A4M MMI | Anti-Aging Medical News - Winter 2020

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A4M | MMI Planning Committee

Andrew Heyman

Pamela W. Smith MD, MPH, MS

Sahar Swidan

MD, MHSA, ABFM, ABIHM

PharmD, BCPS, ABAAHP, FAARFM

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James LaValle

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ANTI-AGING MEDICAL NEWS | WINTER 2020

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ANTI - AGING MEDICAL NEWS | WINTER 2020

TABLE OF CONTENTS Professional Medical Education (Non-CME) . . . . . . . . . 10 2020 Graduates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Product Announcements . . . . . . . . . . . . . . . . . . . . . . . . . 52 Company Spotlight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

ARTICLES 14

Maintaining Memory for Life

24

Fasting for Healthy Longevity

36

Quercetin and Immune Health

42

Benefits Of Epigenetic Testing Beyond Biological Aging

48

Anti-Aging Benefits of Sulforaphane

58

The “Gut -Lung Axis”

66

AMPK Impacts on Metabolic Function & Immune Health

76 84

The Science Behind Cognitive Support Formulas

New Directions for Women in Menopause By: Felice Gersh, MD

By: Lewis Chang, PhD

By: Hannah Went

By: Kasey Hutchinson, RDN

The Importance Of Various Microbial Niches On Pulmonary Health

By: Christopher Shade, PhD

New Approaches to Managing Hypertension Using Central Blood Pressure Measurement and Supplements By: Craig Cooper

Specialized Pro-Resolving Mediators:

Novel Mechanisms for Supporting a Healthy Inflammatory Response By: Caitlin Higgins, MS, CNS, LDN

ANTI-AGING MEDICAL NEWS | WINTER 2020

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ANTI-AGING MEDICAL NEWS | WINTER 2020

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SUNDAY | DECEMBER 13TH 7:55 am - 8:55 am Progress and Updates on the Clinical Science and Application of Fasting

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ANTI-AGING MEDICAL NEWS | WINTER 2020

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Maintaining Memory for Life

The Science Behind Cognitive Support Formulas

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.

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ANTI-AGING MEDICAL NEWS | WINTER 2020


Maintaining Memory for Life | The Science Behind Cognitive Support Formulas

Cognitive challenges can be devastating. Changes in brain health can affect focus, memory, mood, sleep, and even personality. Many people live in fear of memory loss as they get older, while others find themselves supporting loved ones who have lost their ability to function in everyday life because of cognitive impairments. As with most health situations, it’s easier to support the healthy structure and function of the brain than it is to reverse damage once it’s begun. Ideally, supporting brain health and memory starts during childhood and continues through all stages of life. That’s why cognitive support should be a part of everyday practice for all integrative clinicians. The good news is that a holistic approach to whole-body health inherently supports the brain as well. The brain relies on healthy blood-sugar levels, lipid and homocysteine metabolism, along with healthy cellular energy production. That means most integrative clinicians are indirectly supporting brain health for their patients whether they intend to or not. For example, sleep, exercise, and diet are all foundational to brain health. A balanced diet provides nutrients such as B vitamins and zinc that are essential for brain function. Exercise promotes the expression of brain-derived neurotrophic factor (BDNF), which is a protein that supports the growth and connection of new nerve cells. And sleep gives the brain essential time to consolidate memories. Targeted nutritional support can build upon this healthy lifestyle foundation to support brain health and memory. Cognitive-support formulas are designed to do just that.* Some of these formulas contain one or more of the many ingredients with sound science to support their role in cognition and memory. The two most-well researched ingredients include citicoline and huperzine A.* You can read about them in detail in the Ingredient Spotlight on page 34 and in the Research Review on page 40. In this article, we review five more top nutrients you’ll likely find in cognitive support formulas.

PHOSPHATIDLYSERINE Phosphatidylserine is an integral component of

all cell membranes. It is present in every cell of the human body, but concentrated in the nerve cells of the brain. Phosphatidylserine can be synthesized in the human body from phosphatidylcholine. It can also be consumed directly from foods and supplements. Phosphatidylserine is included in cognitive-support formulas mainly because of its ability to support the structure of nerve-cell membranes and the function of receptors and neurotransmitter release at nerve synapses. Phosphatidylcholine and citicoline also work similarly to support the structure of nerve-cell membranes.* Numerous studies show that phosphatidylserine supports brain health in adults, teens, and even children.* A 2014 study found that supplementation with 200 mg per day for two months supported healthy attention and memory in children. And a double-blind, -placebo-controlled trial published in 2010 found that supplementation with 300 mg per day of phosphatidylserine for six months supported healthy memory in older Japanese adults.* The suggested use for phosphatidylserine is 100 to 600 mg per day.

ACETYL - L - CARNITINE Acetyl-l-carnitine is a naturally occurring substance in the body. It forms when an acetyl group (CH3CO) binds to l-carnitine, which is a modified version of the amino acid lysine. Inside the cells of the human body, acetyl-l-carnitine and l-carnitine readily convert from one to the other. But acetyl-l-carnitine has some advantages over l-carnitine as a dietary supplement. Acetyl-l-carnitine more efficiently absorbs from the gut and more readily crosses the blood-brain barrier. Also, the acetyl group can be used in the brain to support the production of the neurotransmitter acetylcholine.* Acetyl-l-carnitine is included in cognitive-support formulas mainly because of its central role in mitochondrial function and cellular-energy production. L-carnitine facilitates the transport of fatty acids into the mitochondria so they can be converted into energy. This mechanism makes l-carnitine synergistic with coenzyme Q10, which

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Maintaining Memory for Life | The Science Behind Cognitive Support Formulas

also supports mitochondrial energy production.* Multiple studies conducted in the 1990s found that acetyl-l-carnitine supplementation supports memory and cognition in older adults.* Also, the authors of a 2003 meta-analysis of 21 doubleblind, placebo-controlled trials wrote that supplementation with 1.5 to 3 grams of acetyl-l-carnitine per day for three to 12 months resulted in a “significant advantage” over placebo for supporting cognition in elderly patients.* The suggested use of acetyl-l-carnitine is 1,500 to 2,000 mg per day.

VINPOCETINE Vinpocetine is a compound derived from vincamine, which is an alkaloid in the seeds of the periwinkle plant (Vinca minor). Vinpocetine is approved by prescription in some countries, and is available as a dietary supplement in the U.S. Vinpocetine is included in cognitive--support formulas because of its ability to support healthy blood flow in the brain. Positron emission tomography (PET) scans of the brain show that vinpocetine readily crosses the bloodbrain barrier. It’s then taken up by brain areas where it supports cellular metabolism and blood flow.* Vinpocetine is not the only compound that supports healthy blood flow to the brain, ginkgo biloba has long been used in the same way. A combination product containing ginkgo biloba and vinpocetine was evaluated in a double-blind study conducted at the Scripps Research Institute in California in 2001. The results of the study showed that 14 days of supplementation supported working memory in healthy adults.* The suggested use of vinpocetine is 10 to 30 mg per day. The FDA has warned that consumption of vinpocetine may be associated with adverse reproductive effects and should not be used by women who are pregnant or could become pregnant.

CURCUMIN Curcumin is a compound extracted from turmeric root (Curcuma longa). Curcumin has been shown to support

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numerous physiological pathways, including healthy responses to inflammation and oxidative stress.* Curcumin is included in cognitive-support formulas primarily because of its ability to support antioxidant defenses against reactive oxygen species. Brain cells are very susceptible to oxidative damage and require ongoing support for cellular antioxidant protection. N-acetylcysteine (NAC) and alpha-lipoic acid (ALA) are often included in cognitive-support formulas for the same reason. A double-blind, placebo-controlled trial published in 2015 found that a solid lipid curcumin formulation (400 mg as Longvida curcumin) supported memory and mood in healthy older adults.* Longvida’s formulation was originally developed by UCLA neuroscientists investigating the action of curcumin on biomarkers of brain health. The bioavailability challenges of curcumin are well known, but Longvida’s patented lipophilic matrix protects and delivers curcumin into circulation and is proven to stay in circulation for a significant amount of time, long enough to cross the blood brain barrier and exert effect. In 2018, researchers at the University of California Los Angeles published an 18-month clinical trial of curcumin (Theracumin) in older adults. Their results showed that 180 mg of curcumin per day supported memory and mood, and correlated with positive changes on PET scans of the brain.* The suggested use of curcumin is 200 to 1,000 mg per day.

COFFEE FRUIT EXTRACT Coffee fruit is the bright red flesh that surrounds coffee beans. Extract of whole coffee fruit contains chlorogenic acid and other antioxidant compounds. Coffee fruit extract is included in cognitive-support formulas because of its ability to support the production of BDNF—a protein that helps grow and repair nerve cells. Based on results from the Framingham Study, published in the Journal of the American Medical Association in 2014, researchers concluded that higher serum BDNF levels protect healthy memory and cognition in aging adults.* Another study found that 100 mg of whole coffee fruit extract boosted BDNF levels in healthy adults by 143 percent in less than two hours. Although other supplement ingredients, particularly fish oil and

ANTI-AGING MEDICAL NEWS | WINTER 2020


Maintaining Memory for Life | The Science Behind Cognitive Support Formulas

curcumin, might also support BDNF, coffee fruit extract is the only ingredient that has been shown to do so in human studies. The suggested use for coffee fruit extract is 100 to 200 mg per day.

CHOOSING A COGNITIVE - SUPPORT FORMULA The brain relies on ALL systems working correctly. It needs cellular energy, adequate blood flow, antioxidant defenses, and all of the nutrient building blocks to support its structural integrity. Consequently, when choosing a cognitive-support formula for a patient, it’s important to look for a combination of ingredients that address multiple mechanisms of action.

When beginning a cognitive-support formula with a patient, remember that not everyone will respond the same way. Many people feel better if they take these supplements in the morning or early afternoon because of the stimulating effect of some ingredients. Always check for potential interactions with other dietary supplements or medications. Many people now expect to live into their 80s and 90s and maintaining cognitive function is of primary concern. It’s never too soon to consider cognitive support as part of any patient’s holistic wellness, but needs naturally increase with age. Practitioners prepared to support patient’s cognitive health in all stages of their life-cycle, are providing proactive support for long term quality of life.

SELECTED REFERENCES Chen M, et al. Neural Regen Res 13, no. 4 (2018): 742–52. Cox KH, Pipingas A, and Scholey AB. J Psychopharmacol 29, no. 5 (2015): 642–51. Gulyás B, et al. Acta Neurol Scand 106, no. 6 (2002): 325–32. Hirayama S, et al. J Hum Nutr Diet 27 Suppl 2 (2014): 284–91. Kato-Kataoka A, et al. J Clin Biochem Nutr 47, no. 3 (2010): 246–55. Kidd PM. Altern Med Rev 4, no. 3 (1999): 144–61. Montgomery SA, Thal LJ, and Amrein R. Int Clin Psycho-pharma--col 18, no. 2 (2003): 61–71. Polich J and Gloria R. Human psychopharmacology. 16 (2001): 409-416. Reyes-Izquierdo T, et al. Br J Nutr 110, no. 3 (2013): 420–25. Small GW, et al. Am J Geriatr Psychiatry 26, no. 3 (2018): 266–77. Weinstein G, et al. JAMA Neurol 71, no. 1 (2014): 55–61. Zhang YS, Li JD, and Yan C. Eur J Pharmacol 819 (2018): 30–34.

ANTI-AGING MEDICAL NEWS | WINTER 2020

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2020 GRADUATES

We would like to extend a well-deserved congratulations to our 2020 graduates! These Fellows have completed the necessary clinical coursework for the following: Fellowship in Anti-Aging, Metabolic and Functional Medicine; Fellowship in Integrative Cancer Therapy; Fellowship in Stem Cell Therapy; and the Aesthetic Anti-Aging Fellowship. Best wishes to this year’s graduates!

