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A4M MMI - Anti-Aging Medical News - Fall 2018

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ANTI-AGING MEDICAL NEWS | FALL 2018


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FALL 2018 DIGITAL EDITION

ARTICLES Fasting: An Emerging Method For Weight Management By: Victoria Hahn, MS, RDN

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Supplementation with Specialized Proresolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series By Lewis Chang, PhD. Metagenics Institute

Ta-65 Improves Cardiovascular Markers In Subjects With Metabolic Syndrome: A Double-Blind, Placebo-Controlled, Randomized Crossover Study

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Prof. Maria Luz Fernandez, Ph.D.

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How Early Screening By Physicians Is Foundational to Addressing CVD Prevention Initiatives and Restoration Treatments By Mitchell J. Ghen, D.O., Ph.D.

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Fasting:

An Emerging Method For Weight Management By: Victoria Hahn, MS, RDN Bio: Victoria is a Registered Dietitian and Nutrition Science Liaison with a Master of Science in Nutrition, Healthspan, and Longevity from the University of Southern California. She also functions as an inpatient clinical dietitian and has a background in nutrition research covering a wide range of topics including nutritional sufficiency in specific populations and the ketogenic diet. She has a passion for research and evidence-based practice.

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.

ABSTRACT: Fasting has been shown to be a topic of

of the body to downregulate the nutrient-sensing pathways

with consumers. As this science becomes commercialized,

results in stress resistance.3,6-8 Perhaps the most well-

growing interest not only within the scientific field, but also we must sort out the evidence from the fiction to support

categorized nutrient sensing pathways are the mechanistic

Fasting can be broken up into three types: time restricted

1 (IGF-1), and protein kinase A (PKA). It has been

the claims that surround fasting as a strategy for weight loss. eating (TRE), intermittent fasting (IF), and prolonged or periodic fasting (PF). Each type of fasting appears to impact weight loss, but evidence suggests that PF is the optimal method for this. Ultimately, more evidence is needed to

support fasting as a medical intervention with validated

protocols to ensure that the fasts are done in a safe manner.

Fasting is an ancient practice that has its roots in religious

practices, and appears to be present universally among

all cultures.1 The definition of fasting is “to abstain from food.”2 It has been cited that fasting is now being used as a medical intervention in many clinics for disease prevention and weight management.

3,4

More so, there has been a

rise in the interest of fasting over the last few years and

increase in consumer interest that has followed.5 With all

this new information, it

target of rapamycin (mTOR), insulin-like growth factor

established that key regulators of these nutrient sensing

pathways include glucose, amino acids, and the energy status within the cell.6

There are several distinct methods of fasting, including

time restricted eating (TRE), intermittent fasting (IF), and

prolonged or periodic fasting (PF) (See Table 1). These

Introduction

categories are separated by a difference in duration of

fasting, as well as the physiological impact of each type. Due to these differences, it has been hypothesized that there is an optimal amount of time during which the body needs to be in the fasting mode in order to induce a more pronounced physiological impact.3,8 This brief review of fasting will try

to tease out the rationale to support each type of fast in the clinical setting as it pertains to weight loss.

Table 1: Types of Fasting

can be difficult for the

Type of Fast

Definition

Example

based information on this

Time Restricted Eating

A daily pattern of eating, usually conducted between 10-12h. The rest of the day would be non-eating hours, or fasting.

8-h Diet (8 hours of eating, with the remaining 16h of the day fasting)

Intermittent Fasting

A pattern of eating little to no calorie intake conducted 2 to 3 times per week.

5:2 Diet (5 days of normal nutrition intake with 2 days of no calorie or low calorie intake per week)

Periodic or Prolonged Fasting

A pattern of eating little to no calorie intake conducted for 4 or more consecutive days.

5 day fasting mimicking diet

clinician to find evidence-

emerging topic, especially given the inherent risk of

over-fasting, or inducing starvation. One of the main benefits of fasting

rests in the natural ability

6

(6) which can in turn stimulate a protective response that

ANTI-AGING MEDICAL NEWS | FALL 2018


Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series

Time Restricted Eating

Intermittent fasting (IF) goes by many definitions in the

rhythms; these are daily cycles of ~24 h that control a multitude

restriction) to no calorie intake conducted 2-3 times per week;

Time restricted eating (TRE) gains its roots from circadian of physiological and behavioral processes including, but not limited to, energy metabolism, gastrointestinal motility, and

sleep-wake cycles.9 TRE has been defined as a daily eating

pattern that is conducted over the span of usually ≤12h in which

all nutrition is consumed within this timeframe; there is no

regard to the composition of nutrition, rather, the focus is when food is consumed. The mechanism by which the circadian 10

rhythm is regulated is complex.

10-12

Briefly, the circadian rhythm

is sustained by an organ specific process that is cell-autonomous, albeit the master oscillator is the suprachiasmatic nucleus (SCN) feedback loop in which specific transcription activators help to

literature, but will be defined as very little (~25% energy

the majority of studies discussed in this section represent the

2-day non-contiguous restriction and 5-day feasting model.

With IF, the upregulation of autophagy, stress resistance, and antioxidant activity, as well as extension of lifespan while

decreasing cellular proliferation, have all been observed.3,24 Note that because of the reduction in the duration of fasting with

IF, the fasting effects are less pronounced when compared to a

PF.3 Somewhat surprisingly, it has also been found that IF may

not impact lifespan at all, so more evidence with a standardized process is needed to support or refute these findings.25

increase the production of the CRY and PER protein levels.10,12

IF has become more prevalent over the years as an alternative

CRY and PER, interact with the nutrient sensing pathways,

inconclusive and occasionally contradictory to popular belief.26-28

The reason this is important is because both of these proteins, including TOR and AKT, as well as other pathways that are upregulated during fasting, such as AMPK and SIRT1.

13-17

There is now evidence to support the postulation that TRE

to caloric restriction; however, clinical trial results have been

In a 1-year trial, 112 subjects who had a BMI between 30-45 kg/ m2 followed a meal pattern where they were to restrict calories to 400/600 kcal (female/male) for two non-consecutive days per

week.29 After 1 year, the IF group had similar weight loss (8.0 kg

within a period of 8-12h without nutrient fluctuation may be

in the IF group versus 9.0 kg, p = 0.6) and improvements in

serve as a novel therapy for treating obesity as well as metabolic

calorie restricted group. In a separate study, 107 premenopausal

utilized to help re-establish these diurnal patterns and potentially diseases.

18-20

Human data are sparse in this emerging field. In

a 16-week feasibility trial, eight overweight individuals were instructed to consume their entire daily caloric intake over the

their cardiovascular risk factors in comparison to the continuous

women with a BMI between 24-40 kg/m2 followed 2 days of

25% kcal restriction and 5 days of normal intake each week over 6 months.30 After 6 months, the women in the IF group

span of a self-selected 10-12h period to determine if this would

had comparable weight loss, which was on average 6.4 kg in

were not only able to reduce their eating duration, but also lost

fat reduction and cardiovascular risk marker reduction were

lead to a reduction in body weight. They found that all subjects 21

weight (average of 3.27 kg). Although the reduction in eating

time also induced a decrease in estimated caloric intake, which

may have contributed to the weight loss observed, there is new evidence to show that the benefits of TRE may be independent of weight loss in a specific population.

22

It is also worth noting

that different physiologies may require a different period of TRE, as seen with the obese population potentially benefitting

from an 8h TRE period for weight loss. Although TRE has 23

proven to be beneficial in a multitude of areas, more research is

needed within this area to determine TRE’s overall effectiveness as a weight loss strategy.

