Natural Medicine Journal Healthy Aging Special Issue 2022 by Diversified Communications

MAY 2022 SUPPLEMENT

SPECIAL ISSUE

Healthy Aging

Antioxidant-Rich Snacks Alter Gut Bacteria in Older Adults Abdominal Obesity, Sex Hormones, Bone Turnover + Longevity

Creatine + Resistance Training in Older Females Cranberry for Urinary Tract Infections Epigenetics and Cellular Aging

Tina Kaczor, ND, FABNO

SPECIAL ISSUE

Editor In Chief

HEALTHY AGING

Lise Alschuler, ND, FABNO

Editor, Abstracts & Commentary

MAY 2022 VOL. 14, NO. 51 (SUPPL)

Deirdre Shevlin Bell

VP of Content and Communications

Contents

Karolyn A. Gazella

Founder and NMJ Podcast Host

Avery St. Onge Associate Editor

Contributors

Karen Sperry

ABSTRACTS & COMMENTARY

Katherine Shagoury

Adding Creatine to Resistance Training in Older Females

Older Adults: Plant-Based Snacks Benefit Plasma Antioxidants and Microbiome

Endocrine and Nutritional Relationships in Centenarians

Fighting Urinary Tract Infections with Cranberry

EXPERT INTERVIEW

Can We Slow Aging at the Cellular Level? An interview with Kara Fitzgerald, ND, IFMCP

Kristin Bjornsen, MA Copyeditor Designer

Group Digital Product Manager

Anna Levesque

Marketing Manager

Kelcey George

Marketing Coordinator

Abigael Sleeper

Marketing Coordinator

Carmella Perrone

Sales Manager, Integrative Practitioner

Shannon Gray

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Group Vice President

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Contributors KARA FITZGERALD, ND, IFMCP, is the first-ever recipient of the 2018 Emerging Leadership Award from the Personalized Lifestyle Medicine Institute in recognition of her work on DNA methylation. Receiving her doctorate in naturopathic medicine from the National University of Natural Medicine, she lectures globally on functional medicine, is on the faculty at the Institute for Functional Medicine (IFM), and is an IFM Certified Practitioner with a clinical practice in Newtown, Connecticut. She runs a Functional Medicine Clinic Immersion program for professionals and hosts the podcast New Frontiers in Functional Medicine. Fitzgerald is also actively engaged in clinical research on the DNA methylome using a diet and lifestyle intervention developed in her practice. Her first study was published in the journal Aging. A consumer book, Younger You, and an application-based program, 3YY, based on the study are scheduled for release January 2022. She lives with her daughter in Connecticut. ADAM RINDE, ND, is a Bellevue, Washington– based naturopathic physician. He has been based in the Seattle area since graduating from Bastyr University in 2006 and completing a residency at the Bastyr Center for Natural Health. His practice is focused on gastrointestinal disorders, autoimmunity, and metabolism. He hosts a podcast called The One Thing Podcast with Dr. Adam Rinde, which features integrative health topics and guests. He enjoys speaking on digestive health and related topics. You can find him at www.soundintegrative.com. PAUL RICHARD SAUNDERS, PHD, ND, DHANP, CCH, completed his PhD in forest ecology at Duke University, his naturopathic degree at Canadian College of Naturopathic Medicine, and his homeopathic residency at National University of Naturopathic Medicine, where he also earned a second naturopathic degree. He is professor of materia medica and clinical medicine at the Canadian College of Naturopathic Medicine; senior naturopathic doctor, Beaumont Health System, Troy Hospital, Michigan; and adjunct professor of integrative medicine, Oakland University William Beaumont Medical School and has a private practice in Dundas, Ontario. Saunders was part of the transition team that formed the Office of Natural Health Products of Health Canada.

