosis. J Cardiovasc Pharmacol 2018;71:325-31. 15. Macpherson ME, Halvorsen B, Yndestad A, et al. Impaired HDL Function Amplifies Systemic Inflammation in Common Variable Immunodeficiency. Sci Rep 2019;9:9427. 16. Kontush A. HDL particle number and size as predictors of cardiovascular disease. Front Pharmacol 2015;6:218.
17. Rock W, Rosenblat M, Miller-Lotan R, Levy AP, Elias M, Aviram M. Consumption of wonderful variety pomegranate juice and extract by diabetic patients increases paraoxonase 1 association with high-density lipoprotein and stimulates its catalytic activities. J Agric Food Chem 2008;56:8704-13. 18. Hamoud S, Hayek T, Volkova N, et al. Pomegranate extract (POMx) decreases the atherogenicity of serum and of human monocyte-derived macrophages (HMDM) in simvastatin-treated hypercholesterolemic patients: a double-blinded, placebo-controlled, randomized, prospective pilot study. Atherosclerosis 2014;232:204-10. 19. Morgan JM, de la Llera-Moya M, Capuzzi DM. Effects of niacin and Niaspan on HDL lipoprotein cellular SR-BI-mediated cholesterol efflux. J Clin Lipidol 2007;1:614-9. 20. Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol 2013;62:1909-10. 21. McEneny J, Wade L, Young IS, et al. Lycopene intervention reduces inflammation and improves HDL functionality in moderately overweight middle-aged individuals. J Nutr Biochem 2013;24:163-8. 22. Shidfar F, Froghifar N, Vafa M, et al. The effects of tomato consumption on serum glucose, apolipoprotein B, apolipoprotein A-I, homocysteine and blood pressure in type 2 diabetic patients. Int J Food Sci Nutr 2011;62:289-94. 23. Basu A, Sanchez K, Leyva MJ, et al. Green tea supplementation affects body weight, lipids, and lipid peroxidation in obese subjects with metabolic syndrome. J Am Coll Nutr 2010;29:31-40. 24. Hernaez A, Sanllorente A, Castaner O, et al. Increased Consumption of Virgin Olive Oil, Nuts, Legumes, Whole Grains, and Fish Promotes HDL Functions in Humans. Mol Nutr Food Res 2019;63:e1800847. 25. Millar CL, Duclos Q, Blesso CN. Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL Function. Adv Nutr 2017;8:226-39. 26. Ren K, Jiang T, Zhao GJ. Quercetin induces the selective uptake of HDL-cholesterol via promoting SR-BI expression and the activation of the PPARgamma/LXRalpha pathway. Food Funct 2018;9:624-35. 27. Rosenblat M, Volkova N, Khatib S, Mahmood S, Vaya J, Aviram M. Reduced glutathione increases quercetin stimulatory effects on HDL- or apoA1-mediated cholesterol efflux from J774A.1 macrophages. Free Radic Res 2014;48:1462-72. 28. Wang S, Moustaid-Moussa N, Chen L, et al. Novel insights of dietary polyphenols and obesity. J Nutr Biochem 2014;25:1-18. 29. Darabi M, Kontush A. Can phosphatidylserine enhance atheroprotective activities of high-density lipoprotein? Biochimie 2016;120:81-6. 30. Riccioni G, Gammone MA, Currenti W, D’Orazio N. Effectiveness and Safety of Dietetic Supplementation of a New Nutraceutical on Lipid Profile and Serum Inflammation Biomarkers in Hypercholesterolemic Patients. Molecules 2018;23.
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• SUMMER 2020
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Introducing
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Exhibitor Listings 74
AC Grace Company
ADigital Health Guide
PO Box 570
1016 Clare Ave., Suite 5
Big Sandy, TX, 75755 | US
West Palm Beach, FL, 34209 | US
Ph: (903) 636-4368
Ph: (561) 247-3839
Email: jhamilton@acgrace.com
Email: a4m@yourhealthmail.com
www.acgrace.com
www.a4m.com/digital-health-guide.html
Natural dietary supplement company with a main focus of Vitamin E.