Intermittent Fasting

the IF group compared to 5.6 kg (p= 0.4). Comparable body

also observed between the groups, but greater declines in fasting serum insulin and improvements in insulin sensitivity in

comparison to the continuous calorie restricted group. There is

evidence to show that the weight loss observed in these studies

may be contingent on the spontaneous reduction of caloric intake on non-IF days, so it may be an overall behavior change that is enabling the potential weight loss to occur rather than the effects of fasting.31

Periodic Fasting

Periodic fasting (PF) can be described as an extension in

duration and sequence of IF in that it is greater than 2-3 days, as well as consecutive days. PF can be categorized as consecutive days of fasting for 4 or more days. The mechanism of PF is a ANTI-AGING MEDICAL NEWS | FALL 2018

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Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series

prolongation of IF because the fast is conducted for a longer period of time, enabling a more pronounced metabolic switch to occur which in turn causes glycogen reserve depletion to enable fat and ketone body catabolism.3 With this longer period of time (72h) in the fasting mode, it has been observed to promote a greater upregulation in the stress response gene HO-1 and antioxidant enzymes SOD2, Gpx1, and GSR.32,33 Moreover, there is evidence to show that a 72h fast in mice decreases key regulators of the nutrient sensing pathways, such as IGF-1 and glucose.34 As eluded to, there appears to be an ideal duration of time to be spent in the fasting mode in order to achieve the benefits of autophagy and multi-system regeneration.35 Due to the difficulty of PF and inherent risk of adverse events, a novel modality that mimics fasting with a diet has been elucidated.35

The diet is a five-day regimen low protein, moderately low carbohydrate, and moderately high fat diet that is also moderately restricted in calories. This diet that mimics PF was found to decrease IGF-1, reduce visceral fat mass, extend median lifespan, promote neurogenesis, enable hepatic regeneration, and increase hematopoietic and mesenchymal stem and progenitor cells in mice.35 Within this same article, a pilot clinical trial of 19 healthy individuals utilizing this 5-day PF mimicking diet found that after three consecutive cycles done once a month, participants lost an average of 3% of body weight and had no lean body mass loss. Additionally, anti-inflammatory effects, such as C-reactive protein reduction, were observed. The pilot trial was replicated in a larger clinical trial with 71 additional healthy individuals who experienced a reduction in body weight (2.6 kg on average), total body fat, trunk fat, waist circumference, IGF-1, and blood pressure without any lean body mass loss.36 Moreover, the effects on body weight, waist circumference, IGF-1, and blood pressure appeared to persist even 3.2 months after having discontinued the protocol.

Conclusion - Where do we go next?

8

Fasting is a wide-ranging topic that spans from a religious practice to an emerging medical therapy. Novel interventions in order to induce fasting have also been elucidated, as well as a variety of eating patterns that enable the body to fast, but for a brief period of time. Although each type of fasting may yield unique findings, there are similarities. For instance, while all types of fasting appear to yield some amount of weight loss, it appears the weight loss for TRE may be attributable to overall decreased caloric intake, and the weight loss attributed

to IF may be comparable to continuous caloric restriction. On the other hand, PF appears to induce a significant amount of weight loss due to the sustained physiological changes of fasting for consecutive days, which may be the root etiology of the effectiveness of the weight lost. We are now starting to obtain evidence that certain types of fasting, particularly PF regimens or regimens that mimic PF, may be the most advantageous for not only weight loss, but also for receiving the most benefits of any type of fast. However, if any of these therapies are to be initiated in clinic for any indication other than maintaining general wellness, it would be of the utmost importance for trained clinicians to guide their patients through their fasting regimens, no matter the type initiated. While early indications are encouraging, more evidence will be needed to further support or refute PF as an ideal strategy, as well as if there are ideal ways to implement IF and TRE for weight loss. Disclosures: The author is affiliated with L-Nutra, Inc.

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2. Fast. Merriam-Webster. https://www.merriam-webster.com/dictionary/ fast. Accessed August 9, 2018. 3. Longo VD, Mattson MP. Fasting: Molecular Mechanisms and Clinical Applications. Cell metabolism. 2014;19(2):181-192. doi:10.1016/j. cmet.2013.12.008.

4. Gustafson C. Alan Goldhamer, dc: Water Fasting—The Clinical Effectiveness of Rebooting Your Body. Integrative Medicine: A Clinician’s Journal. 2014;13(3):52-57. 5. 2018 Food and Health Survey. International Food Information Council Foundation. https://www.foodinsight.org/2018-FHS-Report-FINAL. pdf Updated May 16 2018. Accessed August 9, 2018. 6. Fontana L, Partridge L, Longo VD. Dietary Restriction, Growth Factors and Aging: from yeast to humans. Science (New York, NY). 2010;328(5976):321-326. doi:10.1126/science.1172539.

7. Di Biase S, Shim HS, Kim KH, et al. Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. Locasale J, ed. PLoS Biology. 2017;15(3):e2001951. doi:10.1371/journal.pbio.2001951. 8. Cheng C-W, Adams GB, Perin L, et al. Prolonged Fasting reduces IGF-1/PKA to promote hematopoietic stem cell-based regeneration and reverse immunosuppression. Cell stem cell. 2014;14(6):810-823. doi:10.1016/j.stem.2014.04.014.

9. Froy O. Circadian rhythms, aging, and life span in mammals. Physiology (Bethesda). 2011 Aug;26(4):225-35. doi: 10.1152/physiol.00012.2011. 10. Longo VD, Panda S. Fasting, circadian rhythms, and time restricted feeding in healthy lifespan. Cell metabolism. 2016;23(6):1048-1059. doi:10.1016/j.cmet.2016.06.001. 11. Reddy AB, O’Neill JS. Healthy clocks, healthy body, healthy mind. Trends in Cell Biology. 2010;20(1):36-44. doi:10.1016/j.

ANTI-AGING MEDICAL NEWS | FALL 2018


Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series

tcb.2009.10.005.

12. Hardin PE, Panda S. Circadian timekeeping and output mechanisms in animals. Current opinion in neurobiology. 2013;23(5):724-731. doi:10.1016/j.conb.2013.02.018. 13. Zheng X, Sehgal A. AKT and TOR Signaling Set the Pace of the Circadian Pacemaker. Current biology : CB. 2010;20(13):1203-1208. doi:10.1016/j.cub.2010.05.027. 14. Lamia KA, Sachdeva UM, DiTacchio L, et al. AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation. Science (New York, NY). 2009;326(5951):437-440. doi:10.1126/science.1172156.

15. Asher G, Gatfield D, Stratmann M, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell. 2008 Jul 25;134(2):317-28. doi: 10.1016/j.cell.2008.06.050. 16. Nakahata Y, Kaluzova M, Grimaldi B, et al. The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control. Cell. 2008;134(2):329-340. doi:10.1016/j.cell.2008.07.002.

17. Nakahata Y, Sahar S, Astarita G, et al. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science. 2009 May 1;324(5927):6547. doi: 10.1126/science.1170803. Epub 2009 Mar 12. 18. Chaix A, Zarrinpar A, Miu P, Panda S. Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Cell metabolism. 2014;20(6):991-1005. doi:10.1016/j. cmet.2014.11.001.

19. Hatori M, Vollmers C, Zarrinpar A, et al. Time restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high fat diet. Cell metabolism. 2012;15(6):848-860. doi:10.1016/j. cmet.2012.04.019. 20. Melkani GC, Panda S. Time‐restricted feeding for prevention and treatment of cardiometabolic disorders. The Journal of Physiology. 2017;595(12):3691-3700. doi:10.1113/JP273094.

21. Gill S, Panda S. A smartphone app reveals erratic diurnal eating patterns in humans that can be modulated for health benefits. Cell metabolism. 2015;22(5):789-798. doi:10.1016/j.cmet.2015.09.005.