COREY B. SCHULER, FNP, CNS, CNSC, DC, serves as director of medical science for Gaia Herbs. He is a family nurse practitioner, certified nutrition specialist, and nutrition support clinician. He received his chiropractic doctorate from Northwestern Health Sciences University, master of science in human nutrition from the University of Bridgeport, and master of science in nursing at Graceland University. He continues his education in the doctor-of-nursing practice program at Fort Hays State University. He has additionally earned an executive master of business administration and an undergraduate degree in chemistry. Schuler authored a chapter in the textbook Integrative Medical Nutrition Therapy (Springer, 2020) and serves as an adjunct professor in nutrition and business programs. Schuler practices holistic primary care in Minnesota. TESSAUNDRA SIDDEN is a 7th- trimester naturopathic medicine student at National University of Health Sciences in Lombard, IL. In addition to studying, she is a research fellow in the Research Department and serves as the vice chair of the Naturopathic Medicine Research Club on campus. Her expected graduation date is April 2024. LORINDA SORENSEN ND, LAc, is a naturopathic doctor and acupuncturist who did her training at Bastyr University. She teaches at National University of Health Sciences, East West College of Healing Arts in Portland, OR, and Oregon College of Oriental Medicine. She is a member of the Oregon Association of Naturopathic Physicians and the Washington Association of Naturopathic Physicians, where she also serves on the Continuing Education Committee. She practices at Battle Ground Healing Arts in Southwest Washington state.

ABSTRACT & COMMENTARY

Adding Creatine to Resistance Training in Older Females Results from a meta-analysis REFERENCE

Dos Santos EEP, de Araújo RC, Candow DG, et al. Efficacy of creatine supplementation combined with resistance training on muscle strength and muscle mass in older females: a systematic review and meta-analysis. Nutrients. 2021;13(11):3757. STUDY OBJECTIVE

To determine the influence of creatine and resistance training on muscle strength and mass in older females through systemic review and meta-analysis KEY TAKEAWAY

Creatine supplementation is a promising and safe i ntervention to aid resistance training in older females to reduce dynapenia DESIGN

Systematic review and meta-analysis PARTICIPANTS

In the systematic review, investigators included 10 randomized controlled trials. Participant total was 211. Investigators initially identified a total of 543 studies and 2 additional studies from gray literature, but only 12 met eligibility criteria following screening. Studies met the criteria if they compared creatine only (versus a combination of

By Corey Schuler, FNP, DC, CNS ingredients) and resistance training to placebo in older females (aged greater than 60 years) and used the outcome measures of muscle strength and/or muscle mass. Studies that did not include a placebo control group were excluded, as was a trial that recruited patients with neurodegenerative disease. Two additional studies were not evaluated in the meta-analysis due to lack of access to the raw data. STUDY PARAMETERS ASSESSED

As far as quality of the evidence, investigators assigned a PEDro score to each study included in the analysis. Scores ranged from 6 to 9 with an average PEDro score of 7.7. PEDro scores refer to the Physiotherapy Evidence Database and are scored between 0 and 11, where 11 is the highest quality of evidence. Imprecision was determined to be high in the meta-analysis, and the quality of the evidence, according to GRADE (Grading of Recommendations, Assessment, Development and Evaluation), was low, indicating limited confidence in the effect size. Wide confidence intervals and sample sizes lower than 300 contributed to this quality rating.

PRACTICE IMPLICATIONS & LIMITATIONS Increased risks of disability, frailty, and falls are relevant to aging patients due, in part, to the physiologic and functional declines associated with sarcopenia, which includes the loss of muscle mass and strength.1 Dynapenia is specifically the loss of muscle strength. Strength improvement and increasing muscle mass also have metabolic benefits, including countering insulin resistance. These 2 benefits alone support the recommendation of resistance training in aging patients.2 An additional promising

Risk of bias was minimized as studies with low PEDro scores were not used, and publication bias due to using fewer than 10 studies was not seen in this analysis. KEY FINDINGS

Overall, creatine significantly increased upper-body strength (7 studies with 142 participants [P=0.04]) but had no effect on lower-body strength or muscle mass of upper or lower body. However, when studies had a duration of greater than 24 weeks, both upper-body strength (P=0.05) and lower-body strength (P=0.03) increased in the creatine groups, again without any significant changes in muscle mass. TRANSPARENCY