Increase practice profitability and improve patient outcomes by managing patient care, education and support from virtually any location with our digital health guidance platform and app. Deliver protocol information for lifestyle modification, chronic illness, diet, exercise, mindfulness and more. Then track compliance, biometrics, activity, messaging, telemedicine and more in real time. All private labeled and customizable for your practice. Patients love it. And you will too. Manage patient care virtually anywhere with ADigital Health Guide.
AnazaoHealth
APS Belmar Pharmacy
5710 Hoover Blvd.
231 Violet Street, Suite 140
Tampa, FL, 33634 | US
Golden, CO, 80401 | US
Ph: (800) 995-4363 Ext.1520
Ph: (800) 525-9473
Email: emarketing@anazaohealth.com
Email: pharmacy@belmarpharmacy.com
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www.belmarpharmasolutions.com
AnazaoHealth is a full-service nationwide compounding pharmacy, with both a 503A Traditional Pharmacy and a 503B FDA-Registered Outsourcing Facility. We provide patientspecific and office-use preparations that are not commercially available for Aesthetics, Age Management, HRT, Men’s and Women’s Health, Urology, IV Therapy, Weight Management, PhytoTress® Hair Care Solutions and more.
Belmar Pharma Solutions - your single source for compounded medication, education, and consultation for anti-aging and integrative therapies. Belmar Pharma Solutions operates 503A and 503B pharmacies providing support and medications related to Hormone Therapy, Weight Management, Sexual Wellness, Thyroid, Adrenal and Immune Support, Dermatology, Brain Health and Nutritional Support. This year we welcome APS Pharmacy to our organization, providing physicians sterile and non-sterile medications. APS is 503A facility licensed in 49 states and Puerto Rico.
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Broad-Spectrum • Clinically-Effective
Arterosil - Calroy Health Science
ATCOR
Biocidin
14362 Frank Lloyd Wright, Suite 1000
515 Shuman Blvd., Ste. 515
PO Box 2499
Scottsdale, AZ, 85260 | US
Naperville, IL, 60563 | US
Aptos, CA, 95001 | US
Ph: (800) 609-6409
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The only product clinically proven to protect and restore the endothelial glycocalyx — for improved cardiovascular health and blood flow. Your blood vessels have a protective micro-thin gel lining called the endothelial glycocalyx which protects and regulates the entire endothelium and is therefore the foundation of vascular health. Arterosil supports normal endothelial function, promotes a healthy heart, and improves blood flow.
SphygmoCor XCEL from AtCor facilitates individualization of blood pressure management in both wellness and disease. SphygmoCor is used clinically for central BP waveform analysis to better inform blood pressure management via state-of-the-art brachial BP measurement and noninvasive derivation of the central aortic BP waveform, which in turn provides measures of central pressure, arterial stiffness, and estimated arterial age. Central pressure waveform analysis is reimbursable utilizing CPT code 93050. Coverage varies by state and by payer.
Biocidin® is the flagship brand from a BioBotanical Research®, Inc., the recognized leader in the field of Botanical Supplements. Biocidin® was founded in response to the needs of physicians addressing the microbiome and systemic health and wellness. Our powerful formulations are clinically tested and evidence-based and have been a favorite amongst recognized healthcare practitioners for overall GI and Gut Health for the past 30 years.
PHARMACY Biotics Research
Central Drugs
CRE8 Pharmacy Group
6801 Biotics Research Drive,
520 W. La Habra Blvd.
3700 NW 126th Ave.
Rosenberg, TX, 77471 | US
La Habra, CA, 90631 | US
Coral Springs, FL, 33065 | US
Ph: (800) 231-5777
Ph: (877) 447-7707
Ph: (754) 529-8353
Email: biotics@bioticsresearch.com
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Biotics Research Corporation was formed in 1975 and from day one the foundation has been “Innovation and Quality.” Our goals remain unchanged - innovative ideas, carefully researched concepts, and product development with advanced analytical and manufacturing techniques to develop and produce nutritional products of superior quality and effectiveness available exclusively to healthcare professionals.