22. Sutton EF, Beyl R, Early KS, et al. Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metab. 2018 Jun 5;27(6):1212-1221.e3. doi: 10.1016/j.cmet.2018.04.010. Epub 2018 May 10.

Canadian Medical Association Journal. 2013;185(9):E363-E364. doi:10.1503/cmaj.109-4451.

28. Anton SD, Moehl K, Donahoo WT, et al. Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting. Obesity (Silver Spring, Md). 2018;26(2):254-268. doi:10.1002/oby.22065. 29. Sundfør TM, Svendsen M, Tonstad S. Effect of intermittent versus continuous energy restriction on weight loss, maintenance and cardiometabolic risk: A randomized 1-year trial. Nutr Metab Cardiovasc Dis. 2018 Jul;28(7):698-706. doi: 10.1016/j.numecd.2018.03.009. Epub 2018 Mar 29.

30. Harvie MN, Pegington M, Mattson MP, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomised trial in young overweight women. International journal of obesity (2005). 2011;35(5):714-727. doi:10.1038/ijo.2010.171. 31. Harvey J, Howell A, Morris J, Harvie M. Intermittent energy restriction for weight loss: Spontaneous reduction of energy intake on unrestricted days. Food Science & Nutrition. 2018;6(3):674-680. doi:10.1002/fsn3.586. 32. Lee C, Safdie FM, Raffaghello L, et al. Reduced IGF-I differentially protects normal and cancer cells and improves chemotherapeutic index in mice. Cancer research. 2010;70(4):1564-1572. doi:10.1158/0008-5472. CAN-09-3228. 33. Verweij M, van Ginhoven TM, Mitchell JR, Sluiter W, van den Engel S, Roest HP, Torabi E, Ijzermans JN, Hoeijmakers JH, de Bruin RW. Preoperative fasting protects mice against hepatic ischemia/reperfusion injury: mechanisms and effects on liver regeneration. Liver Transpl. 2011 Jun;17(6):695-704. doi: 10.1002/lt.22243. 34. Parrella E, Longo VD. Insulin/IGF-I and Related Signaling Pathways Regulate Aging in Nondividing Cells: from Yeast to the Mammalian Brain. The Scientific World Journal. 2010;10:161-177. doi:10.1100/ tsw.2010.8.

35. Brandhorst S, Choi IY, Wei M, et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance and healthspan. Cell metabolism. 2015;22(1):86-99. doi:10.1016/j. cmet.2015.05.012. 36. Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017 Feb 15;9(377). pii: eaai8700. doi: 10.1126/ scitranslmed.aai8700.

23. Gabel K, Hoddy KK, Haggerty N, et al. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: A pilot study. Nutrition and Healthy Aging. 2018;4(4):345-353. doi:10.3233/NHA-170036. 24. Harvie MN, Howell T. Could Intermittent Energy Restriction and Intermittent Fasting Reduce Rates of Cancer in Obese, Overweight, and Normal-Weight Subjects? A Summary of Evidence. Advances in Nutrition. 2016;7(4):690-705. doi:10.3945/an.115.011767.

25. Goodrick CL, Ingram DK, Reynolds MA, Freeman JR, Cider N. Effects of intermittent feeding upon body weight and lifespan in inbred mice: interaction of genotype and age. Mech Ageing Dev. 1990 Jul;55(1):69-87. 26. Anton S, Leeuwenburgh C. Fasting or caloric restriction for Healthy Aging. Experimental gerontology. 2013;48(10):1003-1005. doi:10.1016/j. exger.2013.04.011. 27. Collier R. Intermittent fasting: the science of going without. CMAJ :

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Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series By Lewis Chang, PhD. Metagenics Institute 9770 44th Ave. NW, Ste 100, Gig Harbor, WA 98332

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.

BACKGROUND The inflammatory response has an initiation phase and a resolution phase. Ideally, inflammation is a self-limited process, leading to complete resolution that enables tissue healing and a return to previous normal condition.1 However, if the inflammatory response is left unresolved, the surrounding tissues can be negatively impacted over time. Many chronic diseases such as arthritis, diabetes, metabolic syndrome, inflammatory bowel disease, periodontal disease, asthma, age-related macular degeneration, and some neurological disorders have been linked to chronic inflammation.2-7 During the resolution phase, specialized pro-resolving mediators are produced at the affected tissue site, orchestrating the resolution-related activities and facilitating the return to homeostasis.8 18-hydroxyeicosapentaenoic acid (18-HEPE) and 17-hydroxydocosahexaenoic acid (17-HDHA) are two important specialized proresolving mediators derived from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, via enzymatic pathways.1 18-HEPE and 17-HDHA are rapidly taken up by the activated immune cells and converted into other specialized proresolving mediators including resolvins, protectins and maresins.9 Each specialized pro-resolving mediator plays a distinct role in resolving inflammation, and through their combined actions the return to homeostasis is achieved.1 Some individuals may not produce desirable levels of specialized pro-resolving mediators—due to lifestyle behaviors, dietary choices, age, or health status—in response to an immune challenge. As a result, the resolution of their inflammation can be impacted.8,10 Since specialized pro-resolving mediators are essential for the resolution, supplementation of specialized pro-resolving mediators may represent a nutritional approach to support the resolution of inflammation.8

18

Objective The objective of this study was to observe the effect of a supplement containing fractionated lipid concentrate standardized to 18-HEPE and 17-HDHA (LM-O3; Table 1) on select circulating inflammatory biomarkers and on overall well-being assessed by multiple questionnaires in a group of volunteers recruited from 6 clinic sites. METHODS/DESIGN Participants Participants were recruited from the patient base at the study clinics. Eligible participants were adults ages 21-75 y/o with chronic inflammatory conditions [e.g., arthritis or other joint-related conditions, fibromyalgia, chronic pain lasting 3 months or longer, BMI > 30 kg/m2 with high-sensitivity C-reactive protein (hs-CRP) > 4 mg/L]. The study was conducted in compliance with the Helsinki Declaration of 1975, and was approved by the Western Independent Review Board (Seattle, WA). Informed written consent was obtained from all participants prior to enrollment. Study design This 8-week, open-label, case observation study was conducted at 6 clinic sites in the U.S. including 4 MDs, 1 DO and 1 ND. After baseline assessment (Visit 1), participants began to consume 6 softgels once daily of the LM-O3 supplement taken together, and were instructed to consume with a lipid-containing meal. After Week 4 assessment (Visit 2), participants began to consume 8 softgels once daily of the LM-O3 supplement (Table 1). The effect of this increased dose was evaluated at Week 8 (Visit 3). Participants returned to the clinic at Week 4 (Visit 2) and Week 8 (Visit 3) for clinical evaluation and assessment for compliance and adverse events.

ANTI-AGING MEDICAL NEWS | FALL 2018


Supplementation with Specialized Pro-resolving Mediators Reduces Inammatory Biomarkers in Subjects with Chronic Inammatory Conditions: a Multi-Clinic Open-Case Series

Table 1. Nutritional profile summary of the supplement LM-O3 6 softgels

8 softgels

Energy (kcal)

15

20

Total fat (g)

1.5

2.0

1500

2000

Active portion of fractionated marine lipid concentrate (mg)â€

Specialized pro-resolving mediators content standardized to 18-HEPE and 17-HDHA

â€

Laboratory analysis Fasting blood samples obtained at each clinic visit were analyzed within the typical diagnostic laboratories at each study site for biochemical markers including hs-CRP, PGE2, erythrocyte sedimentation rate (ESR), fibrinogen, B-type natriuretic peptide (BNP), serum ferritin, and the pro-inflammatory cytokines tumor necrosis factor alpha (TNF- ), and interleukin-6 (IL-6). Statistical analyses Data collected from all 6 sites were analyzed as one cohort.Those who completed all 8 weeks were included in the final analyses. Changes from baseline to 4 weeks and 8 weeks were analyzed separately using two-sided paired t-test. Missing values were not imputed for these analyses. Data are reported as mean Âą SD. A value of p<0.05 was considered statistically significant. Spearman correlation coefficient was used to explore relationships between variables.