As disclosed by the authors: “D.G.C. has conducted industry sponsored research involving creatine supplementation, received creatine donation for scientific studies and travel support for presentations involving creatine supplementation at scientific conferences. In addition, D.G.C. serves on the Scientific Advisory Board for Alzchem (a company which manufactures creatine). S.C.F. has previously served as a Scientific Advisor for a company that sold creatine.”

benefit of resistance training is support of mitochondrial function within muscle cells, which also declines with age.3 Physical activity and exercise are well-established counter measures against muscle aging and the sequalae of age-related decreases in muscle mass, strength, and regenerative capacity, as well as impairments in muscle metabolism.4 Maximizing this effect with additional diet, lifestyle, or supplemental support is often a strategy used by integrative medicine clinicians. Creatine (creatine monohydrate) is an intervention worthy of consideration.

ABSTRACT & COMMENTARY

In primary care as well as specialty settings, the use of creatine often arouses discussion of safety especially as it relates to renal and liver function. However, in a position statement from the International Society of Sports Nutrition, a review of the available evidence suggests that both short-term and long-term supplementation is safe and well-tolerated in healthy individuals.5 This review also concluded older adults tolerated creatine supplementation well. Most studies evaluating creatine supplementation report no adverse events, even when renal and liver function were assessed.6–8 A prior systemic review and meta-analysis concluded that postmenopausal females can safely use supplemental creatine.9 Being mindful of one’s responsibility to the individual patient, practitioners can corroborate confidence of safety by monitoring with liver function tests (ALT [alanine aminotransferase], AST [aspartate aminotransferase]) as well as renal function tests (BUN [blood urea nitrogen], creatinine). Individualization of patient management requires judgement of the practitioner. For older females, recommending resistance exercise 2 to 3 times per week using compound or multijoint movements such as chest press, bench press, leg press, and hack squat is a relevant intervention. Statistical significance for strength was reached in this meta-analysis of creatine plus resistance training, but the effect size has limited confidence. Thus, it is somewhat challenging to help a patient understand how much the addition of creatine may help, and if it is worth the cost and effort of forming a new habit. In the studies included in this review publication, the dosing of creatine ranged from 5 g daily (typical maintenance

“

Dynapenia is specifically the loss of muscle strength.

From this review the greatest muscle strength benefit suggests exercise duration of more than 24 weeks, but some benefits in upper body strength may be achieved in only 12 weeks. Perhaps the most relevant clinical implication from this systematic review and meta-analysis is that monitoring progress of a resistance-training and creatine regimen in older females should focus on muscle strength rather than muscle mass. Upper-body strength improvements are likely noticed earlier than lower-body strength. Similarly executed reviews in older adults previously suggested improvements in both muscle strength and mass, but these reviews included both males and females.8 The addition of creatine to resistance-training recommendations in older females is promising but still largely based on preference of the patient and individualization of care. REFERENCES 1 2 3 4 5

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7 8

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dose) to 20 g daily for 5 to 7 days, followed by 5 g daily, or a weight-based dosing of 0.1 g per kg daily (for a 150-pound individual, this equates to 6.8 g). Optimal or preferred dosing has not been determined.

Seguin R, Nelson ME. The benefits of strength training for older adults. Am J Prev Med. 2003;25(3 Suppl 2):141-149.

LeBrasseur NK, Walsh K, Arany Z. Metabolic benefits of resistance training and fast glycolytic skeletal muscle. Am J Physiol Endocrinol Metab. 2011;300(1):E3-E10.

Granata C, Caruana NJ, Botella J, et al. High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content. Nat Commun. 2021;12(1):7056. Distefano G, Goodpaster BH. Effects of exercise and aging on skeletal muscle. Cold Spring Harb Perspect Med. 2018;8(3):a029785. Kreider RB, Kalman DS, Antonio J, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. J Int Soc Sports Nutr. 2017;14:18. Candow DG, Chilibeck PD, Forbes SC. Creatine supplementation and aging musculoskeletal health. Endocrine. 2014;45:354-361. Forbes SC, Candow DG, Ostojic SM, Roberts MD, Chilibeck PD. Meta-analysis examining the importance of creatine ingestion strategies on lean tissue mass and strength in older adults. Nutrients. 2021;13:1912.