Central Drugs is an industry leader in the art and science of custom compounding and individualized health-care solutions with a team of expert pharmacists at our state-of-the-art compounding laboratories. Our experience and innovative culture has helped over 800 doctors across the nation cultivate their Bio-Identical Hormone Therapy practice. We provide resources, education, and services to improve the overall health of your patients.
CRE8 Pharmacy offers compounding services for personalized medicine and patient-specific prescriptions. We are a team, working at creating formulations, dispensing orders reliably and resolving issues promptly. Specializing in Peptides, functional medicine and hormone replacement. Sterile & Non-Sterile compounds / Generic & Brand medications / Nutritional Supplementation with our own CRE8 Vitality Nutrition supplement line. Everything a patient needs is shipped in one simple order. Welcome to the future of compounding pharmacy.
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Crystal Clear Digital Marketing
Cyrex Laboratories, LLC
Designs for Health
5750 Major Blvd., Suite 500
2602 S. 24th Street
980 South Street
Orlando, FL, 32819 | US
Phoenix, AZ, 85034 | US
Suffield, CT, *06078 | US
Ph: (407) 793-9254
Ph: (657) 303-3898
Ph: (860) 623-6314
Email: aneff@crystalcleardm.com
Email: michelle.c@cyrexlabs.com
Email: jkopacka@designsforhealth.com
www.crystalcleardm.com
www.JoinCyrex.com
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Crystal Clear is the industry leader in providing world-class software, marketing and consulting solutions for the modern elective medical practice. Named “Top Aesthetic Service Provider” by Aesthetic Everything®, “Best Practice Marketing Company” by THE Aesthetic Guide, and Two-Time Inc. 500/5000 recognized company, Crystal Clear strives to help practices around the globe find, serve and keep more patients profitably through our proven solutions -- custom built for your practice-- for your needs.
Cyrex Laboratories is a clinical immunology laboratory specializing in environmentally-induced autoimmunity. Cyrex delivers next generation assessments for antigenic intestinal and bloodbrain barrier permeability – the gateways to autoimmunity; environmental trigger screening including dietary antigens, pathogens and xenobiotics; and multi-tissue antibody testing for predictive biomarkers of autoimmune reactivity. Through continuous collaboration with leading experts in medical research and clinical practice, Cyrex develops innovative arrays that assess the cross-connections between the body’s immune, gastrointestinal and neurological systems.
Since 1989, Designs for Health has been the health care professional’s trusted source for research-backed nutritional products of superior quality. By providing comprehensive support through our extensive product line, ongoing clinical education, and practice development programs, we are able to maximize the potential for successful health outcomes. Our wide array of added-value services not only set us apart, but indicate the depth of our commitment to you.
DoseLogix FUNCTIONAL TESTING EXPERTS
76
Doctor’s Data, Inc.
DoseLogix | Topi-CLICK
Emerson Ecologics
3755 Illinois Ave.
300 Parkebrook Place, Suite 140
1230 Elm Street, Suite 301
St. Charles, IL, 60174 | US
Woodstock, GA, 30189 | US
Manchester, NH, *03101 | US
Ph: (630) 377-8139
Ph: (877) 870-8448
Ph: (603) 724-4988
Email: info@doctorsdata.com
Email: info@DoseLogix.com
Email: cs@emersonecologics.com
www.doctorsdata.com
www.doselogix.com
www.emersonecologics.com
Doctor’s Data, Inc. has provided innovative specialty testing to healthcare practitioners around the world from our advanced, CLIAlicensed clinical laboratory since 1972. A specialist and pioneer in essential and toxic elemental testing, the laboratory provides a wide array of functional testing to aid in decision making and better patient outcomes. Choose DDI to help you assess and treat heavy metal burden, nutritional deficiencies, gastrointestinal function, hormone status, cardiovascular risk, liver and metabolic abnormalities, and more.