Amina Al Tamini MBBS

MD, MSHS, FAAMFM

Angela Alfaro

Fatemah AlMozayin MD

MD, FAAMFM, ABAARM

Erin Amato

Marisa André

Mary Atkinson

Mariaclara Bago

Promila Banerjee

Diyanah Bani Hani

Edward Barbarito

Branson Collins

Terrence Crowder

Erin Gagne

Angeline Galiano

MBCHB, FAAMM

Yassine Bendiabdallah

Jacqueline Chirco

MPharm, PhD, MRPharm, FAAMM

DO, ABFM, FAAMM, ABAARM

Natalie Ellis

Jamie Faught

MD, ABAARM, FAAMM

Ingemaud Gerber

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DO, FAAMFM

MBChB, CCFP, FAAMM

MD, FAAD

Cary Hatcher

FNP-BC, FAAMM, ABAAHP

MD, FACP

Mary Ann Coffey

RPh, CCN, FAAMFM

Karen Floyd

RPh, FAAMM, ABAAHP

Teresa Iribarren

MD, ABAARM, FAAMFM

MD

MD, ABAARM, FAAMFM

FNP-C, FAAMFM

Rajan Kohli

MD, FAAMFM

MD

MD, FAAMM

MD, FAAOS, FSCT

MD, FAAMFM

Carrie Lam

MD, ABAARM, FAAMFM


Rhet Langley MD, FSCT

Kevin May

Jessica LaPlante FNP, FAAMFM

Linda McIver

MD, FAAMFM, ABAARM

FNP-C, FAAMM, ABAAHP

John Immanuel Navarro

Chaula Patel

Suniel Reddy

Saara Schwartz

Mei Chih Tsai

Sharon Velez Maymi

MD, FAAMFM, FICT, ABAARM

MBBS, FRACGP, FAAMM

MD, ABAARM, FAAMFM

MD, FAAMM

MD, FAAMM

MD, FAAMM

Amanda Whitson

APRN, FNP-C, ABAAHP, FAAMM

Ming-Ho Lee

MD, MSc, ABAARM, FAAMFM

Steven Mills

Dustin Ly MD, DC

Abdullah Mansour S. Abahussain MBBS

MD, ABAARM, FAAMM, CFMP

PhD, FAAMM, ABAAHP

Clifford Morris

Kasey Murphy

Eribeth Penaranda

Josie Philips-Ross

Stéphane Provencher

Kelly Slaughter

Ronald Tolchin

MD, MPH, ABAARM, FAAMM

Alta Skelton

PharmD, FAAMM

FNP-BC, ABAAHP, FAAMFM

APRN, NP-C, FAAMM, ABAAHP

Kien Vuu

Allison Wagstaff

Kristin Wulff

Ravital Yael James

MD, FAAMM, ABAARM

MD, ABAARM, FAAMM

NP, BSN, BS, MSN

MBChB, FAAMFM

PA-C

PhD, DC, ABAAHP, FAAMFM, FICT

DO, FAAMFM

Jennie Welner

FNP-BC, ABAAHP, FAARM


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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.

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ANTI-AGING MEDICAL NEWS | WINTER 2020


Fasting for Healthy Longevity – New Directions for Women in Menopause

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 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 a lower overall life expectancy.2 In contrast, women who go through menopause after age 51, have lower rates of cardiovascular disease and enjoy a 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. 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 situation 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 25year 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 of fasting that are associated with different health benefits. “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, it is called “intermittent fasting.” If a person fasts for a few days up to a week, it 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. Based on my experience as a physician specializing in women’s medicine, and a review of the literature, I have concluded that combining time-restricted eating with a regular program of periodic fasting is likely the most advantageous combination. 5,6,7 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.8,9 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.10 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 studies.11,12 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

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Fasting for Healthy Longevity – New Directions for Women in Menopause

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.13 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 risk 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 (5:2) can effectively address the 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—the fasting mimicking diet. Certain foods, sometimes called stealth foods, can

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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 many of the benefits of periodic fasting, but she won’t experience all of the physical stress and discomfort of actually fasting. Additionally, the diet has been shown to maintain lean body 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 and an advisor for the company it spawned. In my practice, the fasting mimicking diet has proven to be an innovative concept for menopausal women and data I have collected supports that periodic/prolonged fasting is a beneficial form of fasting for long term health and vitality. Indeed, certain cellular functions can only be activated by a longer fast. Pre-clinical studies (e.g., animal studies) have confirmed that healthy cells undergo a process called autophagy, a powerful form of cellular rejuvenation. Although these studies have only been shown in animals due to the technical and ethical limitations of studying autophagy in humans, autophagy is a conserved process seen throughout all living organisms during times of cellular stress. It is such an important process that the 2016 Nobel Prize in Medicine or Physiology was awarded to Dr. Yoshinori Ohsumi for his discoveries of mechanisms involved in autophagy. A study showed that when people follow the fasting mimicking diet once a month for three months, they lose body weight, and belly (e.g., visceral) fat; maintain healthy systolic BP; and maintain lean body mass.14 Every woman must transition through and into menopause, a state that may encompass a full half of her lifespan. Menopause, marked by permanent estrogen deficiency, is complex and the 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. Bio-identical 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.

ANTI-AGING MEDICAL NEWS | WINTER 2020


Fasting for Healthy Longevity – New Directions for Women in Menopause

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.

AUTHOR BIOGRAPHY:

REFERENCES

Felice Gersh, M.D. holds dual board certifications in OBGYN 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. Contact info: fgersh@integrativemgi.com (949) 753-7475

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.

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. Mattson et al. 2017. Aging Research Reviews; 39: 46-58. 6. Panda S. 2016. Science; 354(6315): 1008-1015. 7. Park et al. 2020. Metabolism; 154368.

8. Villanueva et al. 2019. Nature Communications; 10:2700. 9. Regmi et al. 2020. iScience; 23: 101161.

10. Hatcher et al. 2020. Eur J Neurosci; 51(1): 217-228.

11. Corey, et al. 2019. Nutrients; 11(2442) doi:10.3390/nu11102442. 12. Natali, et al. 2017. Anti-Aging Medical News; 77: 199-215.

13. Farshchi, et al. 2005. The American Journal of Clinical Nutrition; 81(2): 388–396. 14. Wei, et al. 2017. Science Translational Medicine; 9(377).

ANTI-AGING MEDICAL NEWS | WINTER 2020

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Quercetin and Immune Health

By: Lewis Chang, PhD 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.

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ANTI-AGING MEDICAL NEWS | WINTER 2020


Quercetin and Immune Health

INTRODUCTION A quick search on ClinicalTrials.gov identified, as of this writing, 58 quercetin-related clinical intervention studies that are currently ongoing (19) or have been completed (39). Diverse health conditions, such as chronic obstructive pulmonary disease, type 2 diabetes, endothelial dysfunction, dyslipidemia, stroke, hepatitis C, acid reflux, inflammation, and oxidative stress, are the subject of interest. And in recent days quercetin’s role in immune health is getting a lot of attention as well. So what exactly is quercetin, where is it from, and what biological properties does it have that have attracted researchers’ attention? Humans have had a long history of discovering remedies from plants. Dietary flavonoids are a large family of plant compounds sharing a polyphenolic structure and can be categorized into six major subfamilies: anthocyanidins, flavan3-ols, flavanones, flavones, flavonols, and isoflavones.1

DIETARY SOURCES AND INTAKE Quercetin is one of the better known flavonoids from the flavanol subfamily.1 The main dietary sources of quercetin for humans are apples, berries, capers, onions, tomatoes, kale, broccoli, nuts, buckwheat and tea.1 How much dietary quercetin (or flavonols) do humans consume? One study involving US health professionals reported a mean flavanol intake of 20 mg per day; about 75% of the total was quercetin.2 Data from a group of nurses in the US revealed an average intake of 15.4 mg quercetin per day.3 However, human consumption behavior is very complex; we are not eating the same things day after day. Some individuals may consume as much as 77 mg per day dietary quercetin, while others consume as little as 1 mg per day.4 The way food is prepared (boiling, frying, etc., can lower the bioavailability) and stored can also have an impact on quercetin concentration. This means many people are not getting the health benefits of quercetin.

major innate defense mechanisms is the activation of NLRP3 inflammasome (protein complexes in the cell that can sense signals from pathogens or dangers), leading to production of IL-1β, an important compound that mediates many aspects of inflammatory responses.6 However, dysregulated activations of inflammasome have been linked to initiation and progression of immune and inflammatory disorders such as atherosclerosis, inflammatory diseases, type 2 diabetes, autoimmune diseases, Alzheimer’s disease, and obesity, as well as collateral tissue damages that occur during infections.6,7 Quercetin has been shown to modulate NLRP3 inflammasome. In several experimental models of inflammatory conditions (including infections), quercetin reduced the production of reactive oxygen species and inhibited the overexpression of different components of NLRP3 inflammasome, resulting in reduced activation of NLRP3 inflammasome and leading to decreased secretion of IL-1β.8,9 Quercetin can also neutralize reactive oxygen species that are known to increase ER stress and mitochondrial dysfunction, both of which can activate NLRP3 inflammasome.10,11 Further, quercetin suppresses NF-κB pathway that also leads to reduced activation of NLRP3 inflammasome and productions of proinflammatory cytokines.12 These data demonstrate quercetin’s involvement in multiple pathways leading to modulation of NLRP3 inflammasome and reduction of downstream proinflammatory cytokine levels. Other researchers have also discovered quercetin’s role in regulating immunity. For example, •

Quercetin reduced TNF-α production in macrophages and lung epithelial cells when stimulated by LPS, an endotoxin found in bacteria that triggers immune response.13,14 This suggests quercetin modulates TNFα-mediated induction of inflammatory cascades.

Quercetin exhibited a regulatory effect on several properties of immune cells such as inhibiting histamine and cytokine release from mast cells and inducing gene expression and production of Th-1-derived interferon (IFN)-g, as well as downregulating Th-2-derived IL-4 production by normal peripheral blood mononuclear cells.15,16 This suggests quercetin may have antiallergic properties.

Quercetin inhibited cells from being infected with influenza virus, Zika virus, and Ebola virus via interaction

ANTI - INFLAMMATORY AND ANTIOXIDATIVE PROPERTIES A major health benefit of quercetin comes from its antioxidant (antioxidative) and anti-inflammatory properties.5 Inflammation is an essential immune response when facing pathogens (e.g., virus, bacteria, and fungus) or dangers (e.g., tissue damage caused by free radicals, cholesterol, amyloid beta, or asbestos). One of the

ANTI-AGING MEDICAL NEWS | WINTER 2020

37


Quercetin and Immune Health

with viral hemagglutinin protein, inhibited virus entry into the cell, or reduced virus replication.17-19 This suggests quercetin has antiviral properties.

made up of normotensive individuals.22 Also, a higher dose of quercetin has been shown to reduce upper respiratory tract infection severity and sick days in older adults.23

SUMMARY The antioxidant and anti-inflammatory as well as immunomodulatory properties of quercetin have inspired researchers to investigate its clinical effects. Quercetin supplementation at ≼ 500 mg/day significantly reduced fasting plasma glucose among patients with metabolic syndrome and related disorders,20 showed a small but significant reducing effect in circulating C-reactive protein levels,21 and significantly reduced blood pressure in cohorts largely

Naturally, more clinical investigation is greatly needed to fully understand quercetin’s clinical application in immune health and various inflammatory conditions. Nevertheless, with so much researchers have learned regarding quercetin and its beneficial biological properties, the future research direction of quercetin looks very promising.

CITATIONS 1. Panche AN et al. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. 2. Sampson L et al. Flavonol and flavone intakes in US health professionals. J Am Diet Assoc. 2002;102:1414-1420. 3. Lin J et al. Dietary intakes of flavonols and flavones and coronary heart disease in US women. Am J Epidemiol. 2007;165:1305-1313. 4. Cassidy A et al. Higher dietary anthocyanin and flavonol intakes are associated with anti-inflammatory effects in a population of US adults. Am J Clin Nutr. 2015;102:172-181. 5. Anand David AV et al. Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn Rev. 2016;10:84-89. 6. Guo H et al. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677-687. 7. Chen IY et al. Response of host inflammasomes to viral infection. Trends Microbiol. 2015;23:55-63. 8. Wang C et al. Quercetin and allopurinol ameliorate kidney injury in STZtreated rats with regulation of renal NLRP3 inflammasome activation and lipid accumulation. PLoS One. 2012;7:e38285. 9. Hu QH et al. Allopurinol, quercetin and rutin ameliorate renal NLRP3 inflammasome activation and lipid accumulation in fructose-fed rats. Biochem Pharmacol. 2012;84:113-125. 10. Wang W et al. Quercetin and allopurinol reduce liver thioredoxininteracting protein to alleviate inflammation and lipid accumulation in diabetic rats. Br J Pharmacol. 2013;169:1352-1371. 11. Jiang W et al. Quercetin suppresses NLRP3 inflammasome activation and attenuates histopathology in a rat model of spinal cord injury. Spinal Cord. 2016;54:592-596. 12. Zhang QY et al. Quercetin inhibits AMPK/TXNIP activation and reduces inflammatory lesions to improve insulin signaling defect in the hypothalamus of high fructose-fed rats. J Nutr Biochem. 2014;25:420-428. 13. Manjeet KR et al. Quercetin inhibits LPS-induced nitric oxide and tumor necrosis factor-alpha production in murine macrophages. Int J

Immunopharmacol. 1999;21:435-443. 14. Huang R et al. Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress. Arch Med Sci. 2015;11:427-432. 15. Nair MP et al. The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochim Biophys Acta. 2002;1593:29-36. 16. Kimata M et al. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy. 2000;30:501-508. 17. Wu W et al. Quercetin as an antiviral agent inhibits influenza A virus (IAV) entry. Viruses. 2015;8. 18. Wong G et al. Antiviral activity of quercetin-3-beta-O-D-glucoside against Zika virus infection. Virol Sin. 2017;32:545-547. 19. Qiu X et al. Prophylactic efficacy of quercetin 3-beta-O-d-glucoside against Ebola virus infection. Antimicrob Agents Chemother. 2016;60:5182-5188. 20. Ostadmohammadi V et al. Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials. Phytother Res. 2019;33:1330-1340. 21. Mohammadi-Sartang M et al. Effects of supplementation with quercetin on plasma C-reactive protein concentrations: a systematic review and metaanalysis of randomized controlled trials. Eur J Clin Nutr. 2017;71:10331039. 22. Serban MC et al. Effects of quercetin on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2016;5. 23. Heinz SA et al. Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacol Res. 2010;62:237-242.