Chilibeck PD, Kaviani M, Candow DG, Zello GA. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: a meta-analysis. Open Access J Sports Med. 2017;8:213-226.

ABSTRACT & COMMENTARY

Older Adults: Plant-Based Snacks Benefit Plasma Antioxidants and Microbiome Results from a single-arm intervention REFERENCE

Zhang JY, Lo HC, Yang FL, Liu YF, Wu WM, Chou CC. Plant-based, antioxidant-rich snacks elevate plasma antioxidant ability and alter gut bacterial composition in older adults. Nutrients. 2021;13(11):3872. KEY TAKEAWAY

Four months of intervention with whole plant-based smoothies combined with sesame seed-based snacks have favorable effects on circulating antioxidant p arameters in the elderly as well as measurable effects on the microbiome. DESIGN

Open-label, single-arm intervention

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Sesame is, unfortunately, a common allergen, ranked 9th among children and adults, and since November 2019 in Canada and the United States, it must be listed on the label if present in a food.

PARTICIPANTS

Healthy and subhealthy older adults (N=42, average age 79.7 ± 8.6 years) in 2 senior living facilities operated by Yonghe Cardinal Tien Hospital, New Taipei City, Taiwan INCLUSION CRITERIA

Aged 65 years or more; resident of the facility for 2 or more months; healthy or subhealthy diagnosis by a physician. Subhealthy was defined as no existing pathology but existing prehypertension, being overweight or underweight, having serum lipids above the borderline, and/or having suboptimal renal or hepatic health. EXCLUSION CRITERIA

Cancer, chronic obstructive pulmonary disease, severe disability, or dementia INSTRUMENTS

Anthropometric measurements (weight, height, waist, and hip circumferences), body mass index (BMI), waist-hip ratio, complete blood count (CBC) with differential, lipid panel, blood urea nitrogen (BUN), creatinine, high-sensitivity C-reactive protein (hs-CRP), antioxidant enzymes in plasma and erythrocytes (thiobarbituric acid reactive substances, reduced glutathione, oxidized glutathione, total sulfhydryl groups, protein bound sulfhydryl groups, non-protein sulfhydryl groups), fecal samples (short-chain fatty acids [SCFA], acetic acid, propionic acid, butyric acid, total bacterial DNA, operational taxonomic units, alpha diversity, beta diversity). Investigators took measurements at baseline, 2 months, and 4 months. INTERVENTION

There were 4 different plant-based smoothies with orange, green, dark green, and purple color. Investigators employed

By Paul Richard Saunders, PhD, ND, R HOM, DHANP, CCH

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the following processes for all of them: “cleaning, pre-preparation, blanching, micro-processing, packaging, and frozen storage at -30 C.” Each smoothie, 150 g, contained 1 exchange of vegetable (2 kinds), 1 exchange of fruit (2 kinds), and 1 exchange of nuts (145–186 kcal, 21–29 g carbohydrates, 4–5 g protein, 7 g lipid, 2.7–4.7 g dietary fiber, and various minerals, vitamins, and phytochemicals, low saturated fats, no cholesterol, low sodium, low sugar, and 10%–15% of daily recommended intake of vitamins A, C, B1, potassium, calcium, and magnesium). In addition, snacks of sesame seed powder and spread (10 g each) at 57.6 kcal and 63.3 kcal, 2.1 g and 2.5 g carbohydrate, 1.6 g and 1.3 g protein, 5.5 g and 5.7 g lipid, respectively, with various vitamins and minerals provided to increase intake of calcium, polyunsaturated fatty acids, vitamin E, and phytochemicals. Each week for 4 months, participants received 1 serving of each type of smoothie (4 types total) and a 5th serving of their choice (for a total of 5 servings per week) and 3 servings of the sesame seed snack. Compliance and consumption were recorded. RESULTS

Investigators recruited 59 older adults, with 30 women and 12 men participating in the intervention and blood collection. One woman and 1 man refused to provide fecal samples after the 4-month intervention. Females were aged 77.7 + 7.6 years; males were aged 85.3 + 8.4 years. There were no significant differences in BMI (baseline=24.0 ± 2.8 kg/m2) or waist-to-hip ratio in females and males.