Concentration of hs-CRP was reduced from 9.2 ¹15.8 mg/L at baseline to 5.2 ¹ 9.5 mg/L at 4 weeks (43% reduction; p=0.031) and to 6.3 ¹ 10.6 mg/L at 8 weeks (32% reduction; p=0.007). The difference between 4 and 8 weeks was not statistically significant (Table 2). Concentrations of PGE2—a lipid molecule active during inflammation initiation and a driver of pain, edema and fever—were also elevated in this cohort at baseline. PGE2 concentrations showed a trend toward decrease from 590.6 ¹ 802.0 pg/mL at baseline to 486.5 ¹ 400.4 pg/mL at 4 weeks (p=0.30), and was significantly reduced to 350.6 ¹ 334.3 pg/mL at 8 weeks compared with baseline (p=0.039). By 8 weeks, the group average was within the normal range of 200-400 pg/mL (Table 2). Table 2. Inflammatory markers from baseline to 8 weeks among participants who completed the 8-week study Biomarker hs-CRP (mg/L) PGE2 (pg/mL) Fibrinogen (mg/dL)

Level

p value

Reference range

Baseline: 9.2 Âą 15.8 4 weeks: 5.2 Âą 9.5

0.031*

8 weeks: 6.3 Âą 10.6

0.007*

0-3

Baseline: 590.6 Âą 802.0 4 weeks: 486.5 Âą 400.4

0.30

8 weeks: 350.6 Âą 334.3

0.039*

200-400

Baseline: 343.9 Âą 93.3 4 weeks: 324.6 Âą 114.0

0.11

8 weeks: 315.0 Âą 74.2

0.007*

193-504

RESULTS Fifty-two participants (all Caucasian) were enrolled from the 6 study clinics and 34 (28 women and 6 men) completed the study. Reasons for dropout included requirement to start study-prohibited medications, unability to attend clinic within specified study time-frame, participant preference to reduce overall medications/ supplements taken, participant preference not to have further blood draws, unanticipated effects of the study product (including asthma symptoms and gastrointestinal disturbances).

*Statistically significant from baseline as assessed by paired t-tests between time points.

The average age of those who completed the study was 49.3 ¹ 10.8 years old, and their BMI was 29.4 ¹ 8.2 kg/m2. Among the 34 participants, 14 subjects had arthritis (rheumatoid arthritis or osteoarthritis), 6 subjects had fibromyalgia, and 15 subjects had chronic pain (including 1 subject who had both chronic pain and fibromyalgia). Additionally, most subjects experienced other co-morbidities, including insomnia, reflux, fatigue, constipation, hypothyroidism, metabolic syndrome, hyperlipidemia, hypertension, migraine, Sjogren’s syndrome, Hashimoto’s, and Lyme disease.

Total scores on the Brief Pain Inventory (BPI)—a tool used to assess the severity of pain and the impact of pain on daily functions in patients with pain from chronic diseases or conditions such osteoarthritis and low back pain, or with pain from acute conditions11—were significantly reduced at 4 and 8 weeks compared with baseline (Figure 1). No statistically significant difference was seen between 4 and 8 weeks. The reduction in scores was related to the baseline score (baseline and 4-week change; rho = -0.644, p<0.001), (baseline and 8-week

Other biomarkers reflective of acute phase response and ongoing inflammation (ESR, ferritin, BNP, IL-6, TNF- ) were within normal limits at baseline and did not significantly change throughout the study period. Functional symptoms of inflammation and pain were improved at 4 and 8 weeks

change; rho = -0.706, p<0.001).

Clinical biomarkers of inflammation were significantly reduced at 4 and 8 weeks

ANTI-AGING MEDICAL NEWS | FALL 2018

19


Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series

Figure 1: BPI total scores from baseline to 8 weeks

*Statistically significant from baseline (p<0.001)

Improvements in health domains reflective of subject clinical condition Health Symptoms Questionnaire (HSQ12) total scores were reduced from 56.4 ± 38.2 at baseline to 33.5 ± 20.1 at 4 weeks (p<0.001) and to 30.5 ± 20.0 at 8 weeks (p<0.001; Figure 2). The difference between 4 and 8 weeks was not significant. Individual MSQ domains—including joints/muscle subscale— reflective of the overall patient population clinical diagnoses were improved. Figure 2: HSQ total scores from baseline to 8 weeks *statistically significant from baseline (p<0.001)

Table 3. SF-12 and ACPA QOL questionnaires from baseline to 8 weeks Questionnaire

Score

p (vs. baseline)

SF-12

Baseline: 34.0 ± 3.2 4 weeks: 34.6 ± 2.7

0.29

8 weeks: 33.6 ± 3.4

0.56

ACPA QOL

Baseline: 7.8 ± 2.0

Scale

4 weeks: 8.8 ± 1.3

0.025

8 weeks: 8.5 ± 1.4

0.042

Adverse events The recorded adverse events included gastrointestinal disturbances, exacerbation of asthma symptoms, occasional fishy burps, and constipation (Table 4). However, none were considered serious adverse events. Table 4. Frequency of reported adverse events at 4 weeks and 8 weeks Event

4 weeks

8 weeks

(6 softgels)

(8 softgels)

3

3

0

2

Fishy burps

0

1

Constipation

1

0

Loose stools, nausea or abdominal discomfort Asthma symptoms exacerbation

Significant improvements reported in health-related quality of life across the study SF-12 was not significantly different and reported overall good quality of life in the participants; however, more clinically focused instruments such as the American Chronic Pain Association Quality of Life Scale (ACPA QOL) highlighted improvements in quality of life linked with specific clinical improvements in this patient group, which included subjects with chronic pain or clinical conditions related to inflammation and chronic pain (Table 3).

20

SUMMARY This 8-week, multi-center, open-case series demonstrated that LM-O3, a specialized pro-resolving mediator supplement containing fractionated lipid concentrate standardized to 18HEPE and 17-HDHA, exerted beneficial effects on biomarkers of inflammation (e.g., hs-CRP and PGE2) in subjects with health conditions associated with chronic unresolved inflammation. Functional symptoms associated with inflammation, as assessed by various health status questionnaires and quality of life questionnaires, were also improved after consumption of LM-O3. Not unexpectedly, results from questionnaires that assessed the severity of pain and the impact of pain on daily functions indicated the potential benefits of LM-O3 in the resolution of pain. Pain is one of the cardinal signs of inflammation, and PGE2 is the best known eicosanoid that causes inflammatory pain.13 In this study, the reduction in PGE2 levels after LM-O3 supplementation may have contributed to the improvement in pain. Mechanistically, specialized pro-resolving mediators decrease production of pro-inflammatory mediators and thus may help reduce swelling and pain.14 14

ANTI-AGING MEDICAL NEWS | FALL 2018


Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series

This open-label case series suggests that supplementation of specialized pro-resolving mediators can positively impact inflammatory markers and subject quality of life measurements in humans. Future placebo-controlled randomized study with a larger sample size will be needed to address the limitations inherent in this observational study design.

Related Substances in the Resolution of Pain. BioMed Research International. 2015;2015:14.

About the Author Dr. Chang received his PhD in Nutritional Sciences from University of Washington.