Lewis Chang is Scientific Editorial Manager at Metagenics. Phone: 253-853-7241 Email: lewischang@metagenics.com

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ANTI-AGING MEDICAL NEWS | WINTER 2020


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Benefits Of Epigenetic Testing Beyond Biological Aging

By: Hannah Went 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.

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ANTI-AGING MEDICAL NEWS | WINTER 2020


Benefits of Epigenetic Testing Beyond Biological Aging

One of the biggest moments in the area of longevity has been the search for an objective molecular marker for the aging process. Although many biomarkers such as proteomics, telomere testing, and transcriptomics have been investigated, none have gathered the attention and notoriety that epigenetic biological age testing has. In several reviews of aging biomarkers, it is also noted to be the best [1]. Epigenetic biological age testing is exciting for many different reasons as described below:

1

IT IS THE MOST CORRELATED BIOMARKERS TO AGE RELATED AND CHRONIC DISEASE

Age is the number one risk factor for most chronic diseases such as metabolic disease, cardiovascular disease, cancer, and neurodegenerative diseases like Parkinson’s and Alzheimer’s. However, there are some serious limitations with just measuring aging. Mainly, these problems occur as the result of phenotypic variation, or the large variation in outcomes that occurs with age. For instance, life expectancy shows considerable variation amongindividuals with equal or similar chronological ages due to diversity in genotypes and in living habits and environments. A 50-year old individual may have 60-year old body functions, and many people look older or younger compared to others at the same chronological age (even twins). Therefore, chronological age is not an optimal indicator for the aging process. Biological aging has the same associations but is much more correlated with the phenotypes of chronic disease. By measuring this, we can predict the risk of most chronic diseases and prevent them before disease manifests.

2

IT ALLOWS US TO VET INTERVENTIONS ON AGING AND THE AGING PROCESS INSTEAD OF LOOKING AT MARKERS OF DISEASE AND DYSFUNCTION One of the implications of this testing is that it allows us to measure the effect of anti-aging interventions. We all know that the aging process is a stepwise process that doesn’t happen overnight. Usually these steps in the aging process are reflected in the 9 hallmarks of aging, but it is often difficult and expensive to get a measurement on each of these hallmarks. Methylation analysis allows us to test an objective, single molecular marker which encompasses the processes that lead to hallmarks of aging. It also allows us to see how interventions are working in real time. Previously, if you wanted to judge how a single intervention was affecting lifespan you would have to complete a placebo controlled trial and look at outcomes 40-50 years in the future. Now, you can see how interventions are affecting lifespan in as little as 8 weeks.

ANTI-AGING MEDICAL NEWS | WINTER 2020

43


Benefits of Epigenetic Testing Beyond Biological Aging

3

IT IS PERSONALIZED, PRECISION MEDICINE Precision medicine is the approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Epigenetics is ideal to merge into any precision approach because epigenetic markers are reflective of personal variables.

4

IT IS EXTREMELY ACCURATE AND SENSITIVE

Many of the complaints with previous biomarkers, such as telomeres, have been that testing variation often makes the results unpredictable. While every test has a margin of error, epigenetic methylation testing is very very accurate. Epigenetic age testing has an accuracy of r = 0.96 on subjects aged between 0 to 100 and r = 0.77 in middle age subjects which is substantially higher than that of other molecular markers such as telomere length (r = 0.5) [2]. As a result, this makes it very predictable and reliable to test change over time. One of the leaders in this field, Dr. Steve Horvath from UCLA, has even said “It’s really more likely that planet Earth will be hit by an asteroid tomorrow than that this predictor doesn’t work”.

5

IT IS CHANGEABLE One of the best things about this measurement is that it is actionable and changeable. Dr. Jim Watson was part of the partnership that famously discovered DNA. At first, even he didn’t want to know his genetic makeup at certain locations because he was scared of knowing that he might inevitably have a disease that he couldn’t change. However, we now know that your DNA is not your destiny, and neither is aging. You can manage the aging process by changing your diet, exercise, sleep, medications, and other lifestyle factors. 60% of your epigenetic methylation markers are changeable [3], and now that we have an objective measure of aging, you can see which anti-aging products objectively have the best effect on your own aging. In addition, due to aging’s relationship to all chronic diseases, changing your rate of aging can have a massive impact on your health. In fact, if you reduced the biological aging rate by 20% it would save the US 3 trillion dollars in healthcare spending over the next 50 years [4]. Additionally, if you reduced the age of every individual in the world by 7 years it would cut disease burden by 50% [5].

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ANTI-AGING MEDICAL NEWS | WINTER 2020


Benefits of Epigenetic Testing Beyond Biological Aging

WHY METHYLATION BASED EPIGENETIC ANALYSIS IS MORE IMPORTANT THAN JUST AGING As described above, there are many reasons to be excited about the future use and implementation of epigenetic biological aging in medical practice. However, epigenetic methylation testing is far more exciting than just studying longevity. Methylation is typically thought of as an epigenetic mechanism to silence gene expression when put onto a promoter region of the genome. As a result, it can be correlated and implicated in many different disease processes and many underlying physiological processes.

LIQUID BIOPSY FOR CANCER DETECTION AND TREATMENT DECISIONS One good example of this is detecting cancer early. Molecular alterations found in the DNA of tumor cells, such as mutations, translocations and methylation, are reflected in DNA that is released from the tumors into the bloodstream [6]. Thus, in recent years, circulating tumor DNA (ctDNA) has gained increasing attention as a noninvasive alternative to tissue biopsies. Cancer can be detected in stage 0 and before any other imaging or testing method by looking at the methylation patterns of these cells. Obviously, detecting cancer early can greatly impact survival rates by implementing treatment protocols quickly. he precision of methylation detection allows this to happen. Through analysis of the methylation, and therefore expressions of the DNA, you can also guide more appropriate treatments through assessing prognosis via methylation. Treatment decisions guided by methylation genetics can greatly improve outcomes.

PHARMACO - EPIGENOMICS Methylation data can also help guide treatments outside of cancer via the new and expanding field of pharmaco- epigenomics. This impacts the world of longevity medicine as well. Recently, there was a published study which showed that epigenetic methylation markers were able to predict patient response to metformin and predicted their likelihood of developing side effects [7]. This predictive algorithm is already being used by some epigenetic testing companies such as TruDiagnostic™. Already, there are many epigenetic medications approved by the FDA. As more patients start to get this testing, the data will provide more insights how to change disease outcomes based on loci specific methylation values.

DISEASE RISK PREDICTION AND PERSONALIZED LIFESTYLE AND DIET RECOMMENDATIONS Many of the complaints with previous biomarkers, such as telomeres, have been that testing variation often makes the results unpredictable. While every test has a margin of error, epigenetic methylation testing is very very accurate. Epigenetic age testing has an accuracy of r = 0.96 on subjects aged between 0 to 100 and r = 0.77 in middle age subjects which is substantially higher than that of other molecular markers such as telomere length (r = 0.5) [2]. As a result, this makes it very predictable and reliable to test change over time. One of the leaders in this field, Dr. Steve Horvath from UCLA, has even said “It’s really more likely that planet Earth will be hit by an asteroid tomorrow than that this predictor doesn’t work”. ANTI-AGING MEDICAL NEWS | WINTER 2020

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Benefits of Epigenetic Testing Beyond Biological Aging

DEVELOPMENT OF NEW AND USEFUL CLINICAL BIOMARKERS: As this testing grows and as companies like TruDiagnostic™ start to develop further diagnostic algorithms, we will be able to detect disease processes earlier. There are already several trials which are looking at how interventions can affect epigenetic age [9] [10]. Soon, we will know which interventions are most likely to change the methylation patterns which contribute to specific disease processes such as Alzhiemer’s, diabetes, and, of course, which patterns will increase lifespan. While aging is one of the most exciting areas of epigenetic investigation, there are many other lessons which can be learned from the data gathered from looking at methylation. Together, the large scale data collected from epigenetic analysis can help us detect disease earlier, understand the best ways to treat disease, and learn about the underlying processes which cause these problems so that we can treat them before they cause health issues.

REFERENCES 1.

Jylhävä J, Pedersen N, Hägg S. Biological Age Predictors. EBioMedicine. 2017;21:29-36. http://dx.doi.org/10.1016/j.ebiom.2017.03.046

2.

Lowe D, Horvath S, Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. 2016;7(8):8524-8531. doi:10.18632/ oncotarget.7383

3.

Marioni RE, Shah S, McRae AF, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome biology. 2015;16(1):25. doi:10.1186/s13059-015-0584-6 Horvath S.The epigenetic clock, biological age, and chronic diseases. NIH Wednesday Afternoon Lecture. Masur Auditorium. 2016.

4.

5.

Levine M. An Epigenetic Clock for Aging and Life Expectancy. Yale Center for Research on Aging, Department of Pathology, Yale School of Medicine, Department of Chronic Disease Epidemiology, Yale School of Public Health. 2018. Lissa D, Robles AI. Methylation analyses in liquid biopsy. Transl Lung Cancer Res. 2016;5(5):492-504. doi:10.21037/tlcr.2016.10.03

6.

García-Calzón S, Perfilyev A, Martinell M, et al. Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes. Science translational medicine. 2020;12(561). doi:10.1126/scitranslmed.aaz1803

7.

Dayeh T, Tuomi T, Almgren P, et al. DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk. Epigenetics. 2016;11(7):482-488. doi:10.1080/15592294.20 16.1178418

8.

Fitzgerald K, Hodges R, Hanes D, Stack E, Cheishvili D, Szyt M, Henkel J, Twedt M, Giannopoulou D, Herdell J, Logan S, Bradley R. Reversal of Epigenetic Age with Diet and Lifestyle in a Pilot Randomized Clinical Trial. medRxiv. 2020. https://doi.org/10.1101/2020.07.07.20148098

9.

Fahy GM, Brooke RT, Watson JP, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging cell. 2019;18(6):e13028. doi:10.1111/acel.13028

BIOGRAPHY Hannah Went is the Director of Operations at TruDiagnostic where she has helped implement large scale methylation testing for clinical practices and is a co-author of several upcoming studies about interventions to address biological aging.

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ANTI-AGING MEDICAL NEWS | WINTER 2020



Anti-Aging Benefits of Sulforaphane

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.

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Anti-Aging Benefits of Sulforaphane

Longevity research consistently links cruciferous vegetable intake with enhanced lifespan, yet the exact mechanisms behind this correlation are only recently being uncovered.1 The Human Genome Project of the 1990’s jump started an entirely new field of research known as nutrigenomics, which seeks to understand how specific nutrients effect gene expression, mitochondrial function, and cellular defense mechanisms. From this research, sulforaphane (SFN) was identified as a significant disease-fighting nutrient and has since risen to the spotlight due to its great clinical potential.2 SFN is derived from cruciferous vegetables, particularly broccoli, cabbage, cauliflower, Brussel sprouts, and kale and belongs to a class of plant-based molecules known as isothiocyanates.2 SFN elicits anti-inflammatory and anti-oxidant responses by inducing the autophagic nuclear factor erythroid 2–related factor 2 (Nrf2) pathway and inhibiting the pro-inflammatory NF-κB cascade.3 It also affects epigenetic factors by inhibiting histone deacetylases (HDAC) and DNA methyltransferases and modifying mitochondrial dynamics.4 Furthermore, due to its lipophilic nature and low molecular weight, the bioavailability of SFN is upwards of 82%.1 This is quite staggering considering that the top 4 most frequently consumed polyphenols have less than 4% bioavailability.2 This underscores SFN’s role in clinical settings, especially in relation to age-associated disease.