Topi-CLICK® by DoseLogix manufactures topical metered-dosing applicators that are accurate, innovative and easy-to-use; which is the focus of every product design including the NEW TopiCLICK Micro® and the Perl® Vaginal Dosing Method. Visit booth #222 for your FREE sample kit or request one at http://doselogix.com/ samples. We’ll also provide copies of the ARL Bio Pharma studies proving Topi-CLICK® is the most accurate topical dosing dispenser among those tested. Visit http://www.doselogix.com for product and ordering information.
With 40 years in the industry, and the largest selection of quality supplements and natural products, Emerson Ecologics is the trusted leader for integrative health practitioners. We’re your complete dispensary solution, providing inoffice or virtual dispensing through Wellevate, the only dispensary with a patient mobile app. We’re committed to providing the highest quality professional-grade supplements, clinical education resources, safe patient protocols, and innovative technological solutions to empower healthcare professionals to succeed in improving patient lives.
ANTI - AGING MEDICAL NEWS • SUMMER 2020
®
Virtual Solutions Genova Diagnostics
HNC Virtual Solutions
Integrative Peptides
63 Zillicoa St.
50430 Pontiac Trail
103 W. Main St.,
Asheville, NC, 28801 | US
Wixom, Michigan, 48393 | US
Hudson, MI, 49297 | US
Ph: (800) 522-4762
Ph: (248) 926-1661
Ph: (310) 955-6278
Email: info@gdx.net
Email: info@hnc-vs.com
Email: lori@integrativepeptides.com
www.gdx.net
www.hncvirtualsolutions.com
www.integrativepeptides.com
Genova Diagnostics is a leading clinical laboratory applying systems-based testing approaches to the diagnosis, treatment and prevention of complex chronic disease. Genova specializes in clinical laboratory services with actionable information.
HNC Virtual Solutions is a telehealth software solutions company that offers a complete system for health care professionals. VideoDoc® is our HIPAA and HITECH compliant telehealth platform that offers extensive video engagement options and utilizes our patented remote patient monitoring technology to capture, secure, and retrieve information on patient physiologies.
Integrative Peptides was born out of the idea that there had to be a better way for patients and their healthcare providers to gain access to safe peptide supplements. Physicians interested in peptides are currently limited to high priced options or risky, unvetted overseas or research only suppliers. Enter Integrative Peptides, founded in 2018 with one purpose: to offer over a peptide supplement that meets the highest standards of quality, safety, and value.
KBMO Diagnostics
Kimera Labs, Inc.
L-Nutra
4 Business Way
2810 N Commerce Pkwy
8000 Beverly Blvd.
Hopedale, MA, *01747 | US
Miramar, FL, 33025 | US
Los Angeles, CA, 90048 | US
Ph: (617) 933-8130
Ph: (224) 254-0956
Ph: (310) 775-3655
Email: klamont@kbmodiagnostics.com
Email: adamkoster@kimeralabs.com
Email: aperez@l-nutra.com
www.kbmodiagnostics.com
www.kimeralabs.com
KBMO Diagnostics is a fully integrated medical diagnostics company. Our FIT (Food Inflammation Test) is the only test that measures food sensitivities, inflammation and intestinal permeability combined. The patented test enables us to measure the IgG1-4 as well as complement activation via C3d and by combining these pathways, we eliminate the false positives associated with IgG only testing. We are releasing a FIT 176, a FAST Test, and a New Zonulin Assay later this year.
Kimera Labs Inc. is a biotechnology company that develops perinatal exosome products for research and therapeutic purposes. Since 2012, Kimera Labs has invested significant resources into exosome isolation and therapy protocols. As a regenerative medicine focused biotechnology company, Kimera Labs develops therapies that heal from within. By providing regenerative cellular signals under the control of messenger and miRNA, we believe it is possible to initiate the healing processes that can benefit patients of any age.
www.prolonpro.com/hcp-register/?register_ type=a4m
ANTI - AGING MEDICAL NEWS • SUMMER 2020
L-Nutra’s team of researchers and collaborators are leaders in the field of nutrition related to longevity and healthspan. L-Nutra develops nutritechnologies that mimic the effects of fasting, to enhance the body’s natural ability to rejuvenate itself and promote longevity. These technologies are the result of decades of lab research, proof of concept testing, and preclinical and clinical trials to demonstrate that they are safe and effective.