REFERENCES: 1. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. Jun 5 2014;510(7503):92-101. 2. Nathan C, Ding A. Nonresolving inflammation. Cell. Mar 19 2010;140(6):871-882.

3. Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. Jan 11 2013;339(6116):166172. 4. Libby P. Atherosclerosis: the new view. Scientific American. May 2002;286(5):46-55.

5. Mushtaq G, Khan JA, Kumosani TA, Kamal MA. Alzheimer’s disease and type 2 diabetes via chronic inflammatory mechanisms. Saudi Journal of Biological Sciences. Jan 2015;22(1):4-13. 6. Fuentes E, Fuentes F, Vilahur G, Badimon L, Palomo I. Mechanisms of chronic state of inflammation as mediators that link obese adipose tissue and metabolic syndrome. Mediators of Inflammation. 2013;2013:136584.

7. Parmeggiani F, Romano MR, Costagliola C, et al. Mechanism of inflammation in age-related macular degeneration. Mediators of Inflammation. 2012;2012:546786.

8. Spite M, Claria J, Serhan CN. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metabolism. Jan 7 2014;19(1):21-36.

9. Recchiuti A. Immunoresolving Lipid Mediators and Resolution of Inflammation in Aging. J Gerontol Geriat Res. 2014;3:151. 10. laria J, Nguyen BT, Madenci AL, Ozaki CK, Serhan CN. Diversity of lipid mediators in human adipose tissue depots. American Journal of Physiology. Cell Physiology. Jun 15 2013;304(12):C1141-1149.

11. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. The Clinical Journal of Pain. Sep-Oct 2004;20(5):309-318.

12. Medical Symptoms Questionnaire. In: Jones DS, Quinn S, eds. Textbook of Functional Medicine. Gig Harbor, WA: The Institute for Functional Medicine; 2005:784-785. 13. Kawabata A. Prostaglandin E2 and pain--an update. Biol Pharm Bull. 2011;34(8):1170-1173. 14.

Lim JY, Park C-K, Hwang SW. Biological Roles of Resolvins and

ANTI-AGING MEDICAL NEWS | FALL 2018

21


Don’t Block it. Resolve it. A specialized, fractionated marine lipid concentrate offering a targeted nutritional approach that is designed to support the body’s natural capacity to respond to physical challenges and resolve the immune response.* The body has a natural and active process for resolving the negative effects of tissue stress initiated by numerous circumstances, including lifestyle factors, the normal aging process, and exercise or overexertion, in addition to an unhealthy diet. Specialized Pro-resolving Mediators (SPMs) are natural compounds the body produces and uses to support this resolution process. Incorporating SPM Active into supplementation protocols represents a targeted nutritional approach to SPM replenishment to support the body’s natural capacity to respond to physical challenges and resolve the immune response.* Resolve it with SPM Active— SPM Active is a revolutionary new formula developed through advanced fractionation technology that features standardized levels of SPMs—offering a targeted nutritional approach to supporting the body’s natural SPM levels. • Support for a healthy immune response and resolution-related activities* Visit SPMActive.com to learn how you can start the resolution with your patients today with SPM Active!

*These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.

SEM521 073018 © 2018 Metagenics, Inc. All Rights Reserved.


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Ta-65 Improves Cardiovascular Markers In Subjects With Metabolic Syndrome: A Double-Blind, Placebo-Controlled, Randomized Crossover Study Prof. Maria Luz Fernandez, Ph.D. Department of Nutritional Sciences University of Connecticut, Storrs, CT 06269, USA Tel: 860-486-5547; Fax: 860-486-3674; E-mail: maria-luz.fernandez@uconn.edu 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.

Background: Metabolic syndrome (MetS) refers to

concomitant manifestation of several cardiovascular risk factors, such as obesity, hyperglycemia and dyslipidemia.1 Around 33% of the people in the United States have been estimated to be afflicted with MetS,2 and the prevalence keeps increasing among every socioeconomic group in United States3 and elsewhere.4 Physical activity,5,6 diet7 and genetic factors8 are associated with the onset and/or severity of MetS among others.

Similarly, such diverse factors influence the onset or progression of aging as well by modulating telomeres9, which are the repetitive sequences of DNA (TTAGGG) that protect chromosomal ends. One of the hallmarks of aging is the progressive attrition of telomeres. Attrition of telomeres is counteracted by telomerase, an enzyme that adds back telomere repeats. Activation of telomerase, therefore, was proposed to counteract aging by lengthening or maintaining telomeres. Telomerase is composed of two components: telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC). TA-65 is a plantderived, small molecule that activates telomerase in a variety of cells10 and lengthens telomeres in humans11.

prompted Association between short telomere and MetS us to hypothesize that TA-65 might benefit subjects afflicted with MetS. 12,13

Objective: The main objective of this study is to evaluate

whether oral intake of TA-65 can mitigate some or all the manifestations of MetS.

Trial design: This was a single center, randomized, doubleblind, placebo-controlled, and crossover study. Full details of the trial protocol are available upon request.

Trial Registration: The study was approved by Institutional Review Board (IRB), and was registered at ClinicalTrials.gov (NCT02531334).

Participants: Eligible participants were all adults aged

between 32 to 70 years and were diagnosed with MetS as defined by American Heart Association/National Heart,

28

Lung, and Blood Institute14. Eligibility criteria for participants of this study can be found in the following link: https://clinicaltrials.gov/ct2/show/ NCT02531334?term=NCT02531334&rank=1

Study settings and location: This study was conducted

at University of Connecticut, Storrs, CT USA from August 2015 to August 2017. MetS is prevalent among 30% of the population in the New England region which includes Connecticut 15.

Intervention: Subjects were randomly assigned to one of the two groups, and orally took two capsules per day. The first group took two placebo capsules per day for 12 weeks; following three weeks of washout period, this group switched to two TA-65 (250 Units) capsules per day for the next 12 weeks. The second group took two TA-65 (250 Units) capsules per day for 12 weeks; following three weeks of washout period, this group switched to two placebo capsules per day for the next 12 weeks. Outcomes: The primary endpoint was improvement in insulin resistance in subjects with MetS. Secondary endpoints include serum HDL levels and blood pressure.

Randomization, allocation concealment and blinding: Computer-generated sequence of numbers were used to randomly assign subjects to one of two groups. TA-65 (250 Units) and placebo capsules were identical in appearance and were prepackaged in bottles. The details of the series were unknown to participants of this study, any of the investigators who recruited and monitored the study participants, and any of the investigators who measured or analyzed the outcomes of the study.

Statistical methods: We aimed to assess whether data provided evidence of superiority of TA-65 to placebo. Student’s t-test (paired, one tailed) was used to compare the clinical and laboratory readings taken at the end of placebo or TA-65 intervention.

ANTI-AGING MEDICAL NEWS | FALL 2018


Supplementation with Specialized Pro-resolving Mediators Reduces Inammatory Biomarkers in Subjects with Chronic Inammatory Conditions: a Multi-Clinic Open-Case Series

RESULTS

Subjects: A total of 94 subjects were assessed for eligibility to participate in this study; 54 subjects did not meet eligibility criteria and were excluded. The remaining 40 subjects were enrolled and randomized, of which 3 subjects discontinued the study: one subject voluntarily left the study; two subjects were removed from the study due to increase in plasma glucose levels. A total of 37 subjects (11 men and 29 women) completed the study, the result of which were analyzed and reported here. Flow of participants through each stages of the study is summarized in Figure 1. Participants visited the study center at the baseline (beginning of period 1), end of period 1, end of washout period, beginning of period 2, and the end of period 2. Baseline characteristics

Diet did not confound the outcome of this study

Diet plays a significant role in determining the degree of

risks in subjects with MetS,16, and hence one of the potential

confounding factors in this study. We therefore wanted to ensure that the dietary activities do not dramatically change between

the periods when the subjects were on placebo and on TA-65. Dietary records of subjects, summarized in Supplementary Table 1, show that nutrient intake do not differ significantly between the two periods, with the only exception being a-carotene. This

result overrules any potential confounding effect of diets on the outcome measures of this study.