BIOAVAILABILITY AND FOODS SOURCES Sulforaphane is a particularly interesting nutrient. It is created through an enzymatic conversion between the molecule glucoraphanin and the enzyme myrosinase, which exist in different areas of the plant cell. When cruciferous vegetables are damaged, for example by chewing, blending, chopping, or lightly cooking, myrosinase and glucoraphanin mix together and react, creating the bioactive nutrient sulforaphane. Due to this conversion process, maximizing sulforaphane intake through vegetable consumption can be a confusing and tedious process. Broccoli sprouts appear to be the best food source for sulforaphane. However, research suggests that using SFN supplements supply a precise and guaranteed nutraceutical dose. Thus, SFN supplementation represents an effective administration method, particularly when paired with other botanical nutrients such as curcumin.6

NRF2 ACTIVATION The most prominent nutrigenomic characteristic of SFN is its ability to activate the transcription factor, Nrf2, which subsequently increases several endogenous antioxidant compounds.3 Nrf2 is considered by some researchers as a “guardian of health span and a gatekeeper of species longevity” due to its ability to activate a large number of cellular defense mechanisms.3 Essentially, Nrf2 is sequestered into proteins called Keap-1 proteins. When Keap-1 proteins detect a stressor that may threaten the cell’s integrity, the Nrf2 detaches from Keap-1 and travels to the nucleus of the threatened cell, where it may induce expression of its many target genes.3 One of the most important mechanisms stimulated by Nrf2 is Phase II detoxification, which activates important antioxidant genes and upregulates glutathione production. The sulfur contained within SFN is thought to be responsible for the activation of the Nrf2-Keap-1 complex. Because of its direct effect on Nrf2, SFN has the potential to modulate the expression of genes associated with redox balance, inflammation, detoxification, and antimicrobial capacity which are all considered key components of the upstream cellular defense processes. Nrf2 activation has a preventative effect on numerous age-related diseases because it is ubiquitously expressed throughout the body, including the kidneys, muscle, lung, heart, liver, and brain.3

SFN, NRF2, AND CANCER In a recent study, researchers assessed the effects of oral SFN administration on prostate-specific antigen (PSA) concentrations in patients with recurrent prostate cancer.7 Increases in serum levels of PSA are common in prostate cancer patients after prostatectomy and are signs of biochemical recurrence of disease. In this study, 78 patients received daily oral administration of 60 mg of a stabilized free SFN for 6 months, followed by 2 months without treatment. Results indicated that PSA increases were consistently lower in sulforaphane-treated men and these trends were sustained even after 3 months of discontinuation of SFN.7

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Anti-Aging Benefits of Sulforaphane

SFN, NRF2, AND TYPE 2 DIABETES Other clinical trials have looked at how SFN supplementation impacts patients with type 2 diabetes (T2DM). Age is one of the most important risk factors for T2DM, with the burden of disease increasing dramatically in elderly populations. In the US, diabetes prevalence is 20% in adults ages 65 and older. This is more than eight times the prevalence among adults 18 to 44 years of age (2.4% prevalence).8 In a 4-week randomized, controlled clinical trial, researchers administered daily doses of SFN (5 grams) and broccoli sprout powder (10 grams) in 81 T2DM patients.9 Cardiometabolic and inflammatory biomarkers were used as outcome measures. Results showed that SFN reduced lipid peroxidation and produced favorable redox status as demonstrated by a decrease in plasma malondialdehyde and oxidized LDL.9 Lipid peroxidation is considered an important factor in the pathogenesis of T2DM complications. Similarly, SFN is shown to play a role in downregulating inflammatory biomarkers in patients with obesity.3 Researchers speculated that the positive outcomes of SFN in T2DM patients could improve quality of life and increase longevity in these individuals.

SFN, NRF2 AND NEURODEGENERATIVE DISEASE But that’s not all. Insufficient Nrf2 activity is also implicated in neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, mutiple sclerosis, and more.10 Numerous animal studies show that SFN administration improves cognitive impairment, protects the brain from amyloidogenic damage, and ameliorates neurobehavioral deficits related to Alzheimer’s disease.11,12 These outcomes are attributed not only to SFN’s ability to act on the Nfr2 complex, but also its inhibition of cytochrome P450 enzymes, reduction of lipopolysaccharide-induced inflammation, and induction of heat shock proteins for protein repair.12 This research highlights the innumerable ways that SFN protects the brain and neurons of the central nervous system against numerous insults that accelerate the aging process. Heat shock protein activation, in particular, represents a novel concept by which SFN contributes to cognitive function, neural protection, and enhanced longevity.

HEAT SHOCK PROTEINS Recent evidence has unearthed specific SFN mechanisms that activate heat shock proteins (HSPs). HSPs guard against the misfolding of cellular proteins while also stimulating important

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immune responses, such as enhancing antigen presentation and T-cell proliferation.13 Misfolded proteins, specifically amyloid-beta proteins, give rise to amyloid plaque formation in the brain of Alzheimer’s disease patients. This causes apoptosis of neurons, leading to severe cognitive impairment. In a recent study, researchers treated mammalian cells with SFN under in-vitro conditions and discovered that SFN activated heat-shock protein 27 (Hsp27). This consequently stimulated proteosome activity, leading to reduced levels of oxidized proteins and amyloid β-induced cytotoxicity.13 In vivo research has confirmed these studies using murine models. Animals receiving oral gavage of SFN showed a significant reduction in monomeric and polymeric forms of amyloid-β, which was due to an increase in Hsp27 and Hsp27 interacting protein (CHIP).14 Furthermore, SFN amended memory defects as indicated by an improvement in object/location recognition tests and contextual fear conditioning tests.14 Proteosomes are essentially protein complexes that destroy unneeded or damaged proteins via proteolysis, a chemical reaction that breaks peptide bonds. They are necessary not only for the prevention of brain diseases such as Alzheimer’s, but also for cancers and chronic muscle wasting diseases. Proteosome activation is associated with increased cellular lifespan, cytoprotective gene expression, and prevention of neurodegeneration.4,5 Researchers suspect these mechanisms are responsible for the neurologic health benefits associated with cruciferous vegetable intake.

ENHANCED DETOXIFICATION Through the removal of potentially noxious substances, metabolic detoxification pathways can spare tissue from free radical damage and help maintain mitochondrial function.15,16 Indeed, several human and animal studies suggest that lifespan may be increased through the stimulation of these fundamental detox pathways, which can be categorized in two phases.16 Phase I detoxification is described as functionalization, or the addition of oxygen to form a reactive site on the toxic compound.15 Phase II involves conjugation, or the process of adding a water-soluble group to this now reactive site.15 Each of these phases involves a superfamily of enzymes, with Phase I enzymes being dictated by the cytochrome P450 gene.15 This group of enzymes are involved in the biotransformation of xenobiotics, steroid hormones, and pharmaceuticals. These enzymes are found mainly in the liver, and to a lesser extent in the intestines, lungs, brain, and kidneys.15 Detoxification pathways are particularly important for elderly populations, as

ANTI-AGING MEDICAL NEWS | WINTER 2020


Anti-Aging Benefits of Sulforaphane

polypharmacy is widespread in this age group and can lead to the accumulation of toxic byproducts that are found circulating the bloodstream following pharmaceutical metabolism. Neutralizing these substances is paramount to preserving liver health. Human studies show that cruciferous vegetables act as inducers of many important Phase I detoxification enzymes involved in pharmaceutical metabolism. Furthermore, SFN is one of the most important inducers of Phase II antioxidant and detoxification enzymes.15 A recent study evaluated the impact of cruciferous vegetable intake on the metabolism of methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogen found in cooked foods.17 Twenty apparently healthy subjects completed the study, which consisted of three 12-day phases: two periods of avoidance of cruciferous vegetables (phases 1 and 3) and one period of high cruciferous vegetable intake (phase 2). High cruciferous vegetable intake was defined as 250 g each of Brussels sprouts and broccoli per day, which provides approximately 1,200 mg of SFN. At the end of each study phase, the subjects consumed a meal of cooked meat containing 4.90 micrograms of PhIP, and urine samples were collected for up to 48 hours. Results indicated that urinary excretion of PhIP metabolites after cruciferous vegetable consumption was 127% and 136% higher than metabolite levels observed in phases 1 and 3, respectively. The

increase in PhIP metabolite excretion shows that carcinogen metabolism was completed at a significantly higher rate after SFN consumption, indicating the induction of detoxification enzymes. Researchers indicate that elimination of carcinogens via increased SFN intake may reduce risk of certain cancers, as indicated by numerous epidemiologic studies.1,18 Indeed, animal studies have revealed a decrease in carcinogen-induced cancer tumors following oral administration of SFN.18 Broccoli, kale, and other cruciferous vegetables have long been recognized for their contribution to longevity and disease prevention. With the explosion of new scientific domains such as nutrigenomics, researchers have been able to pinpoint the exact phytonutrients and mechanisms behind the health benefits of such cruciferous vegetables. Sulforaphane rightfully takes center stage as one of the most potent nutrients for detoxification, life extension, anti-inflammation, and antioxidant activity. SFN is recognized for its ability to offset aesthetic characteristics of aging, such as UV skin damage and hair loss, but more importantly SFN is distinguished for its disease-fighting properties. Furthermore, SFN is one of the most bioavailable phytonutrients, making it a supreme and valuable nutrient for clinical applications.

“Kasey Hutchinson is a Registered Dietitian and Content Specialist for Microbiome Labs, an innovative nutraceutical company establishing new frontiers in functional medicine and probiotic spore supplementation.”

REFERENCES 1.

Zhang X, et al. Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality. Am J Clin Nutr. 2011;94(1):240-246. doi:10.3945/ajcn.110.009340

2.

Houghton CA, et al. Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician’s Expectation Be Matched by the Reality?. Oxid Med Cell Longev. 2016;2016:7857186.

3.

Houghton, et al. Sulforaphane: Its “Coming of Age” as a Clinically Relevant Nutraceutical in the Prevention and Treatment of Chronic Disease. HINDAWI. 2019; 2716870.

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Santín-Márquez R, et al. Sulforaphane - role in aging and neurodegeneration. Geroscience. 2019;41(5):655-670. 7

5.

Sikdar, et al. What do we know about sulforaphane protection against photoaging? JCD. 2016; (15)1:72-77

6.

Cheung KL, et al. Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharm Res. 2009;26(1):224-31.

7.

Cipolla BG, et al. Effect of Sulforaphane in Men with Biochemical Recurrence after Radical Prostatectomy. Cancer Prev Res (Phila). 2015;8(8):712-719.

8.

Z. Bahadoran, et al. Broccoli sprouts reduce oxidative stress in type 2 diabetes: a randomized doubleblind clinical trial. European Journal of Clinical Nutrition. 2011; 65(8):972–977.

9.

Selvin E, Parrinello CM. Age-related differences in glycaemic control in diabetes. Diabetologia. 2013;56(12):2549-2551. doi:10.1007/s00125-013-3078-7

10.

Ramsey CP, et al. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 2007;66(1):75-85.

11.

Zhang R, et al. Sulforaphane ameliorates neurobehavioral deficits and protects the brain from amyloid β deposits and peroxidation in mice with Alzheimer-like lesions. Am J Alzheimers Dis Other Demen. 2015;30(2):183-191.

12.

Kim HV, et al. Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model. Amyloid. 2013;20(1):7-12.

13.

Gan N, et al. Sulforaphane Activates Heat Shock Response and Enhances Proteasome Activity through Up-Regulation of Hsp27. The Journal of Biological Chemistry. 2010; 285(46): 35528–35536.

14.

Lee S, et al. Sulforaphane Upregulates the Heat Shock Protein Co-Chaperone CHIP and Clears Amyloid-β and Tau in a Mouse Model of Alzheimer’s Disease. Mol Nutr Food Res. 2018;62(12):e1800240.

15.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/

16.

Wen H, et al. Enhanced phase II detoxification contributes to beneficial effects of dietary restriction as revealed by multi-platform metabolomics studies. Mol Cell Proteomics. 2013;12(3):575-586.

17.

Walters DG, et al. Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. Carcinogenesis. 2004;25(9):1659-1669

18.

Bauman JE, et al. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane. Cancer Prev Res (Phila). 2016;9(7):547-557

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The “Gut Lung Axis�

The Importance Of Various Microbial Niches On Pulmonary Health

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.

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ANTI-AGING MEDICAL NEWS | WINTER 2020


The “Gut - Lung Axis� - The importance of various microbial niches on pulmonary health.

Respiratory conditions, both chronic and acute, are some of the most common issues seen in clinical practice. In 2016, chronic obstructive pulmonary disease (COPD) alone accounted for around 3 million deaths, and was the third leading cause of death worldwide.1 Asthma is one of the most common chronic diseases globally affecting nearly eight percent of people (over 24 million) in the US alone. Childhood onset of asthma can impair airway development, and persist into adulthood. Adult asthma may accelerate the decline of pulmonary function, and increase susceptibility to infection. Both children and adults with severe asthma have impaired innate antiviral immunity with altered cytokine responses, and increased risk of hospitalization - an issue of particular concern currently. Comorbid conditions are common, with almost two-thirds of those with asthma having at least one comorbidity. The most common comorbidities are diabetes, osteoporosis, metabolic syndrome, cardiovascular disease, and mental illnesses.1 Lower respiratory infections were the 5th leading cause of death and the leading cause of infectious death globally in 2015.2 With the prevalence of both chronic and acute respiratory illnesses, it is in the best interest of our patients to identify and address root cause and practice prevention. Accumulating evidence has highlighted the influence of the gut microbiota on lung immunity -- the gut-lung axis -- and current research has drawn a strong correlation between dysbiosis of several anatomical areas and pulmonary health or disease. Here is a synopsis of current research focusing on the microbiome, the Gut-Lung Axis, and their roles in pulmonary health. Every chronic lung condition exhibits an altered pulmonary microbiome - Until recent years, the lungs were thought to be sterile, which has been proven untrue. In fact, pulmonary health can be predicted by the presence of healthy microorganisms. Asthma, COPD, pneumonia, cystic fibrosis and all other chronic lung diseases have an unhealthy balance of beneficial and pathogenic organisms.2 The microbiome influences the host immune system Beneficial microorganisms in the gastrointestinal tract assist in the development of healthy immune function including defense through regulation of T cells, systemic inflammation and tolerance. Pathogenic organisms contribute to immune imbalances and a shift toward allergy and autoimmunity.2 3 Immune cells in the lungs recruit from primed immune cells

in the gastrointestinal (GI) lymphatics - In an illustration of the complexity and the beauty of human physiology, when we get exposure to a pathogen in the sinuses, mouth and throat, the bugs are swallowed and read by the lymphatics in the gut (Gut-associated lymphoid tissue, or GALT), which then produce an artillery of defenses just in case an infection occurs. When it does, the immune system in the lung actively recruits those defenses to fend off illness.5 The gut and lung microbiota contribute to exacerbations of lung disease - Gastrointestinal dysbiosis can contribute to oral and pulmonary dysbiosis, all of which can result in exacerbations of lung disease.5 One study reported that more than 70 percent of people with severe lung disease also have gastroesophageal reflux disease (GERD), a common association with GI dysbiosis. The microbiome of the lung is most closely associated with the oral microbiome - During sleep, microaspiration of saliva occurs, resulting in the transfer of microorganisms from the mouth to the lungs. Since plaque and periodontal pockets are sources of microorganisms, oral hygiene and the oral microbiome need to be tended as well.1 The gut microbiota contributes to acute lung injury - Bacterial metabolites, such as lipopolysaccharides (LPS), mediate systemic inflammation and tissue injury via stimulation of toll-like receptor 4 (TLR4) receptors. Reducing endotoxins via modulating the microbiome can assist in maintaining a balanced immune/ inflammatory response, allowing for immunity that protects - but is regulated - to prevent damage.5 The vagus nerve is involved - When the vagus nerve is sending healthy signals, it prevents shock induced organ injury - including in the lungs - and prevents gut barrier injury.5 However, gastrointestinal dysbiosis can result in damage to the vagus nerve as endotoxins migrate to the brain and cause inflammation.1 Beneficial microorganisms reduce systemic inflammation - Production of short chain fatty acids such as butyrate and acetate by beneficial bacteria helps to reduce inflammation throughout the whole body, establishing balanced and effective immune activity .6

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The “Gut - Lung Axis” - The importance of various microbial niches on pulmonary health.