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INTRODUCING
POTASSIUM IODIDE The clean form of iodine for your thyroid.* This highly bioavailable Potassium Iodide can displace thyroid-bound iodine, thus allowing for the rapid renal elimination of undesirable forms of iodine and bromide stored in the body.*
KEY COMPONENTS: • 23 mg iodine • 7 mg potassium
protocolforlife.com • 877-776-8610 sales@protocolforlife.com Family Owned and Operated
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.
TM
TM
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LabCorp
Metagenics
Microbiome Labs
531 S. Spring Street
25 Enterprise, Ste. 200
101 E. Town Pl, Suite 210
Burlington, NC, 27215 | US
Aliso Viejo, CA, 92656 | US
Glenview, IL, 60025 | US
Ph: (888) 522-2677
Ph: (800) 692-9400
Ph: (904) 940-2208
Email: rotthoe@labcorp.com
Email: Info.customerservice@metagenics.com
Email: info@gomegaspore.com
www.labcorp.com
www.metagenics.com/
www.microbiomelabs.com
LabCorp is a leading global life sciences company that is deeply integrated in guiding patient care through its comprehensive clinical laboratory. The company provides diagnostic and technologyenabled solutions for more than 120 million patient encounters per year. Employing nearly 61,000 employees worldwide, the company’s mission is to improve health and improve lives by delivering world-class diagnostics, accelerating the availability of innovative medicines to patients, and using technology to change the way care is delivered.
Metagenics was founded on a revolutionary idea: Our genes do not predetermine our health potential, and through nutrition, we can impact how our genes express themselves. Embodied by our company motto—genetic potential through nutrition—this groundbreaking principle drives us to deliver high-quality, science-based nutritional supplements, medical foods, and lifestyle programs to support healthcare practitioners in their efforts to help patients achieve their health and wellness goals.
Microbiome Labs was originally established as Physicians Exclusive in 2013 as an organization focused on providing probiotic bacteriotherapy. Since then, Microbiome Labs has made it a goal to provide integrative solutions and clinical research data to address indications that stem from digestive and immune health issues.
Mito Q Ltd.
Mitochondrial Rescue
NuMedica
14 Viaduct Harbour, L2
11104 Green Bayberry Dr
9503 E. 55th Place
Auckland, AK, *01010 | NZ
Palm Beach Gardens, FL, 33418 | US
Tulsa, OK, 74145 | US
Ph: (760) 822-4833
Ph: (561) 767-0721
Ph: (800) 869-8100
Email: caprice@mitoq.com
Email: drraja@mitochondrialrescue.com
Email: jose.rivas@numedica.com
www.mitoq.com
www.mitochondrialrescue.com
www.numedica.com
MitoQ is a positively-charged antioxidant health brand, created with word-first, multipatented biotechnology in New Zealand. MitoQ supplements are manufactured by MitoQ Limited based in New Zealand. The company is dedicated to advancing the science of mitochondria-targeted antioxidant solutions, promoting mitochondrial health and helping people get the most out of their lives. The company’s world-first ingredient Mitoquinol, holds 39 global patents, has been the subject of over 400 peer-reviewed published papers and $60M in research funding.
Mitochondrial Rescue is an international organization supporting Practitioners utilizing revolutionary mitochondrial wearable technology and HRV-based complimentary online training coupled with proprietary neuropeptides to quantitatively improve patients’ voltage, mitochondrial oxygen levels, autonomic dysregulation and cellular communication in a telemedicine ecosystem. Mitochondrial Rescue understands that all chronic disease comes from having a lack of mitochondrial power that can be regenerated to improve outcomes with researchdriven peptide therapy. Backed by Research, Built for Resilience!
NuMedica® is a leading brand of clinical nutrition in the professional market. Our mission is to partner with healthcare professionals in helping patients achieve better health. Learn more at www.numedica.com.