ABSTRACT & COMMENTARY

Compliance with smoothies and snack was 88.0% for females and 92.5% for males. Body weight increased significantly after 2 months (P=0.028), and then decreased to about 1 kg above baseline while BMI, waist and hip circumference, and waist-hip ratio did not change significantly. Red blood cells (RBC), hematocrit, albumin, and BUN decreased significantly at 4 months; hemoglobin, cholesterol, and high-density lipoproteins (HDL) also increased significantly, but the change in low-density lipoprotein (LDL) cholesterol was not significant. Reduced glutathione (P<0.001), total sulfhydryl (P<0.015), protein bound sulfhydryl (P<0.019), and total antioxidant capacity (P<0.015) increased significantly over the 4 months. Oxidized glutathione (P<0.001) decreased significantly over the 4 months, while there was no significant change in thiobarbituric acid reactive substances. Fecal SCFAs were unchanged at 4 months, as were the various SCFA contents. Bacterial species in the feces were significantly decreased at 2 and 4 months. The 4 dominant phyla were Firmicutes, Bacteroidetes, Proteobacteria, and Verrucomicrobia throughout the study, accounting for 95% of total bacterial count. Investigators identified 28 bacterial taxa at baseline, and at 2 and 4 months. The older adults had decreased Bacilli, Streptococcus, Ruminiclostridium, Deltaproteobacteria, Patescibacteria, and increased Lactobacillus after 2 and 4 months compared to baseline. At 2 months there were increased Bacteroidetes, and Bacteroides thetaiotaomicron, and at 4 months increased Agathobacter compared to baseline. A comparison of microbiota and total antioxidant capacity (TAC) found Ruminiclostridium_5, Agathobacter, Bacteroidetes, and Fusobacteriales negatively associated with TAC (P=0.003). Lactobacillus salivarius was positively associated with TAC (P=0.005). Sample sizes were determined to be adequate to detect interactions between gut bacteria composition and antioxidant enzymes. KEY FINDINGS

Plant-based, antioxidant-rich snacks and smoothies can improve antioxidant capacity and alter gastrointestinal microbiota in older adults over 4 months when consumed on a regular basis. TRANSPARENCY

The authors do not disclose any conflicts of interest. Funding was through grants from the Ministry of Science and Technology, Taiwan. 8

PRACTICE IMPLICATIONS Diets high in vegetables, fruits, whole grains, and nuts have antioxidant, anti-inflammatory, and, thus, antiaging effects and reduce frailty.1,2 Higher intake of flavonoids in fruits and vegetables is associated with reduced subjective cognitive decline in older American adults.3 One of the unfortunate facts is that as adults age, their ability to chew, swallow, and digest decreases, an assumption made for this study population and, thus, a factor in the design of this study.4 Active phytochemical constituents with antioxidant properties are associated with food that is colorful: fruits, vegetables, nuts, and seeds.5 The question that clinicians would like answered is: Which fruits, vegetables, nuts, and seeds will cause the most effective, or the most problematic, shift in a patient’s microbiome if they have prediabetes, cognitive impairment risk factors, cancer risk factors, and so forth?6 Clinical questions are ahead of scientific answers in this regard. Sesame seeds, Sesamum indicum, Pedaliaceae, are presumed to be native to sub-Sahara Africa and India, to be the first human oil-seed crop, and to have been domesticated more than 5,500 years ago as a drought-tolerant plant.7 Production in 2018 was more than 6 million tons. In 100 g or 3.5 ounces, there are 573 calories, 5% water, 23% carbohydrate including 12% dietary fiber, 50% fat, 18% protein, and 20% or more of the recommended daily requirement of several B vitamins, iron, magnesium, calcium, phosphorus, and zinc.7 Also present are phytic acid, a known binder of minerals that can reduce their absorption in the small intestine, and the lignans sesamolin, sesamin, pinoresinol, and lariciresinol.8 What gut bacteria sesame supports or reduces is largely unknown. Sesame is, unfortunately, a common allergen, ranked 9th among children and adults, and since November 2019 in Canada and the United States, it must be listed on the label if present in a food.9 Some 17% of children are allergic to sesame, with 20% to 30% presumed to outgrow this allergy.8 This study of 4 months revealed that it was a reasonable length of time to assess for some biome changes. Very limited data were provided on the study subjects; for instance,