It is clear that targeting the microbiome may benefit overall health, including the lungs. Providing support to the gastrointestinal microbiome is important, and it is also vital to remember the influence of the oral microbiome on the gastrointestinal microbiome. Research has shown that organisms that exist in the mouth can translocate to the gut, and cause dysbiosis there. Additionally, since the pulmonary microbiome is most closely related to that of the mouth, if left untreated and unbalanced, the oral microbiome may be a source of persistent illness in the lungs and the GI tract. Furthermore direct translocation of pathogens from the mouth to systemic blood flow can occur, resulting in damage to the lungs other organs. “Less than 1 minute after an oral procedure, organisms from the infected site may have reached the heart, lungs, and peripheral blood capillary system”.1

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 Gram positive and Gram-negative organisms. Goldenseal, Black Walnut, White Willow, Raspberry Leaf and Garlic are a few that have been studied. Bacteriostatic agents inhibit the reproduction of biofilm organisms and so help to control the spread of infection. Berberine has been proven bacteriostatic for S. epidermidis. One study showed that sub-minimal inhibitory concentrations blocked the formation of S. epidermidis biofilms. Both Gentian and Goldenseal contain berberine and are most useful additions to the biocidal combination for biofilm

As clinicians, we are always on the lookout for clinically effective products and practices. Botanicals offer well tolerated and effective options. Virtually all botanicals carry multiple activities in the body. Herbal medicines have been utilized in the treatment of infection for thousands of years, and provide a safe and effective option for addressing biofilms and dysbiosis, while simultaneously supporting healthy immune response. Using the properties of more than one botanical in a combination or formula provides a broader spectrum of activity against multiple classes of organisms. The resulting formulations, or “biocidal combinations”, are powerful allies that may be used to address infection.

BOTANICALS ARE EFFECTIVE AGAINST BIOFILMS AND PLANKTONIC ORGANISMS 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 auto inducers 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 anti-microbial ability. This new understanding of how they can combat biofilms highlights their clinical and historical significance.

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The “Gut - Lung Axis” - The importance of various microbial niches on pulmonary health.

control. Grape Seed and Bilberry contain condensed tannins that prevent adherence of biofilms, and may inhibit swarming One study, performed at the University of Binghamton in 2013 shows the complete eradication of biofilms and remarkably broad spectrum of activity with exposure to a Biocidal formula containing Bilberry extract, Noni, Milk Thistle, Echinacea (purpurea & angustifolia), Goldenseal, Shiitake, White Willow, Garlic, Grape Seed extract, Black Walnut (hull and leaf ), Raspberry, Fumitory, Gentian, Tea Tree oil, Galbanum oil, Lavender oil, and Oregano oil. This botanical combination was tested on both planktonic organisms and biofilm communities. Pathogens

including pseudomonas, e.coli, and candida biofilms were eliminated in a matter of hours and did not recur.

BOTANICALS IN ORAL INFECTION Botanicals have a long history of use for oral health. A recent pilot study illustrates the potential of a liposomal botanical formula to significantly reduce pathogen load. In this study, 35 pathogens were detected, followed by one month of treatment with the botanical formula. The result can be seen below, with the bacteria reduced to four remaining pathogens. The study showed clearance of bacterial, viral, amoeba, and fungal pathogens.

“The Liposomal botanicals used in our study appear to be a wonderful adjunct in the treatment of periodontal disease. This statement is based on actual controlled pilot studies that I have performed clinically in my office. The periodontal study was utilizing classic clinical periodontal parameters and phase contrast microscopy. Based on these studies, I am using these as an adjunct in my office every day and would highly recommend them.” ~John A. Rothchild,

DDS, MAGD, IMD, DAAPM, NMD, IBDM.

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The “Gut - Lung Axis” - The importance of various microbial niches on pulmonary health.

There is a wealth of data available definitively demonstrating the usefulness of botanicals as a safe and effective strategy addressing bacterial, viral, and fungal infections. 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 for supporting immune function both by balancing the various microbiota and by direct modulation of immune activity in the oral and gatrointestinal mucosa.

https://www.researchgate.net/publication/309251855_Emerging_pathogenic_links_between_microbiota_and_the_gut-lung_axis

REFERENCES 1. https://www.statista.com/topics/4339/chronic-obstructivepulmonary-disease-copd-in-the-us/#dossierSummary__chapter1

7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751994/pdf/ nihms756902.pdf

2. https://www.frontiersin.org/articles/10.3389/fped.2019.00246/full

8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751994/pdf/ nihms756902.pdf

3. https://www.healio.com/news/infectious-disease/20170829/lowerrespiratory-tract-infections-remain-leading-infectious-cause-ofdeath-worldwide 4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751994/pdf/ nihms756902.pdf 5. https://www.tandfonline.com/doi/full/10.1080/104084 1X.2016.1176988

9. https://journals.physiology.org/doi/full/10.1152/ajpgi.00412.2001 10. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0757.1994. tb00019.x?sid=nlm%3Apubmed 11. https://www.researchgate.net/publication/330679419_The_Effects_ of_a_Botanical_Blend_on_Post-Exercise_Mucosal_Antimicrobial_ Proteins

6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595839/

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INTRODUCING

THE LONGEVITY WHEEL AMPK

Regulates metabolic health and flexibility, autophagy, and lipolysis

HORMONES Regulates internal communications to maintain homeostasis

SIRTUINS Regulates DNA repair, cellular signaling, energy metabolism, inflammatory response

Target Hormones: Estrogen • DHEA • Progesterone • Testosterone • Pregnenolone •

Activating Compounds: • NAD+ • Resveratrol • Quercetin • Pterostilene

SENOLYTICS Manages the presence and activity of senescent cells Senolytic Compounds: Quercetin • Luteolin • Fiestin •

Activating Compounds: • Resveratrol • PQQ • Quercetin • Silymarin • Berberine Ma • Many more

NAD+ TELOMERES Regulates gene expression, cellular aging

Introducing Quicksilver Scientific's Longevity Wheel, a cutting-edge theory of longevity developed by Dr. Chris Shade. The Longevity Wheel is based on the most well researched and interconnected areas long of longevity, including activation of AMPK, sirtuins and telomerase, along with production of NAD+, mitigation of cellular senescence, and optimization of hormones. 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.

Telomerase Activators: • Glutathione • Astragaloside IV • Cycloastragenol

Regulates energy metabolism, DNA Repair NAD+ Precursors: • Nicotinamide mononucleotide (NMN) • Nicotinamide riboside (NR)

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quicksilverscientific.com


AMPK Impacts on Metabolic Function & Immune Health

By: Christopher Shade, Ph.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.

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AMPK Impacts on Metabolic Function & Immune Health

In the United States and many other industrialized countries, we are dealing with two simultaneous health threats: The global COVID-19 pandemic and the epidemic of poor metabolic health. Recent statistics indicate that a mere 12 percent of U.S. adults are metabolically healthy, indicating that a massive proportion of our population is metabolically unfit.1 Unfortunately, our poor collective metabolic health appears to be a significant factor in the pandemic we currently face as a global society. A rapidly-growing body of research indicates that disease outcomes in COVID-19 and poor metabolic health are

inexorably linked. Poor metabolic health significantly increases the risk of suffering a severe course of COVID-19 and experiencing lingering, troublesome symptoms after the resolution of the illness, such as cognitive impairment.2,3 To survive this pandemic and protect our health going forward, we must prioritize our metabolic health. We can’t just wait until metabolic health crumbles apart in full-blown Type 2 diabetes and cardiovascular disease; we must approach metabolic health head-on with proactive, evidence-based interventions. AMPK activation represents an emerging, powerful strategy for metabolic health optimization.

ARTICLE AT A GLANCE • What is AMPK? • How AMPK Impacts Metabolic Function & Immune Health • Autophagy and Cellular Detoxification • Mitochondrial Efficiency • Immune Health and Function • Gut Health • Liver Function • Healthy Aging and Longevity • Nutraceutical and Lifestyle Strategies for AMPK Activation • The relationship between NAD+ and AMPK AMPK-Activating Phytonutrients

Lifestyle Strategies

Berberine

Fasting

Quercetin

Ketogenic Diet

Resveratrol

Exercise

Apigenin

Sleep-Low Eating and Exercise Strategy

Curcumin Alpha Lipoic Acid

WHAT IS AMPK? AMP-kinase, known as AMPK, is an enzyme and cellular energy sensor that plays vital roles in cellular energy homeostasis. It is a central regulator of metabolism, energy, and body weight and is one of the body’s most critical biochemical pathways. AMPK senses when cellular energy levels are

depleted by detecting low adenosine monophosphate (AMP), an ATP with two of its high-energy phosphates removed. Upon sensing low AMP, AMPK activates pathways that promote cellular energy generation.4 AMPK is activated by various inputs, including calorie restriction, fasting, reduced blood insulin levels, and exercise. Activation of AMPK produces multiple beneficial health effects, including reduced

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AMPK Impacts on Metabolic Function & Immune Health

inflammation and enhanced insulin sensitivity. We will expand on the many benefits of AMPK activation momentarily. The mammalian/mechanistic target of rapamycin (mTOR) pathway works mostly in opposition to AMPK. Whereas AMPK is activated by a low cellular energy state, mTOR is an anabolic pathway activated when nutrients and cellular energy are plentiful. While mTOR activation plays essential roles in several physiological functions, including growth and development and the skeletal muscle response to exercise, chronic mTOR activation is problematic and promotes sustained inflammation and metabolic dysfunction. In our ancestral environment, intermittent food availability necessitated periodic fasting. Today, scientific research indicates that fasting is one of the most potent activators of AMPK; this finding suggests that our bodies evolved to regularly experience intermittent AMPK activation. Conversely, living life in a chronically “fed” state, as many of us do in the modern-day Western world, inhibits AMPK and activated mTOR, preventing us from realizing the health benefits of the powerful AMPK pathway. When we miss out on AMPK activation, our metabolic health and immune function suffer. Conversely, an active AMPK pathway improves numerous physiological processes underlying metabolic wellbeing and healthy immune function.

HOW AMPK IMPACTS METABOLIC FUNCTION & IMMUNE HEALTH The AMPK protein has profound, far-reaching effects on metabolic health.5 More recently, AMPK has also been identified as an essential player in regulating the immune system. An active AMPK pathway powers metabolic health and robust immunity, two aspects of health that have never been more important than in our current environment.

MODULATES INFLAMMATORY BALANCE At a foundational level, AMPK modulates the body’s inflammatory balance. Chronic, low-level inflammation is an underlying factor in numerous chronic diseases, including dysfunctional metabolic states such as type 2 diabetes and cardiovascular disease. By resolving inflammation, AMPK creates a foundation for whole-body health, including healthy metabolic function and immunity.

IMPROVES INSULIN SENSITIVITY AND

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GLYCEMIC HOMEOSTASIS AMPK has profound impacts on glycemic homeostasis. AMPK activation attenuates insulin resistance and hyperinsulinemia, stepping stones in the progression of metabolic dysfunction.6 These changes shift the body from burning primarily glucose for fuel to utilizing fat for fuel. The shift to fat burning for energy production reduces reactive oxygen species generation, creating cleaner-burning energy. The shift towards fat-burning also helps the body better access fat stores for fuel; this may reduce body fat mass. Reducing body fat mass alleviates the vicious cycle of inflammation and metabolic dysfunction perpetuated by excessive amounts of adipose tissue, a highly metabolicallyactive organ that produces proinflammatory cytokines.7

IMPROVES LIPID HOMEOSTASIS While the idea that total cholesterol, and even total LDL cholesterol, contribute appreciably to cardiovascular disease has been debunked, several more nuanced subcategories of blood lipids do indeed influence cardiometabolic disease pathogenesis. The subcategories include the total LDL particle number and oxidized LDL levels. Here too, AMPK activation exerts beneficial modulatory effects. AMPK inhibits acetyl coenzyme A carboxylase (ACC) and 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzymes for fatty acid and cholesterol biosynthesis. The inhibition of these enzymes reduces total cholesterol production and may reduce the number of LDL particles generated by the body.8 It also inhibits endoplasmic reticulum stress, a form of cellular stress, triggered by oxidized LDL particles.9 AMPK also improves cardiovascular health by improving carbohydrate metabolism.10 AMPK activation also inhibits NF kappa B, reducing vascular inflammation. Vascular inflammation Is a critical risk factor for cardiovascular disease.11 It also increases endothelial nitric oxide synthase (eNOS) and nitric oxide production while decreasing reactive oxygen species, further improving vascular function.