ANTI - AGING MEDICAL NEWS • SUMMER 2020
Ortho Molecular Products
OxyHealth, LLC
PAINWeek
1991 Duncan Place
10719 Norwalk Blvd,
6 Erie Street
Woodstock, IL, 60098 | US
Santa Fe Springs, CA, 90670 | US
Montclair, NJ, 07042 | US
Ph: (815) 206-6586
Ph: (562) 906-8888
Ph: (973) 415-5100
Email: contactus@ompimail.com
Email: events@oxyhealth.com
Email: info@painweek.com
www.orthomolecularproducts.com
www.oxyhealth.com
www.painweek.org
For more than 30 years, Ortho Molecular Products has researched and manufactured highquality, efficacious nutraceuticals sold exclusively to thousands of health care professionals nationwide and in Canada. Ortho Molecular Products is headquartered in the Chicagoland area, with FDA-audited, cGMP-certified manufacturing facilities in Stevens Point, WI. Our commitment to efficacy, uncompromising manufacturing and legendary customer service establishes us as a leader in the nutrition industry.
OxyHealth has forever changed the way the medical industry practices hyperbaric therapy. Since our inception, we are devoted to providing quality and brilliantly safe portable hyperbaric chambers to physicians, professional athletes, wellness centers, and families. All OxyHealth chambers are designed for patients to easily self-treat, which has fostered a cutting-edge trend in hyperbaric technology.
PAINWeek is the preferred resource for frontline practitioners treating acute and chronic pain. For over a decade, we have demonstrated that “education is the best analgesic’’ by presenting over 12,000 hours of content across our national and regional conferences, conducting hundreds of Expert Opinion interviews, and publishing an array of faculty authored articles in our quarterly journal.
Power2Practice
Precision Analytical Inc.
Professional Health Products
2907 Butterfield Rd., Suite 100
3138 NE Rivergate, #301c
PO Box 97227
Oak Brook, IL, 60523 | US
McMinnville, OR, 97128 | US
Pittsburgh, PA, 15229 | US
Ph: (800) 590-7459
Ph: (503) 687-2050
Ph: (800) 245-1313
Email: sales@power2practice.com
Email: info@dutchtest.com
Email: support@phpltd.com
www.power2practice.com
www.dutchtest.com
www.phpltd.com
Power2Practice is specifically designed for functional and integrative medicine. With features such as customized note templates, cash-based billing module/superbills, specialty lab integrations, Fullscript interface, Power2Practice gives you all the EMR capabilities you expect, plus the specialized features you need. Our intuitive patient portal facilitates patient communication, online scheduling, appointment reminders and much more. Plus, with the addition of our newly released Televisit module, Power2Practice streamlines the efficiencies of the charting, front office and patient experience.
Precision Analytical Inc. is improving global wellness by providing important insight into hormones and their function. Their state-ofthe-art innovation in hormone testing uses the acronym DUTCH (Dried Urine Test for Comprehensive Hormones). Precision is now the world leader in hormone testing as their DUTCH™ test provides the most comprehensive look at hormones through simple collection and helps practitioners answer the most complex clinical questions. Lastly, DUTCH testing is built to optimize HRT monitoring.
Cutting corners when it comes to quality is a common practice in the supplement industry. PHP is committed to using the highest quality ingredients, backed by science, in our formulations since our beginning in 1978. Integrity and ingenuity goes into every product in our comprehensive line; making the partnership we have with clinicians above industry standard. From homeopathy to pristine ECO glandulars, we proudly offer a variety of products used by clinicians for various conditions.
Be it live, digital, or print, PAINWeek provides education and insight 365 days/year!