Table 1 summarizes baseline characteristics of subjects participated in this study. Number of subjects who fulfilled the evaluating criteria of MetS are summarized in Table 2.

TA-65 group improved on subset of risk factors

Table 1: Baseline characteristics

HDL/LDL ratio, TNF-a and TAC/8-isoprontanes significantly

Parameters Age (Yrs.) BMI (kg/m2) Waist circumference (cm) Men Women Blood pressure (mm Hg) Systolic Diastolic Cholesterol (mg/dL) Total LDL HDL Men Women HDL/LDL ratio Triglycerides (mg/dL) Glucose (mg/dL) Hb1Ac (%) Insulin (pmol/L) TNF-a (pg/mL) TAC/8-isoprontanes (pg/mL)

decreased in MetS subjects while they were on TA-65 (Table 3).

Mean ¹ S.D.†52.4 ¹ 9.5 32.3 ¹ 3.7

These results indicate that oral intake of TA-65 exerts beneficial effects on subjects with MetS.

113.9 Âą 13.2 106.0 Âą 8.9

Table 3: Parameters analyzed after the oral intake of placebo or TA-65 for 12 weeks

126.3 Âą 12.5 84.1 Âą 7.9 183.6 Âą 33.9 104.5 Âą 30.6 40.1 Âą 9.2 56.1 Âą 19.0 2.2 Âą 0.9 136.8 Âą 71.5 105.8 Âą 9.9 5.6 Âą 0.5 52.4 Âą 30.0 6.5 Âą 3.2 0.03 Âą 0.03

n (%)

Men

≼ 102 cm

9 (82%)

Women

≼ 88 cm

29 (100%)

≼ 150mg/dL

18 (45%)

Men

<40 mg/dL

5 (45%)

Women

<50 mg/dL

12 (41%)

Systolic BP

≼ 130 mmHg

16 (40%)

Diastolic BP

≼ 85 mmHg

21 (53%)

≼100 mg/dL

28 (70%)

HDL Cholesterol

Blood pressure (BP)

Fasting glucose

TA-65

BMI (kg/m )

32.8 Âą 3.9

32.6 Âą 3.8

Waist circumference (cm)

109.8 Âą 10.8

108.8 Âą 10.1

0.019

Systolic

124.9 Âą 13.5

123.8 Âą 10.5

0.290

Diastolic

84.4 Âą 9.6

83.0 Âą 7.2

0.154

Total

182.2 Âą 40.4

178.8 Âą 32.5

0.177

LDL

104.4 Âą 36.6

100.4 Âą 27.9

0.126

HDL

49.9 Âą 18.3

52.4 Âą 21.1

0.081

HDL/LDL ratio

2.35 Âą 1.2

2.1 Âą 0.8

0.051

Triglycerides (mg/dL)

131.0 Âą 62.5

130.5 Âą 75.2

0.477

Glucose (mg/dL)

103.8 Âą 11.9

104.4 Âą 13.1

0.347

Hb1Ac (%)

5.6 Âą 0.5

5.6 Âą 0.5

0.487

Insulin (pmol/L)

56.5 Âą 42.2

62.4 Âą 43.9

0.216

TNF-a (pg/mL)

6.3 Âą 3.1

5.6 Âą 2.4

0.044

TAC/8-isoprontanes (pg/mL)

0.03 Âą 0.03

0.05 Âą 0.05

0.032

Cholesterol (mg/dL)

Waist Circumference

Triglycerides

Placebo

Blood pressure (mm Hg)

Table 2: Manifestation of diagnostic features of metabolic syndrome among the participants of this study at baseline Defining levels

p valueâ€

Parameters 2

†Standard deviation

Risk factor

The mean values of body mass index, waist circumference,

0.045

†p values ≤0.05 are indicated in bold fonts

Discussion

In this study, we demonstrated that TA-65 was effective in resolving some of the components of metabolic syndrome related

to oxidative stress and dyslipidemias as demonstrated by the higher

concentrations of HDL cholesterol and the lower LDL/HDL as

well as the lower concentrations of TNF- and TAC/8 isoprontanes.

ANTI-AGING MEDICAL NEWS | FALL 2018

29


Supplementation with Specialized Pro-resolving Mediators Reduces Inflammatory Biomarkers in Subjects with Chronic Inflammatory Conditions: a Multi-Clinic Open-Case Series

This is the first study that addressed the effect(s) of TA-65 on subjects with MetS. The preponderance of female subjects (73%) is a limitation of our study. However, since the intervention included subjects with any degree of severity in terms of the manifestation of MetS, the results from this study may be generalizable for any subjects with MetS.

Supplementary Table 1: Dietary intake of participants while on placebo or TA-65 Total Energy (kcal)

T.A. Sciences Inc. funded this study. T.A. Sciences Inc. was involved in the design of the study and provided logistical support during the trial. Employees of the sponsor worked with the investigators to prepare the statistical analysis plan, but the analyses were performed by the University of Connecticut. The article was prepared by Dr. Gunasekaran Singaravelu and reviewed by Dr. Anitha Suram.

Mean

TA-65

S.D.

Mean

p value

S.D.

1757.57

496.33

1686.08

469.92

0.414

Fat Energy (%)

39.84

11.08

40.61

6.64

0.648

Carbohydrate Energy (%)

45.65

31.96

44.25

38.61

0.480

Protein Energy (%)

19.27

11.91

19.50

6.95

0.865

3.56

4.53

3.04

4.32

0.448

81.73

37.74

79.28

30.03

0.727

184.35

69.55

171.07

71.19

0.327

74.42

19.70

74.92

20.66

0.903

285.70

147.36

285.00

122.36

0.978

SFA (g)

25.84

10.06

26.81

11.31

0.665

MUFA (g)

27.51

10.32

26.56

10.65

0.589

PUFA (g)

16.89

10.15

16.21

5.91

0.689

Trans Fatty Acids (g)

2.64

1.47

2.47

1.18

0.494

Omega-3 Fatty Acids (g)

1.79

1.66

1.86

0.84

0.820

Added Sugar (g)

37.95

40.85

34.81

27.40

0.701

Total Fiber (g)

17.54

7.81

16.34

5.92

0.293

5.85

2.43

6.07

2.19

0.602

Insoluble Fiber (g)

11.62

6.17

10.18

4.56

0.108

Glycemic Index

59.22

5.32

58.84

5.37

0.737

Glycemic Load

98.81

38.66

92.51

43.09

0.450

b-carotene

3321.57

2575.64

2641.49

2837.06

0.235

a-carotene

597.76

587.79

341.86

438.66

0.009

Cryptoxanthine (ug)

142.41

287.00

120.43

362.71

0.779

Lutein + Zeaxanthin (ug)

2385.14

2773.05

2415.97

4393.00

0.967

Lycopene (ug)

3679.54

3770.25

3317.51

3073.32

0.649

Calories from Alcohol Fat (g) Carbohydrates (g) Protein (g)

Conflict of interest

Placebo

Cholesterol (mg)

Soluble Fiber (g)

REFERENCES:

1. Huang PL. A comprehensive definition for metabolic syndrome. Dis Model Mech. 2009;2(5-6):231-237.

2. Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA. 2015;313(19):1973-1974. 3. Moore JX, Chaudhary N, Akinyemiju T. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988-2012. Prev Chronic Dis. 2017;14:E24.