PROMOTE AUTOPHAGY AND CELLULAR DETOXIFICATION AMPK is a potent activator of autophagy, the body’s cellular “housekeeping” system. Autophagy via AMPK

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AMPK Impacts on Metabolic Function & Immune Health

activation and mTOR blocking offers a profound level of detoxification that cleanses the body at a cellular level. Abundant research indicates that both exogenous and endogenous toxins drive metabolic and immune dysfunction. Clearing toxins from the system through detoxification is essential for achieving metabolic clarity and optimal immune health. By promoting autophagy, AMPK activation jump-starts the removal of health-hindering toxins.

INCREASE MITOCHONDRIAL EFFICIENCY As discussed earlier, one of the primary goals of AMPK activation is to restore cellular ATP levels. One mechanism through which AMPK accomplishes this goal is via the activation of mitochondrial biogenesis.12 Improvements in mitochondrial function induced by AMPK exert downstream benefits on blood glucose regulation and inflammation. Amplify Immune Health

the body’s frontline defense against pathogens.

OPTIMIZE GUT HEALTH Over 80 percent of the human immune system resides in the gut, making gut health the foundation for a robust, resilient immune system.17 Furthermore, a growing body of research indicates that gut health and the gut microbiota influence metabolic health parameters, including blood glucose control.18 Here too, AMPK plays an essential role. AMPK activation has been found to repair paracellular tight junctions, improving intestinal barrier integrity and inhibiting “leaky gut,” a phenomenon that may underlie numerous chronic diseases.19 Fascinatingly, research indicates that certain gut bacteria modulate AMPK activity, influencing the course of metabolic function. Gut microbes may exert these modulatory effects on AMPK through short-chain fatty acids (SCFA), metabolites produced through microbial metabolism of dietary fibers.20

The global pandemic has brought the human immune system into the spotlight, highlighting the need for novel immunemodulating strategies that can enhance our resilience against this, and future, environmental immune challenges. While most of the world waits with bated breath for a vaccine for SARS CoV-2, we at Quicksilver Scientific believe in taking a more proactive approach by bolstering our own internal immune defenses. One powerful, yet underappreciated, way to enhance healthy immune function is through AMPK activation.

FACILITATE LIVER FUNCTION

Metabolism can either inhibit or enhance immune vigilance, the process by which the immune system surveys the body’s internal environment for immune threats such as pathogens. A primary mechanism through which poor metabolic health may increase the risk of contracting threats, such as viral infection, is by impairing immune surveillance. AMPK activation may improve immune function by enhancing immune surveillance and the host defenses against infectious invaders.13

AMPK activation attenuates fatty liver disease by reducing inflammation, attenuating the adverse metabolic effects of overnutrition, and upregulating autophagy.21

A healthy liver is a prerequisite for metabolic health. However, poor metabolic health also contributes to compromised liver function, mainly through the development of non-alcoholic fatty liver disease (NAFLD). In NAFLD, excess fat builds up in the liver due to impairments in glucose and lipid metabolism caused by overnutrition, chronic inflammation, and gut dysbiosis.

PROMOTE HEALTHY AGING AND LONGEVITY

Emerging research indicates that modulation of autophagy also impacts immune function.14,15 Here too, AMPK can play a supportive role via its autophagy-enhancing effects.

Preliminary research indicates that accelerated biological aging predicts an increased risk of contracting and suffering from COVID-19.22 Whether accelerated biological aging is associated with other infections remains to be seen; regardless, these findings suggest that attenuating the biological aging process is vital for supporting immune function and resilience.

A special subset of autophagy, called xenophagy, is also activated by AMPK.16 Xenophagy is a selective form of autophagy by which macrophages capture pathogens in autophagosomes, and then fuse the autophagosomes with lysosomes to eliminate the pathogens. Xenophagy is an essential component of the innate immune response,

AMPK activates the production of two sets of proteins involved in healthy aging and longevity, the sirtuins and FOXO proteins. Sirtuins are a family of seven proteins that play regulatory roles in almost all cellular functions. Sirtuins regulate inflammation, cell growth, circadian rhythms, energy metabolism, neuronal function, and stress resistance.23 FOXO proteins, on the other

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AMPK Impacts on Metabolic Function & Immune Health

hand, are transcription factors that bind to specific regions on DNA, controlling the transmission of genetic information. FOXO proteins are transcriptional regulators that influence cell replication, DNA repair, autophagy, and metabolism. At the nexus of these pathways, FOXO also appears to influence aging.24 The AMPK and FOXO pathways are closely linked in that active AMPK directly phosphorylates FOXO. In fact, the relationship between AMPK and FOXO may play a crucial role in the longevity-enhancing effects of caloric restriction.25 Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for sirtuins.26 Without sufficient NAD+, sirtuins cannot effectively perform their numerous vital roles within the body.

NUTRACEUTICALS FOR AMPK ACTIVATION The role of phytochemicals as mediators of human metabolic health has an evolutionary basis. Just as our bodies are evolutionarily wired to benefit from AMPK signaling, so too are our bodies biologically designed to interact with and reap health benefits from phytochemicals present in edible plants.27 In fact, some scientists suggest that a dietary deficiency of phytochemicals contributes to disorders of energy metabolism; a lack of consumption of AMPK-activating phytochemicals may be an important part of our metabolic health puzzle. A variety of phytonutrients have been found to activate AMPK. Let’s discuss each of these phytochemicals in turn.

BERBERINE Berberine is an alkaloid compound found in the root, rhizomes, and bark of a variety of plants, including plants in the Berberis genus such as Barberry and Oregon Grape. It has powerful effects on glycemic control and blood lipid homeostasis that can be traced back to its impact on the induction of AMPK activity. Induction of AMPK activity by berberine results in improvements in insulin sensitivity due to increased GLUT4 translocation into cells, allowing for increased cellular glucose uptake and reduced lipid accumulation in 3T3-L1 adipocytes, a cell line of adipose cells used in animal research.28 Through AMPK activation, berberine may help cells use up stored fat energy from adipocytes and suppresses inflammatory responses in macrophages.29 In clinical trials, berberine has been found to beneficially alter the

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lipid profile of individuals at risk for cardiovascular disease.30

QUERCETIN Quercetin is a flavonoid found in an array of fruits and vegetables, including apples, capers, onions, and berries. It offers antioxidant activity largely through AMPK activation. It inhibits lipid accumulation in the liver in response to a high-fat, high carbohydrate processed diet.31 Quercetin also activates AMPK and SIRT1 to reduce obesity-associated inflammation.32

RESVERATROL Resveratrol is a polyphenol primarily concentrated in red grapes and red wine. Resveratrol is a potent AMPK activator.33 It has been found to reduce reactive oxygen species generation and increase reduced glutathione levels via a mechanism dependent on AMPK activation.34 By enhancing the activation of AMPK, resveratrol also promotes mitochondrial biogenesis and neurogenesis; notably, these effects are interdependent on sirtuins, demonstrating clear connections between the NAD+-dependent sirtuin proteins and AMPK. Interestingly, a combination of quercetin and resveratrol has been found to attenuate obesity and adipose tissue inflammation in animals fed a high-fat, high-sugar processed diet.35

APIGENIN Apigenin is a flavonoid found in parsley, celery, onions, chamomile, thyme, oregano, and basil. Unlike berberine, quercetin, and resveratrol, it is not a potent direct AMPK activator. On the contrary, it exerts rather weak AMPK-activating effects. However, it may indirectly support AMPK activity, and other metabolic pathways that intersect with AMPK, by inhibiting CD38, a glycoprotein found on immune cells that is a prolific consumer of NAD+.36 The inhibitory effects of apigenin on CD38 preserve cellular NAD+ homeostasis, sparing NAD+ for other crucial functions, such as sirtuin activation.

CURCUMIN Curcumin is a phytochemical found in the bright orange root of the turmeric plant, Curcuma longa. Curcumin is a truly pleiotropic molecule, with effects ranging from antioxidant activity to prebiotic properties on the gut microbiota. Recent research has added another function to the long list of curcumin’s effects – AMPK activator.

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AMPK Impacts on Metabolic Function & Immune Health

Curcumin’s AMPK-activating effects dampen gluconeogenesis, enhance insulin sensitivity, and induces autophagy.37,38,39

ALPHA LIPOIC ACID (ALA)

may be impaired in those with pre-existing metabolic dysfunction, suggesting that a multifaceted approach may be needed in these individuals to improve skeletal muscle AMPK activity.

SLEEP - LOW EATING AND EXERCISE STRATEGY

While not a phytochemical, alpha-lipoic acid is a naturallyoccurring thiol-based molecule and nutraceutical with AMPK activity, and thus is worthy of our attention. Alpha-lipoic acid enhances skeletal muscle function and endothelial function and exerts anti-obesity effects through AMPK activation.40,41,42 Phytochemical-based AMPK activators exist on a spectrum, with quercetin, resveratrol, and berberine exerting the strongest AMPK-activating effects.

LIFESTYLE STRATEGIES FOR AMPK ACTIVATION FASTING Fasting is a well-known activator of AMPK. AMPK activation in skeletal muscle during fasting results in the phosphorylation and inhibition of acetyl-CoA carboxylase and a subsequent increase in fatty acid oxidation, otherwise known as “fat burning.”43

KETOGENIC DIET A ketogenic diet, defined as a very-low-carb, moderate protein, high-fat diet, is another tool for activating AMPK. By suppressing insulin levels, the ketogenic diet removes an important barrier to AMPK activation. Furthermore, beta-hydroxybutyrate, one of the ketone bodies produced in nutritional ketosis, suppresses inflammation through AMPK activation.44

EXERCISE Skeletal muscle is a metabolically active tissue that plays a vital role in the body’s metabolic homeostasis. It is a significant site for the uptake of circulating blood glucose; accelerated uptake of glucose by active skeletal muscle reduces blood glucose levels, inhibiting hyperglycemia and improving blood sugar homeostasis. Another mechanism through which skeletal muscle influences metabolism is its impact on AMPK activation when the muscle is actively engaged in exercise. Several forms of exercise have been found to activate AMPK, including sprints, high-intensity interval training (HIIT), and aerobic exercise.45,46,47,48 Interestingly, muscle AMPK activation

AMPK is clearly involved in the body’s physiological adaptations to exercise. A robust body of research indicates that adaptations to exercise can be further enhanced with nutrition. One method for enhancing physiological adaptation to exercise that further capitalizes on AMPK activation is the “sleep low” nutrition strategy. The “sleep low” nutrition strategy involves training late in the day and eating a low-carb meal for dinner, thereby causing you to go to bed in a carbohydrate-restricted state. The next morning, you do low-intensity exercise, such as jogging or walking, first thing in the morning while still in the fasted state. You then eat normally, with plenty of carbohydrates, for the rest of the day until you do another evening workout. This strategy is best used twice a week on days where you plan to engage in high-intensity workouts late in the day; it is not intended to be used daily. Research suggests it can offer significant exercise performance benefits, in part through AMPK activation, when incorporated into a comprehensive training regimen.

THE RELATIONSHIP BETWEEN NAD+ AND AMPK How are NAD+ and AMPK related? NAD+ is a critical cofactor for sirtuins, a family of seven proteins involved in cellular health and longevity. Sirtuins and AMPK, in turn, engage in crosstalk and share many common target molecules.50 For example, sustained activation of AMPK activates sirtuins. Sirtuins and AMPK, in turn, work together to regulate aspects of metabolic health, including the metabolic health benefits of exercise. 51 The sirtuin-activating effects of AMPK necessitate a high level of NAD+, an essential cofactor for sirtuin activation. Without sufficient NAD+, it may not be possible to realize the full spectrum of health benefits offered by AMPK activation. Both NAD+ production and AMPK signaling decline with age, causing defects in metabolic function.52,53 In animal studies, restoring NAD+ levels ameliorates age-associated decrements in health, including impairments in metabolic health. Furthermore, immune cells rapidly use up NAD+ when fighting off pathogens; exposure to pathogens and other immune threats may thus deplete NAD+ stores.54 Supplementation with NAD+ precursors, such

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AMPK Impacts on Metabolic Function & Immune Health

as NMN, represent a potential intervention for restoring and maintaining our metabolic health and immune function as we age and in the presence of environmental immune threats.55

and immune resilience. Through diet and lifestyle changes and strategic supplementation, it is possible to induce a therapeutic activation of AMPK and experience the downstream benefits on multiple aspects of metabolic health and immunity.