ANTI - AGING MEDICAL NEWS • SUMMER 2020
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82
Protocol For Life Balance
Quest Diagnostics - Cleveland HeartLab
Quicksilver Scientific
244 Knollwood Drive
500 Plaza Drive
1960 Cherry St
Bloomingdale, IL, 60108 | US
Secaucus, NJ, *07094 | US
Louisville, CO, 80027 | US
Ph: (877) 776-8610
Ph: (610) 334-3125
Ph: (303) 531-0861 Ext. 146
Email: sales@protocolforlife.com
Email: swati.x.doshi@questdiagnostics.com
Email: bree.rankin@quicksilverscientific.com
www.protocolforlife.com
www.questdiagnostics.com
www.quicksilverscientific.com
Protocol For Life Balance is a well-researched, potent, and efficacious brand of high-quality dietary supplements and natural products sold exclusively through licensed healthcare practitioners. Protocol For Life Balance offers many unique formulas and products, that come with a money -back guarantee if any patient is less than 100% satisfied. Our mission is simply to provide quality products that lead to healthy patients and satisfied physicians. Family Owned and Operated.
Quest Diagnostics and its Cleveland HeartLab Cardiometabolic Center of Excellence are committed to empowering people to take action to improve health outcomes. Through our menu of advanced cardiovascular tests, our diagnostic insights reveal new avenues to identify cardiovascular risk that go beyond cholesterol testing along. This insight allows more targeted treatment to help improve healthcare management and reduce risk over one’s lifetime. QuestDiagnostics.com.
Quicksilver Scientific® is a leading manufacturer of advanced nutritional systems with a focus on detoxification. We specialize in superior liposomal delivery systems and heavy metal testing to support optimal health. We are passionate about health and well-being and are committed to improving the lives of everyone we touch.
Riordan Technologies
T.A. Sciences
Tailor Made Compounding, LLC
11496 Luna Rd., Suite 800
420 Lexington Ave., Suite 2900
200 Moore Drive
Dallas, TX, 75234 | US
New York, NY, 10170 | US
Nicholasville, KY, 40356 | US
Ph: (972) 807-5916
Ph: (212) 588-8805
Ph: (859) 887-0013
Email: info@signaturebiologics.com
Email: eric@tasciences.com
Email: ataylor@tailormadehealth.com
www.neilriordan.com/about
www.tasciences.com
www.tailormadecompounding.com
Riordan Technologies represents a group of companies pioneered by Neil Riordan, PA, Ph.D.: Dallas-based Aidan Products, Signature Biologics, and Riordan Medical Institute, and Panama-based Stem Cell Institute and Medistem. Riordan Technologies’ network of companies have long been involved in innovative technological advances across multiple scientific fields. Riordan Technologies strives to improve the human condition through innovation in scientific research, regenerative medicine, and stem cell therapy.
T.A. Sciences® is dedicated exclusively to creating research-based, clinically tested wellness products that help address cellular aging through the science of Telomerase Activation. Built upon a foundation strongly grounded in scientific evidence, T.A. Sciences® is widely recognized as the leader in the field of Telomere Biology. T.A. Sciences® spends over $1 million each year on leading edge scientific research, including double-blind, placebocontrolled studies proving the safety and effectiveness of its premiere product, TA-65.
Tailor Made Compounding medications are designed to complement existing therapies but, more often, provide a more suitable alternative to standard prescription and over-the-counter medicines. We don’t believe in a ‘one size fits all’ approach to health. Our patients and physicians have unique needs and can rely on us for the highest quality, custom, compounding solutions. Specializing in peptides, hormone replacement therapy and IV formulations. Tailor Made Compounding, positively disrupting medicine using innovative technology.
ANTI - AGING MEDICAL NEWS • SUMMER 2020
Toolbox Genomics
University Compounding Pharmacy
Vital Nutrients
2950 Buskirk Ave., Ste.300
1875 3rd Ave.
45 Kenneth Dooley Drive
Walnut Creek, CA, 94597 | US
San Diego, CA, 92101 | US
Middletown, CT, *06457 | US
Ph: (415) 722-4393
Ph: (800) 985-8065 Ext. 5700
Ph: (860) 740-5543
Email: info@toolboxgenomics.com
Email: customersupport@ucprx.com
Email: ssedlock@vitalnutrients.net
www.toolboxgenomics.com
www.ucprx.com
Toolbox Genomics is revolutionizing precision medicine through actionable genetic insights. We offer a comprehensive, end-to-end DNA testing and reporting solution for practitioners. Using a simple buccal swab, practitioners are able to see Health Action Plans which focus on clinically relevant interpretation and application. Driven by Toolbox’s genetic risk score algorithm, recommendations for intervention cover 5 domains: Supplements, Diet, Exercise, Lifestyle and Further Testing. We focus on being the genomic experts so you don’t have to.