I would like to have known how many were classified as healthy versus subhealthy adults and if there were outcome differences between the 2 groups. There was no indication if the snacks were taste-tested to make them palatable or attractive to the study subjects, a factor that could limit consumption. Similarly, there were no data on the selection of the 5th smoothie and whether this was based on taste, color, both, or neither. Neither were there details on the constituents of the 4 smoothies. Finally, the investigators described the foods as “texture modified,” but we do not know if that improved their ability to be chewed, swallowed, and digested, nor how the texture was modified, nor how well the subjects liked the smoothies and snacks. The study was generally well-written, but not all subheadings matched that section’s content.

REFERENCES

Plant-based, antioxidant-rich smoothies including unknown vegetables, fruits, and nuts along with snacks prepared from sesame seeds can improve antioxidant capacity and alter gastrointestinal microbiota in older, presumably Taiwanese, adults over 4 months when consumed on a regular basis.

Forni C, Facchiano F, Bartoli M, et al. Beneficial role of phytochemicals on oxidative stress and age-related diseases. Bio Meds Res Int. 2019:8748253.

Hengeveld LM, Wjiunhoven HAH, Olthof MR, et al. Prospective association of diet quality with incident frailty in older adults: the health, aging, and body composition study. J Am Geriatric Soc. 2019;67(9):1835-1842.

Yeh TS, Yuan C, Aschgerio A, Rosner B, Willett W, Blacker D. Long-term flavonoid intake and subjective cognitive decline in US men and women. Neurology. 2021;97(10):e1041-e1056.

Cichero JAY. Age-related changes to eating and swallowing impact frailty: aspiration, choking risk, modified food texture, and autonomy of choice. Geriatrics. 2018;3(4):69.

Sudher S, Gangwar P, Usmani Z, et al. Shaping the gut microbiota by bioactive phytochemicals: an emerging approach for the prevention and treatment of human disease. Biochimie. 2022;193:38-63.

Jiang Z, Sun TY, He Y, et al. Dietary fruit and vegetable intake, gut microbiota and type 2 diabetes: results from two large human cohort studies. BMC Medicine. 2020;18(1):371.

Oplinger ES, Putnam DH, Kaminski AR, et al. Sesame. Alternative field crops manual: sesame. Purdue University website. https://hort.purdue.edu/newcrop/afcm/ sesame.html. Accessed April 2022.

Milder IEJ, Arts ICW, van de Putte B, Venema DP, Hollman PCH. Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol, and matairesinol. Br J Nutr. 2007:93(3):393-402.

News Desk. FDA may add sesame to list of major food allergens requiring label disclosure. Food Safety News website. https://www.foodsafetynews.com/2019/11/ fda-may-add-sesame-to-list-of-major-food-allergens-requiring-label-disclosure/. Accessed April 2022.

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ABSTRACT & COMMENTARY

Endocrine and Nutritional Relationships in Centenarians Results from a retrospective cohort study REFERENCE

Fu S, Ping P, Li Y, et al. Centenarian longevity had inverse relationships with nutritional status and abdominal obesity and positive relationships with sex hormones and bone turnover in the oldest females. J Transl Med. 2021;19(1):436. STUDY OBJECTIVE

This study was implemented to explore the links among sex hormones, bone turnover, abdominal obesity, nutritional status, and centenarian longevity in the oldest females, comparing those aged more than 100 years to those younger. DESIGN

Retrospective cohort study using data collected from the China Hainan Centenarian Cohort Study. PARTICIPANTS

Five hundred centenarian females and 237 females aged 80 to 99 years Inclusion criteria: (1) Participants were aged at least 80 years old; (2) Participants volunteered to join the study with written informed consent; (3) Participants were conscious and were able to complete home interviews, physical examinations, and blood analyses. Exclusion criteria: If personal identity information was incomplete; identification cards showed an age of less than 80 years; or participants refused to comply with study requirements, including the collection of blood samples. No participants received vitamin D, exogenous steroids, or other treatments that could affect their sex hormones and bone turnover. No centenarians with oophorectomies participated in the current study. STUDY PARAMETERS ASSESSED