An abundance of research at our fingertips indicates that AMPK activation is an essential process for optimizing metabolic health

ARTICLE SUMMARY • What is AMPK? AMP-kinase, known as AMPK, is an enzyme and cellular energy sensor that plays vital roles in cellular energy homeostasis. • How AMPK Impacts Metabolic Function & Immune Health: An active AMPK pathway powers metabolic health and robust immunity supporting inflammatory balance, insulin sensitivity, and lipid and glycemic homeostasis. • Autophagy and Cellular Detoxification: AMPK is a potent activator of autophagy, the body’s cellular “housekeeping” system. Autophagy via AMPK activation and mTOR blocking offers a profound level of detoxification that cleanses the body at a cellular level. • Mitochondrial Efficiency: AMPK activates mitochondrial biogenesis to restore cellular ATP levels. • Immune Health and Function: AMPK activation may improve immune function by enhancing immune surveillance and the host defenses against infectious invaders. • Gut Health: AMPK activation has been found to repair paracellular tight junctions, improving intestinal barrier integrity and inhibiting “leaky gut,” a phenomenon that may underlie numerous chronic diseases. • Liver Function: AMPK activation attenuates fatty liver disease by reducing inflammation, attenuating the adverse metabolic effects of overnutrition, and upregulating autophagy • Healthy Aging and Longevity: AMPK activates the production of two sets of proteins involved in healthy aging and longevity, the sirtuins and FOXO proteins. • Nutraceutical and Lifestyle Strategies for AMPK Activation: The role of phytochemicals as mediators of human metabolic health has an evolutionary basis. In fact, some scientists suggest that a dietary deficiency of phytochemicals contributes to disorders of energy metabolism; a lack of consumption of AMPK-activating phytochemicals may be an important part of our metabolic health puzzle. AMPK-Activating Phytonutrients

Lifestyle Strategies

Berberine

Fasting

Quercetin

Ketogenic Diet

Resveratrol

Exercise

Apigenin

Sleep-Low Eating and Exercise Strategy

Curcumin Alpha Lipoic Acid • The relationship between NAD+ and AMPK: Sirtuins and AMPK, in turn, work together to regulate aspects of metabolic health, including the metabolic health benefits of exercise.

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REFERENCES 1 Araujo J, et al. Prevalence of optimal metabolic health in American adults: National health and nutrition examination survey 2009–2016. Metab Syndr Relat Disord. 2019; 17(1): 46-52. 2 Ayres JS. A metabolic handbook for the COVID-19 pandemic. Nature Metab. 2020. 2: 572-585. 3 Zhou H, et al. The landscape of cognitive function in recovered COVID-19 patients. J Psychiatr Res. 2020; 129: 98-102. 4 Garcia D and Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017; 66(6): 789-800.

5 Garcia D, et al. Genetic liver-specific AMPK activation protects against dietinduced obesity and NAFLD. Cell Rep. 2019; 26(1): 192-208.e6.

6 Ruderman NB, et al. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013; 123(7): 2764-2772. 7 Zatterale F, et al. Chronic adipose tissue inflammation linking obesity to insulin resistance and Type 2 diabetes. Front Physiol. 2019; 10: 1607. 8 Foretz M and Viollet B. Activation of AMPK for a break in hepatic lipid accumulation and circulating cholesterol. EBioMedicine. 2018; 31:15-16.

9 Dong Y, et al. Activation of AMP-activated protein kinase inhibits oxidized LDLtriggered endoplasmic reticulum stress in vivo. Diabetes. 2010; 59(6): 1386-1396.

10 Srivastava RAK, et al. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res. 2012; 53(12): 2490-2514. 11 Shirwany NA, et al. AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 2010; 31(9): 1075-1084. 12 Herzig S and Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018; 19(2): 121-135.

13 Silwal P, et al. AMP-activated protein kinase and host defense against infection. Int J Mol Sci. 2018; 19(11): 3495. 14 Jang YJ, et al. Modulation of autophagy for controlling immunity. Cells. 2019; 8(2): 138.

15 Levine B, et al. Autophagy in immunity and inflammation. Nature. 2011; 469: 323-335.

16 Losier TT, et al. AMPK promotes xenophagy through priming of autophagic Kinases upon Detection of Bacterial Outer Membrane Vesicles. Cell Rep. 2019; 26(8): 2150-2165.

17 Vighi G, et al. Allergy and the gastrointestinal system. Clin Exp Immunol. 2008; 153 (Suppl 1): 3-6.

18 Janssen AWF, et al. The role of the gut microbiota in metabolic health. FASEB J. 2015; 29(8): 3111-3123. 19 Sun X and Zhu MJ. AMP-activated protein kinase: a therapeutic target in intestinal diseases. Open Biol. 2017; 7(8): 170104.

20 Yu H, et al. Alteration of the gut microbiota and its effect on AMPK/NADPH oxidase signaling pathway in 2K1C rats. Biomed Res Int. 2019; Article ID 8250619.

21 Zhao P and Saltiel AR. From overnutrition to liver injury: AMP-activated protein kinase in non-alcoholic fatty liver diseases. J Biol Chem. 2020; 295(34): 1227912289. 22 Kuo CL, et al. COVID-19 severity is predicted by earlier evidence of accelerated aging. MedRxiv. 2020; doi: https://doi.org/10.1101/2020.07.10.20147777. 23 Rajman L, et al. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018; 27(3): 529-547.

24 Martins R, et al. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 2016; 15(2): 196-207. 25 Greer EL, et al. AMP-activated protein kinase and FoxO transcription factors in dietary restriction–induced longevity. Ann N Y Acad Sci. 2009; 1170: 688. 26 Imai SI and Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24(8): 464-471. 27 Johns T. Phytochemicals as evolutionary mediators of human nutritional physiology. Int J Pharmacognosy. 1996; 34(5): 327-334.

28 Lee YS, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006; 55(8): 2256-2264.

29 Jeong HW, et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol. 2009; 296(4): E955-E964. 30 Derosa G, et al. Effects of berberine on lipid profile in subjects with low

cardiovascular risk. Exp Opin Biol Ther. 2013; 13(4): 475-482.

31 Liu L, et al. Quercetin alleviates high-fat diet-induced oxidized low-density lipoprotein accumulation in the liver: Implication for autophagy regulation. Biomed Res Int. 2015; Article ID: 607531. https://doi.org/10.1155/2015/607531 32 Dong J, et al. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKα1/SIRT1. J Lipid Res. 2014; 55(3): 363-374

33 Price NL, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012; 15(5): 675-690. 34 Moraes DS, et al. Sirtuins, brain and cognition: A review of resveratrol effects. IBRO Reports. 2020; 9: 46-51.

35 Zhao L, et al. Combination treatment with quercetin and resveratrol attenuates high fat diet-induced obesity and associated inflammation in rats via the AMPKα1/SIRT1 signaling pathway. Exp Ther Med. 2017; 14(6): 5942-5948.

36 Escande C, et al. Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38 Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome. Diabetes. 2013; 62(4): 1084-1093.

37 Kim T, et al. Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. Biochem Biophys Res Commun. 2009; 388(2): 377382. 38 Mohiti-Ardekani J, et al. Cogent Food Agr. 2019; 5(1): Article: 1577532.

39 Xiao K, et al. Curcumin induces autophagy via activating the AMPK signaling pathway in lung adenocarcinoma cells. J Pharmacol Sci. 2013; 123(2): 102-109.

40 Wang Y, et al. Alpha-lipoic acid increases energy expenditure by enhancing AMPK-PGC-1α signalling in the skeletal muscle of aged mice. Metabolism. 2010; 59(7): 967-976. 41 Lee WJ, et al. Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol. 2005; 25(12): 2488-2494.

42 Kim MS, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004; 10(7): 727-733. 43 Bujak AL, et al. AMPK Activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metab. 2015; 21(6): 883-890.

44 Bae HR, et al. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 2016; 7(41): 66444-66454. 45 Guerra B, et al. SIRT1, AMP-activated protein kinase phosphorylation, and downstream kinases in response to a single bout of sprint exercise: influence of glucose ingestion. Eur J Appl Physiol. 2010; 109(4): 731-743.

46 Gibala MJ, et al. Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle. J Appl Physiol. 2009; 106(3): 929-934. 47 Kido K, et al. Enhanced skeletal muscle insulin sensitivity after acute resistancetype exercise is upregulated by rapamycin-sensitive mTOR complex 1 inhibition. Sci Rep. 2020; 10: 8509. 48 Kjobsted R, et al. AMPK in skeletal muscle function and metabolism. FASEB J. 2018; 32(4): 1741-1777. 49 Jeukendrup AE. Periodized nutrition for athletes. Sports Med. 2017;

47(Suppl 1): 51-63.

50 Ruderman NB, et al. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010; 298(4): E751-E760.

51 Vargas-Ortiz K, et al. Exercise and sirtuins: A way to mitochondrial health in skeletal muscle. Int J Mol Sci. 2019; 20(11): 2717. 52 Imai SI and Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014; 24(8): 464-471.

53 Salminen A, et al. Age-related changes in AMPK activation: Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev. 2016; 28: 15-26. 54 Singhal A and Cheng CY. Host NAD+ metabolism and infections: therapeutic implications. Int Immunol. 2019; 31(2): 59-67.

55 Omran HM, et al. Influence of NAD+ as an ageing-related immunomodulator on COVID 19 infection: A hypothesis. J Infect Public Health. 2020; 13(9): 1196-1201.

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New Approaches to Managing Hypertension Using Central Blood Pressure Measurement and Supplements By: Craig Cooper 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.

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New Approaches to Managing Hypertension Using Central Blood Pressure Measurement and Supplements

Many patients diagnosed with high blood pressure may think they have it under control but are still at risk of arterial and organ damage because of elevated blood pressure levels. According to a study at the Baylor College of Medicine, only 27% of Americans who have high blood pressure are able to keep it at levels lower than 140/90 mmHg(1) which is still much higher than the 120/80 mmHg level recommended for optimal health. In fact, the most recent data from the National Health and Nutrition Examination Survey (NHANES), has found that control rates among Americans with hypertension declined approximately 10% to around 44% from the peak a few years earlier.(2) This decline is especially alarming in light of the fact that hypertension has been identified as an important factor tied to more serious consequences from COVID-19. Patients may believe that because they are taking antihypertensive medication, they do not need to worry about having a cardiovascular event, but medication adherence is just one piece of the puzzle. Reining in high blood pressure takes more than a one-shot approach because it is multifaceted condition. Drugs may not be enough for some, while for others might not necessary at all. A customized approach that combines medication, diet and nutrition, stress management, and lifestyle modifications work best to control hypertension. This can also include nutritional supplements that support arterial health and advanced diagnostic tools and screening methods that go beyond the standard brachial cuff such as central blood pressure measurement which provide clinicians additional data to personalize treatment plans.

HIGH BLOOD PRESSURE AND ENDOTHELIAL DYSFUNCTION: A LETHAL MATCH

One of the key factors to consider in the regulation of blood pressure is the integrity and tone of the blood vessels through which the blood flows. Namely, the endothelial cells that line the inside walls of your blood vessels. These cells have a critical role in the regulation of blood pressure and blood flow because they release substances that contribute to the relaxation and contraction of vascular smooth muscle. Other factors that impact blood vessel tone include stress, medications, numerous diseases, and diet.(3) In health individuals, the body naturally provides a balance between the substances that relax and contract the lining of your blood vessels. The introduction of high blood pressure, however, changes that balance which increases the risk of vascular disease. At the same time, the endothelial dysfunction can arise if the endothelial cells cannot respond to the demands for greater blood flow by widening or dilating the vessels. Endothelial dysfunction is a primary player in the development of hardening of the arteries, aka atherosclerosis. Therefore, there are two scenarios that are important here. One, you need to help support and promote endothelial function as a way to reduce the risk of stroke, heart attack,

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New Approaches to Managing Hypertension Using Central Blood Pressure Measurement and Supplements

and cardiovascular death associated with hypertension. (4) Two, you should focus on maintaining a healthy blood pressure to ensure the integrity of your endothelial cells.