UNIVERSITY COMPOUNDING PHARMACY (UCP) a nationally recognized leader in drug and device therapies. For 28 years our expert Pharmacists and experienced Physician Liaison team have been dedicated to support an unbiased product line, devising the management of BHRT conditions for your patients. We meet FDA & BOP prescription requirements and dispense in nearly 50 states.
Vital Nutrients is dedicated to manufacturing high quality supplements that promote health, wellness and vitality. Our stringent standards and extensive laboratory analyses has led to our supplements being used and trusted by hospitals, healthcare practitioners and consumers worldwide. Nothing is more important than the quality of our supplements.
Wells Pharmacy Network
Your CBD Store
ZRT Laboratory
3420 Fairlane Farms Rd., Ste.300
411 19th Street South
8605 SW Creekside Pl
Wellington, FL, 33414 | US
St. Petersburg, FL, 33712 | US
Beaverton, OR, 97008 | US
Ph: (800) 622-4510
Ph: (813) 426-1708
Ph: (866) 600-1636
Email: info@wellsrx.com
Email: dseaman@cbdrx4u.com
Email: info@zrtlab.com
www.wellsrx.com
www.cbdrx4u.com
www.zrtlab.com
Wells Pharmacy Network is a privately held, nationwide, compounding pharmacy specializing in solutions for wellness and anti-aging medicine including: Bio-Identical Hormone Replacement Therapy, Peptide & Regenerative Therapies, Weight Management, Sexual Wellness, Aesthetic Dermatology and Thyroid & Adrenal Health. This includes operating a 20,000SF 503A pharmacy and a 21,000SF FDA Registered 503B Outsourcing Facility that produces bulk medication. Our mission is to elevate compounding industry standards through a unique combination of superior science and service.
Your CBD Store began with one woman, one story, and one store. Today, we have countless success stories and over 600 stores nationwide. We believe in providing the most transparent and dependable CBD products that utilize natural plant synergies. That’s why we have rigorous standards for quality and consistency and harvest only the highest-quality hemp products, grown in the U.S. We are dedicated to our community; earnestly providing contributions to our local and national partnerships.
ZRT laboratory, a CLIA-certified commercial and research laboratory, is the recognized leader in innovative and meaningful hormone and wellness testing. ZRT provides comprehensive test results that allow providers to create personalized treatments for optimal outcomes, with the help of our knowledgeable clinical consultants.
ANTI - AGING MEDICAL NEWS • SUMMER 2020
83
GI360™ Stool Profiles, multiplex PCR GI360.com | DoctorsData.com The GI360™ by Doctor’s Data is a powerful, evidence-based tool to profile the microbiome using PCR analysis. The novel, focused Dysbiosis Index included in the GI360™ was developed and validated in a clinical setting, utilizing research-based methodology to discern dysbiosis vs. normobiosis. This expanded view of clinically significant bacteria offers actionable data to the practitioner, particularly in combination with the complementary methodologies employed by Doctor's Data in the GI360™ profile.
Microbiome Diversity and Abundance; PCR Viruses, Pathogens, and Parasites; PCR Bacterial and Fungal Culturomics w/ Direct Susceptibilities; MALDI-TOF MS Expanded Parasitology; Microscopy Stool Chemistries Beta-Glucuronidase
SEPTEMBER
SEPTEMBER 11-13 Bio-Identical Replacement Therapy Symposium Module III: Neurology Module VII: Inflammaging and AutoImmunity
OCTOBER
9
OCTOBER 3 Business Power Summits
10 OCTOBER 17-18 IV Therapy Symposium
Module IV: Gastroenterology
DECEMBER
Pellet Therapy
12
DECEMBER 11-13 | LAS VEGAS 28th Annual World Congress Module I - Endocrinology Module V: Clinical Intensives Module XVI D: Advanced Cardio