4. Lee SE, Han K, Kang YM, et al. Trends in the prevalence of metabolic syndrome and its components in South Korea: Findings from the Korean National Health Insurance Service Database (2009-2013). PloS one. 2018;13(3):e0194490. 5. Zhang D, Liu X, Liu Y, et al. Leisure-time physical activity and incident metabolic syndrome: a systematic review and dose-response meta-analysis of cohort studies. Metabolism. 2017;75:36-44. 6. Tucker JM, Welk GJ, Beyler NK, Kim Y. Associations Between Physical Activity and Metabolic Syndrome: Comparison Between Self-Report and Accelerometry. Am J Health Promot. 2016;30(3):155-162. 7. Pan Y, Kong LD. High fructose diet-induced metabolic syndrome: Pathophysiological mechanism and treatment by traditional Chinese medicine. Pharmacol Res. 2018.

8. Osei K, Gaillard T. Disparities in Cardiovascular Disease and Type 2 Diabetes Risk Factors in Blacks and Whites: Dissecting Racial Paradox of Metabolic Syndrome. Front Endocrinol (Lausanne). 2017;8:204. 9. Xi H, Li C, Ren F, Zhang H, Zhang L. Telomere, aging and age-related diseases. Aging clinical and experimental research. 2013;25(2):139-146. 10. Shay J. TA-65® activates telomerase and lengthens telomeres: Evidence from cell-culture and clinical studies. TA Sciences’ Internal Document. 2016;2016(003):3.

11. Salvador L, Singaravelu G, Harley CB, Flom P, Suram A, Raffaele JM. A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study. Rejuvenation Res. 2016;19(6):478-484.

12. Cheng YY, Kao TW, Chang YW, et al. Examining the gender difference in the association between metabolic syndrome and the mean leukocyte telomere length. PloS one. 2017;12(7):e0180687. 13. Revesz D, Verhoeven JE, Picard M, et al. Associations Between Cellular Aging Markers and Metabolic Syndrome: Findings From the CARDIA Study. J Clin Endocrinol Metab. 2018;103(1):148-157.

14. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-2752. 15. Gurka MJ, Filipp SL, DeBoer MD. Geographical variation in the prevalence of obesity, metabolic syndrome, and diabetes among US adults. Nutr Diabetes. 2018;8(1):14. 16. Shab-Bidar S, Golzarand M, Hajimohammadi M, Mansouri S. A posteriori dietary patterns and metabolic syndrome in adults: a systematic review and meta-analysis of observational studies. Public Health Nutr. 2018:1-12

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How Early Screening By Physicians Is Foundational to Addressing CVD Prevention Initiatives and Restoration Treatments By Mitchell J. Ghen, D.O., Ph.D. Due to screening technology and recent breakthroughs in total system treatments for cardiovascular restoration, such as nutritional intervention, it appears the opportunity now exists for addressing CVD repair, if physicians adopt a 3-step proactive strategy: (a) early sign detection, (b) in-depth follow-up testing, and (c) lifestyle reprogramming.

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.

INTRO Why is repair of arterial damage and stiffness rarely a current goal for the physician encountering cardiovascular disese (CVD)? Standard medical treatment options are reactive, inclusive of statins, anti-hypertensives and anti-platelet aggregators. Unfortunately, for the most part, these interventions do not repair the endothelial lining defects responsible for the disease progression. They may appear effective as defensive initiatives, but have limited reliability as restorative treatments. Using digital screening devices able to return waveform data on a range of patient risk factors, we can begin to explore and uncover the state of underlying functions involved in heart health. For the physician, it is step one in the search for causation. The key to effective restoration treatment is early detection. Screening for diseases prior to patient complaints of symptoms can make them ultimately easier to treat. To acquire cardiovascular and nervous system data feedback and related wellness analytics we used the UNIsource Health Integral-8 screening system (RM-3A) along with additional blood tests and ANS examinations, which set the stage for a potentially effective restorative program based on nutritional and integrative treatments. Having an FDA-cleared and insurance-accepted digital screening capability at the physician’s office is a major step forward for front-line practices, where early diagnosis is most likely. Coronary artery disease (CAD) and metabolic syndrome are the #1 killers in the U.S. Their development to serious and sometimes fatal consequences takes decades. Unfortunately, expensive special equipment available at certain hospitals, labs or clinics tend to uncover issues only at a later stage, after dysfunction and damage may require inva-

sive and defensive strategies. ASSESSING CARDIAC FUNCTIONALITY AND ARTERIAL INTEGRITY Based on an initial screening report, electrocardiogram and metabolic stress tests can lend further support to a diagnosis. Family and personal medical history, age, weight, blood pressure, and lifestyle (physical activity, smoking, dieting) factors also contribute to building a CVD profile. Once the signs of present risk are clear, a suite of blood tests related to cardiac function and arterial integrity may be used to look for predictive traces regarding the chances of a cardiovascular event, such as a heart attack or stroke. They can signal the degree of risk (remote, moderate or high) as well. A lipid profile by itself is not enough to determine cardiovascular risk. An ultrasound vascular screening, such as an echocardiogram, as well as ankle brachial index, electrocardiogram, angiography/arteriography and cardiac cauterization may add details and visibility. A single blood test alone is unlikely to determine a patient’s risk of heart attack, but a spectral approach to testing may reveal influential factors about whether or not cholesterol has oxidized leading to foam cell formation and impeding heart disease. As inflammation is involved in the process of atherosclerosis, in which fatty and calcified deposits clog arteries, patients with known risk of heart disease may be tested for C-reactive protein (CRP). Factoring in hs-CRP test results with other blood tests such as plasma ceramides, B-type natriuretic peptide (BNP), homocysteine, MPO, Lp-PLA2, oxidized LDL, direct LDL, Lp (a), apolipoprotein A and B, fibrinogen, CoQ10, and magnesium, and risk factors for heart disease helps create an overall picture of heart health.

ANTI-AGING MEDICAL NEWS | FALL 2018

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How Early Screening By Physicians Is Foundational to Addressing CVD Prevention Initiatives and Restoration Treatments

INTEGRATING ANS WITH BLOOD TESTS The sympathetic nervous system increases heart rate and contractility. The parasympathetic nervous system slows heart rates and decreases blood pressure. Sudomotor screening can uncover disturbances to the autonomous regulatory functions, whether chronic or temporary, as well as the severity and distribution of the dysfunctions. Testing the Autonomic Nervous System (ANS) requires the measurement of Heart Rate Variability (HRV) and Cardiac Autonomic Reflex Tests (CARTs). Diabetes and Parkinson’s disease are two examples of chronic conditions that can lead to autonomic dysfunction. Additional ANS testing options for severity and distribution of a diagnosed progressive autonomic neuropathy include vasomotor adrenergic innervation and cardiovagal innervation. These, along with HRV abnormalities, increase the risk for a fatal dysrhythmia. An ANS analysis is essential to measuring neuro-cardiac functions reflecting on heart-brain interactions and autonomic nervous system dynamics. As the autonomic nervous system is a likely contributor to the function of virtually every organ system, clinical observation of autonomic dysfunction may involve just about any disease. This is why it is critical for early cardiovascular screening to include ANS factors. Three well-proven technologies with a plethora of literature support are noted with ANS instrumentation. These include pulse width velocity, galvanic stimulation and impedance. These technologies combined reveal both ANS and CVD risk factors; coupled with the comprehensive blood testing described earlier, it makes a formidable duo in accurate diagnosis of CVD. NUTRITIONAL INTERVENTION When dysfunction is identified, nutritional intervention becomes a viable repair-supportive modality. Treatment and improvement of CVD symptoms and blood parameters may include diet, oral and parenteral nutraceuticals, exercise, lifestyle modifications, and, when necessary, pharmaceutical intervention. The impact of nutritional causation for CVD becomes clear when comparing the number of deaths from myocardial infarction: 3000 per year in the early 1900s to 500,000 in 1960, and nearly doubling since then. Although the popularity of diets focus on weight loss, the nutritional value of a dietary regime is essential to CVD prevention. Clifton1 suggests a basic low carbohydrate, moderate protein, moderate good fat, whole food diet, but patient profiles may require a more targeted approach. They need personalized dietary guidelines and recommendations regarding types of fats consumed, sodium content, elimination of artificial flavors, additives, and inflammatory foods all of which can cause CVD.