ENHANCING STANDARD TREATMENTS WITH SUPPLEMENTS Most people are familiar with the standard treatments for hypertension, which include lifestyle changes - avoiding salt, losing excess weight, not smoking, regular exercise – combined with prescription medications. Drugs such as diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers are commonly prescribed. Physicians may also order alpha-blockers, alpha-beta blockers, aldosterone antagonists, central-acting agents, and vasodilators. Natural supplements can also be helpful in managing blood pressure, in particular the following substances: Grape seed extract – Grapeseed extract is obtained from the pulverized seeds of red wine grapes. Numerous studies have shown that this extract has an ability to improve poor circulation as well as tackle high cholesterol, two factors involved in hypertension. The power of grape seed extract comes from its high content of polyphenols, which are potent antioxidants with an ability to increase the dilation of blood vessels.(5) One study, a 2016 meta-analysis of the use of grape seed

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extract in patients with hypertension, analyzed data from 16 clinical trials and 810 subjects. The reviewers found that grape seed extract was associate with a significant decline in both systolic and diastolic blood pressures. The impact was more notable among individuals younger than 50 and those who were obese, as well as anyone with metabolic disorders.(6) Another benefit of grape seed extract is an ability to help improve endothelial function. The results of a laboratory study showed that the extract was able to inhibit the production of a protein associated with endothelial dysfunction and death.(7) Grape seed extract also can protect against another cardiovascular disease risk: oxidation of low-density lipoprotein (LDL). After eating, elevated levels of lipids (fats, oils, steroids) increase the risk for heart disease in part because they are highly susceptible to oxidation. Research has shown that when individuals consumed grape seed extract along with a meal, the LDL particles were better able to resist oxidative changes. This suggested to investigators that grape seed extract could reduce cardiovascular risk.(8) The suggested dose of grape seed extract is between 100 and 300 mg/day. This is the amount that has been used in studies and is being prescribed in some countries in Europe.(6) Coenzyme Q10 – The potent antioxidant coenzyme Q10 (CoQ10; aka, ubiquinone) is known for its ability to help cells produce energy. However, researchers have also demonstrated

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New Approaches to Managing Hypertension Using Central Blood Pressure Measurement and Supplements

how it can lower both systolic and diastolic blood pressures. In a meta-analysis involving 12 clinical trials and 362 patients, use of coenzyme Q10 was shown to reduce systolic blood pressure by up to 17 mmHg and diastolic pressure by up to 10 mmHg without any significant side effects. (9) In a more recent (2018) review involving 17 trials and 684 patients, use of coenzyme Q10 significantly lowered systolic but not diastolic pressure.(10) A typical dose of CoQ10 is 100 to 200 mg daily, but higher doses have been used in research. Pomegranate extract and juice – Both pomegranate (Punia granatum L) extract and juice have demonstrated an ability to help support cardiovascular health, and high blood pressure in particular.(11) Pomegranates are especially high in numerous phytonutrients, including punicalagins, the main antioxidant found in the fruit and one that is unique to pomegranates.(12) In fact, this is the phytonutrient emphasized in quality supplements because it is believed to provide the greatest health benefits. The results of a recent review and meta-analysis showed evidence of these benefits. The research was limited to pomegranate juice, which lowered systolic pressure by a mean of about 5 mmHg and diastolic pressure by 2 mmHg. The authors of the study concluded that “this evidence suggests it may be prudent to include this fruit juice in a heart-healthy diet.”(13) What about pomegranate extract? In a 2017 article appearing in the Journal of Nutritional Science, 55 subjects were given either a pomegranate extract or placebo daily for eight weeks. At the end of the trial, there was a significant decrease in diastolic blood pressure, but not in systolic pressure. (14)

ADDITIONAL SCREENING TO SUPPORT TREATMENT Uncontrolled hypertension can directly result in end-organ failure, including kidney failure, heart failure, and other deadly conditions. Although guidelines indicate the need to evaluate patients with hypertension for such organ failure, methods to assess subclinical vascular damage (i.e., blood vessel and other associated damage that is not yet readily noticeable) are not universally incorporated into clinical practice. The definition of optimal blood pressure has been changing over the past few decades. The Joint National Committee of the US Department of Health and Human Services had defined 120/80 mmHg as optimal for lowering the risk

of experiencing cardiovascular events (15) but also added readings of 120-139/80-89 mmHg as “prehypertension.”(16) However, in 2006, researchers determined that blood pressures of 120-129/80-84 mmHg were associated with an 81% higher risk of coronary heart disease, ischemic stroke, and other cardiovascular diseases when compared to optimal blood pressure of less than 120/80 mmHg. The experts also noted that blood pressure levels of 130-139/85-89 mmHg were associated with a 133% greater risk of cardiovascular events.(17) In 2017, the American College of Cardiology and the American Heart Association provided new guidelines, stating that stage 1 hypertension was defined as greater than or equal to 130/80 mmHg. An increase of systolic pressure by 20 mmHg and of diastolic by 10 mmHg doubles a person’s risk of dying from stroke and other cardiovascular diseases.(18) These changing guidelines highlight the need for greater adoption and use of accurate and comprehensive hemodynamic assessment tools. Clinicians may wonder which blood pressure is optimal to measure, brachial or central blood pressure (cBP) but both should be used to get a more complete picture of the patient’s arterial health. Clinicians are most familiar with brachial systolic pressure which measures the pressure or force of blood as it pushes against the walls of blood vessels using an arm-cuff device, but central blood pressure pulse wave analysis can help individualize hypertension management and better targeted drug selection. Central systolic blood pressure – the measurement of the pressure in the aorta – can be measured using one of several methods. A noninvasive way to take central systolic blood pressure is to use a tonometer, a small device that is placed on the skin over the brachial artery in the arm to measure the pulse. Another approach involves using a conventional blood pressure cuff that is attached to a specialized device that reads pulse waveforms. Central systolic blood pressure is believed to present a more accurate assessment of an individual’s risk of a cardiovascular event or organ damage if left untreated because of its proximity to key organs. It is important to understand that central systolic blood pressure can be significantly different from brachial systolic readings and that medications can affect brachial and central systolic blood pressures differently. Research indicates that central

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New Approaches to Managing Hypertension Using Central Blood Pressure Measurement and Supplements

blood pressure is more strongly related to end-organ damage than is brachial blood pressure, which suggests central blood pressure is the reading clinicians should be measuring to help them improve management of hypertension.(19-24)

evaluation of left ventricular hypertrophy and geometry and arterial pressure waveforms and more efficient ways to refine hypertension management decisions and prevent morbidity and mortality associated with high blood pressure.

THE BOTTOM LINE Hypertension and arterial stiffness should not be taken lightly. Lifestyle modifications like diet, exercise, stress management, and in addition to supplemental nutrients may help patients control hypertension and maintain good health as they age. But given the lack of symptoms, it is critical to understand an individual’s risk through central blood pressure measurement as well as standard brachial blood pressure. If we really want to prevent or reduce hypertension and its complications we need better screening for secondary hypertension, new ways to assess flow dynamics, and

Craig Cooper is CEO and Managing Director of both CardieX and ATCOR, global health technology companies focused on hypertension, cardiovascular disease, and other vascular health disorders.

REFERENCES 1. Hyman DJ, Pavlik VN. Poor hypertension control: let’s stop blaming the patients. Cleveland Clinic Journal of Medicine 2002 Oct; 69(10):793-9 2. Egan B et al, Hypertension Control In The U.S. 2009 To 2018: Rapidly Reversing Years Of Progress. Hypertension 2020 Sept. 3. Guyton AC, Hall JE. Textbook of Medical Physiology. 10th ed. Philadelphia, PA: WB Saunders Co.; 2000 4. Puddu P et al. Endothelial dysfunction in hypertension. Acta Cardiologica 2000 Aug; 55(4):221-32. 5. Siva B et al. Effect of polyphenolics extracts of grape seeds (GSE) on blood pressure (BP) in patients with metabolic syndrome (MetS). FASEB. 2006;San Francisco, CA 6. Zhang H et al. The impact of grape seed extract treatment on blood pressure changes, Medicine (Baltimore) 2016 Aug; 95(33): e4247 7. Corder R et al. The procyanidin-induced pseudo laminar shear stress response: a new concept for the reversal of endothelial dysfunction. Clinical Science (London) 2004 Nov; 107(5):513-17. 8. Natella F et al. Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. Journal of Agricultural and Food Chemistry 2002 Dec 18; 50(26):7720-25 9. Rosenfeldt FL et al. Coenzyme Q10 in the treatment of hypertension: a meta-analysis of the clinical trials. Journal of Human Hypertension 2007; 21:297-306 10. Tabrizi R et al. The effects of coenzyme Q10 supplementation on blood pressures among patients with metabolic diseases: a systematic review and meta-analysis of randomized controlled trials. High Blood Pressure & Cardiovascular Prevention 2018 Mar; 25(1): 41-50 11. Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 2001 Sep; 158(1):195-98 12. Gil MI et al. Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. Journal of Agriculture and Food Chemistry 2000 Oct; 48(10):4581-89 13. Sahebkar A et al. Effects of pomegranate juice on blood pressure: a systematic review and meta-analysis of randomized controlled trials. Pharmacological Research 2017 Jan; 115:149-61

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14. Stockton A et al. Effect of pomegranate extract on blood pressure and anthropometry in adults: a double-blind placebo-controlled randomized clinical trial. Journal of Nutritional Science 2017 Aug 9; 6:e39 15. Vasan RS et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. New England Journal of Medicine 2001 Nov 1; 345(18):1291-7. 16. Chobanian AV et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003 Dec; 42(6):1206-52 17. Kshirsagar AV et al. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. American Journal of Medicine 2006 Feb; 119(2):133-41 18. American College of Cardiology. New ACC/AHA high blood pressure guidelines lower definition of hypertension. 2017 Nov 13 19. Pucci G et al. Effects of B-blockers with and without vasodilating properties on central blood pressure: systematic review and meta-analysis of randomized trials in hypertension. Hypertension 2016; 67:316-24 20. Williams B et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFÉ) study. Circulation 2006; 113:1213-25 21. Boutouyrie et al. Amlodipine-valsartan combination decreases central systolic blood pressure more effectively than the amlodipine-atenolol combination: the EXPLOR study. Hypertension 2010; 55:1314-22. 22. Asmar RG et al. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001; 38:922-26 23. Kollias A et al. Association of central versus brachial blood pressure with target-organ damage: systematic review and metaanalysis. Hypertension 2016; 67:183-90 24. Sharman JE et al. Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study. Hypertension 2013; 62:113845

ANTI-AGING MEDICAL NEWS | WINTER 2020


PERSONALIZED. PREVENTIVE. PRECISE.

PERSONALIZED AND PRECISE BLOOD PRESSURE MANAGEMENT. The health hazards of high blood pressure are well understood — elevated risk of heart attack, stroke, and kidney damage, as well as arterial disease, erectile dysfunction, and dementia. But chronic hypertension can also cause premature aging — with a wide range of cardiovascular, cognitive, and cosmetic complications.

ATCOR is the gold standard for assessing noninvasive central blood pressure (NcBP) and arterial stiffness, the primary cause of age-related hypertension. The standard brachial blood pressure test does not measure blood pressure where it really matters—at target organs like the brain, kidneys, and the heart itself. For that you need central blood pressure. Central blood pressure is the most reliable indicator of cardiovascular risk and the most reliable guide for precise, personalized blood pressure management.

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Specialized Pro-Resolving Mediators: Novel Mechanisms for Supporting a Healthy Inflammatory Response By: Caitlin Higgins, MS, CNS, LDN 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.

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Specialized Pro-resolving Mediators: Novel Mechanisms for Supporting a Healthy Inflammatory Response

WHAT ARE PRO - RESOLVING LIPID MEDIATORS? Specialized pro-resolving mediators (SPMs) are produced in human blood, milk, and brain tissue from naturallyoccurring 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 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 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 naturallyproduced 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, inflammatoryrich/nutrient-poor diets, chronic stress, infections, and other insults. Research suggests that supplementation with pro-resolving 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 omega-3s, coupled with high-quality, highly-concentrated supplemental SPMs, is shown to have favorable effects in reducing overall inflammation.12

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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 pro-resolving 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/s41598-018-36679-4 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 sulfido- conjugated 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), 1746-1755. 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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SPM Supreme™ Highly Concentrated, Synergistic Blend of 3 Specialized Pro-Resolving Mediators

Provides 150 mcg of SPMs per softgel Designed to help support the body’s natural ability to respond to physical challenges and “resolve” the initial steps in the natural inflammatory processes.*

SPM Supreme™ promotes healthy inflammatory responses by*:

Supporting a normal pain response

Helping the body respond to inflammation-related challenges

Promoting tissue repair

Supporting wound healing

Supporting healthy aging

Bypassing the inefficient, multi-step conversion processes from dietary essential fatty acids to SPMs

www.designsforhealth.com *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.


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CELLULAR REJUVENATION

Fat-burning ramps up, contributing to the initiation of ketogenesis (ketone production). By the end of this day (48 hours), ketosis may occur.

Cellular cleaning and rejuvenation continue. Fat-burning and ketosis continue.

EXPERIENCE THE BENEFITS1

Weight loss, greater energy levels, increased mental clarity and focus, better relationship with food, and fewer cravings.

ProLon is not intended to diagnose, treat, cure or prevent any diseases and has not been evaluated as such by the FDA.

Use code A4M125 to receive ProLon® Professional for just $125* *Discount is valid until Dec. 28th

Antonia Perez 310-775-3655 aperez@l-nutra.com


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Offering Flexibility & Convenience with our At-Home Collection Suite Saliva, blood spot and dried urine are used for the minimally-invasive hormone testing that is the hallmark of ZRT Laboratory. The simplicity of sample collection and stability of samples in storage and transport have made these ideal for clinical use as well as research.

Today’s Most Convenient Testing Saliva 

ZRT developed the methodology making at-home saliva hormone testing commercially viable.

Saliva testing’s non-invasive nature also make it ideal for tests requiring multiple collections, such as diurnal cortisol.

No special shipment methods required. Samples are stable during shipping, even over the weekend and holidays.

Dried Blood Spot 

ZRT developed the science for accurately measuring steroid hormones in dried blood spot and is the only lab to offer this at-home technology commercially.

No phlebotomist, freezing / refrigeration or special shipment required. Samples are stable at room temperature for 30 days.

Dried Urine 

Dried urine testing is the latest scientific advancement pioneered by ZRT Laboratory.

Eliminates the disadvantages of 24-hour liquid urine collections commonly used for testing.

No freezing / refrigeration or special shipment required. Samples are stable at room temperature for 30 days.

866.600.1636 | info@zrtlab.com | www.zrtlab.com


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