38

Intervention treatments focus on repair and replacement and rely on nutritional serum concentrations administered via IV and oral nutrient therapy. Magnesium is one of the key ingredients. It is used successfully to prevent/convert atrial fibrillation showing a significant decrease in the number of episodes of atrial fibrillation along with vasodilatory potential. In IV therapy, Potassium (K) may be administered to provide solution balance and repletion of deficiency. Other nutrients might be beneficial:

• Taurine plays a major role in the normal functioning of electrically excitable tissues. It is effective for dysrhythmia, cardiomyopathy, congestive heart failure, mitral valve prolapse, and cholesterol reduction. • Carnitine is concentrated in the heart more than in any other organ. Carnitine has the ability to increase fat oxidation; the heart utilizes fat oxidation extensively for energy production. • Niacin is currently one of the most effective drugs for lowering LDL-C and raising HDL-C.

• Phosphatidylcholine (PC) use in CVD centers on its possible effect of raising HDL cholesterol. PC infusions can be alternated with chelating agents such as EDTA.

• And of course, vitamin C, the only safe substance known to solubilize calcifications of the arteries.

• In oral restoration therapy, nitric oxide boosters to vasodilate, essential fatty acids (EFAs), resveratrol, magnesium, vitamin D, CoQ10 and other nutrients are used to lower risk and initiate restoration. In addition: • Low levels of Vitamin D have been associated with the cardiovascular disease risk factors of hypertension, obesity, diabetes mellitus and the metabolic syndrome, as well as cardiovascular disease events including stroke and congestive heart failure. • Research has shown that orally administered CoQ10 can improve functioning of myocardial tissue, strengthening the heart’s contractions and making it beat more strongly (positive inotropic effect) and more regularly (anti-dysrhythmia effect).

• EFAs fight inflammation decreasing the risk of atherosclerotic plaque development in arteries. Patients should be advised to avoid the PUFAs. Supplementation needs to be managed. The standard regard for efficacy based on valuations derived by simple addition of benefits from single supplements has given way to an integral model. As Bowen2 observes, “Epidemiological research illustrates the importance of considering the total diet and the interrelatedness of nutrients in a dietary pattern.” OPTIONS FOR REVERSING CVD Reversal of CVD depends largely on reprogramming a patient’s nutritional lifestyle. Its goal is to reverse the inflammatory process

ANTI-AGING MEDICAL NEWS | FALL 2018


How Early Screening By Physicians Is Foundational to Addressing CVD Prevention Initiatives and Restoration Treatments

and repair the endothelial lining. Exercise and optimal nutrition with fruits, nuts and vegetables, plus reduction of poor health habits, have shown to be effective in achieving a 5% regression compared to an 8% progression in plaque size in a single year.3 The level of C-reactive protein (CRP) produced by the liver rises when there is inflammation throughout the body. Elevations of fibrinogen will accompany the rise thereby increasing blood viscosity. Natto bean derivatives and increased water consumption helps to keep the blood viscosity within normal limits. Lowering CRP is critical to reversing vascular risk and its progression. Tools such as nutrition, nutraceuticals, hormonal balance and lifestyle changes and primarily intravenous nutrition offer excellent support for reversing its impact on CVD. Lifestyle changes should be focused on adding good habits and eliminating poor ones. Nutrition studies reveal that a high quality Mediterranean style diet provides increased antioxidant content. It reduces risk of CVD by 20%. Regular consumption of water reduces inflammation and blood viscosity. Avoidance of polyunsaturated vegetable oils will cut out free radicals that can cause damage to arteries and initiate plaque formation. Exercise is an essential aspect of a reversal initiative as it strengthens the cardiovascular system, cardiac output and lowers resting heart rate. Meditation and heart rate variability training also reduce risk. They are helpful in inducing restful sleep essential to CVD reversal. Parasympathetic training helps the stressed sympathetic driven individual (easily identified on ANS evaluation) to create more balance. Cold water showers, humming, singing, and earthing along with exercise and meditation helps achieve this goal. More recently, the most in-depth integrative model for the reversal of CVD pathology has been unveiled by the study of the underlying mechanisms that precede disease in light of molecular and cellular biology. Controlled by networks of specialized cardiac cells governing automaticity and cardiac impulse conduction, the structural and molecular components for regulating the properties of the myocardium and systems are critical to the conduction system. While proper cardiac function requires the synchronized electrical activation of the myocardium, improper function is the cause for inflammation associated with cardiac dysfunction. Molecular tools have an increasingly important role in addressing pathogenic pathways involved in disease onset and progression, including host, viral genetics and environmental factors. Inherited Cardiac Conduction Disease (ICCD) can be either structural, functional or there can be overlap between these two mechanisms. As patients with inherited structural or functional ICCD suffer from fundamentally different diseases, the implications for diagnosis, treatment and reversal must be approached differently.

It takes a proactive physician, using advanced testing protocols and an integrated treatment approach, to offer patients hope for prevention, restoration and reversal of cardiovascular disease. In other words, outcome must begin with initiative. As an ancient proverb suggests, “Whether one makes a thousand mile journey successfully depends on the determination embedded in the first step.” By acquiring cardiovascular and nervous system data feedback and related wellness analytics for 8 critical risk factors using the UNIsource Health Integral-8 screening system (RM-3A) the physician is provided with a restorative methodology that works. 1. The 8 essential risk factors screen for: 2. Cardiovascular Disease 3. Autonomic Nervous System Dysfunction 4. Cardiac Autonomic Neuropathy 5. Cardio-Metabolic Risk 6. Sudomotor Dysfunction 7. Small Fiber Neuropathy 8. Endothelial Dysfunction 9. Insulin Resistance The algorithms that are used to derive these eight essential risk factors are tried and true, and hold to the medical standards of excellent sensitivity and specificity values. The critical contribution of an integrated screening solution using non-invasive waveform technology can help physicians take charge of progressive diseases such as CVD. Early diagnosis coupled with integrated preventive practices is the best model for a front-line physician seeking to make a difference in helping people live longer, healthier lives, while keeping others from getting sicker.

REFERENCES:

1. Clifton PM, et al. High protein diets decrease total and abdominal fat and improve CVD risk profile in overweight and obese men and women with elevated triacylglycerol. Nutr Metab Cardiovasc Dis. 2009 Oct; 19(8):548-54. 2. Bowen KJ, Sullivan VK, Kris-Etherton PM, Petersen KS. Nutrition and Cardiovascular Disease - an Update. Curr Atheroscler Rep. 2018 Jan 30;20(2):8. doi: 10.1007/s11883-018-0704-3. 3. Piya, Harte, et al. Metabolic endotoxaemia: Is it more than just a gut feeling? Curr Opin Lipidol. 2013 Feb 24(1):78-85.

EARLY SCREENING IS KEY TO RESTORATION ANTI-AGING MEDICAL NEWS | FALL 2018

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