• Geriatric nutritional risk index

Lorinda Sorensen, ND, LAc Tessaundra Sidden, ND Candidate

PRIMARY OUTCOME MEASURES

• Nutritional status

• Abdominal obesity • Sex hormones • Bone turnover KEY FINDINGS

There were lower levels of height, weight, waist circumference, serum albumin, and geriatric nutritional risk index (P<0.05 for all) in oldest female participants compared to females aged 80 to 99 years. Abdominal obesity was lower in the oldest of old compared to those aged 80 to 99 years (P<0.05). Centenarian females had lower levels of FSH and higher levels of PRL, progesterone, and estradiol compared to females aged 80 to 99 years (P<0.05 for all). The oldest of old females had higher levels of osteocalcin, Beta-CrossLaps, and PTH and greatly decreased levels of 25(OH)D3 than females aged 80 to 99 years (P<0.05 for all). Geriatric nutritional risk index had an inverse relationship with LH, FSH, progesterone, estradiol, osteocalcin, Beta-CrossLaps, and PTH (P<0.05 for all). Abdominal obesity had an inverse relationship with LH, FSH, osteocalcin, Beta-CrossLaps, and 25(OH)D3 (P<0.05 for all). LH levels had a positive relationship with osteocalcin, Beta-CrossLaps, and PTH. It had a significant inverse relationship with 25(OH)D3 (P<0.05 for all).

• Abdominal obesity

FSH levels had a positive relationship with osteocalcin, Beta-CrossLaps, and PTH (P<0.05 for all).

• Prolactin (PRL), progesterone, estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH)

Progesterone levels had a positive association with osteocalcin and Beta-CrossLaps (P<0.05 for all).

• Osteocalcin, Beta-CrossLaps, parathyroid 25-hydroxycholecalciferol D3 (25(OH)D3)

Estradiol levels had a positive relationship with Beta-CrossLaps but a negative relationship with 25(OH)D3 (P<0.05 for all).

hormone,

PRACTICE IMPLICATIONS It is estimated that by 2030 the number of people aged more than 65 years in the United States will be more than 73 million,1 and those who are aged 80-plus years will number around 20 million.2 Soon there may be more elders in the world than ever before, increasing the incidence of age-related conditions, such as heart disease, diabetes, osteoarthrosis, chronic obstructive pulmonary disease (COPD), cancer, and Alzheimer disease. Researchers and clinicians alike are interested in evidence-based ways to slow the aging process to reduce age-associated health problems, and the data are increasing. One population of interest is the oldest of old, the centenarians. It is thought that centenarians have fewer (or more specifically, they postpone) age-related conditions, collectively described as “deceleration aging.” This is characterized by a combination of having less inflammation and more resilience, and maintaining functional integrity longer than their peers.3 Elderly people are at risk of reduced endogenous vitamin D production, and possibly reduced absorption of vitamin D when it comes from food and supplements. Elderly people are likely to be less physically active; therefore, they are less likely to get adequate ultraviolet B radiation. In addition, skin tissues also change with age, with an estimated 4-fold reduction in vitamin D in a 70-year-old compared to a 20-year-old.4 Vitamin D is a fat-soluble essential nutrient that has various roles in the body including immune function, bone metabolism, and newfound implications in the process of aging. There has been research on vitamin D receptor (VDR) gene polymorphisms involved in healthy aging and longevity.5 With certain VDR gene polymorphisms, there may be a greater chance for a lifespan that extends past 100 years of age. Two of these polymorphisms, BsmI and ApaI, have been found to be associated with survival to utmost old age.6 Regardless of the VDR gene, there is a vital need for vitamin D supplementation in the oldest of old individuals due to the progression of an age-dependent decline in endogenous previtamin D3 synthesis in the skin.7 Considering the age-related decline in vitamin D synthesis, it is necessary to

“

It is thought that centenarians have fewer (or more specifically, they postpone) age-related conditions, collectively described as ‘deceleration aging.’

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also consider supplementation with calcium in those who are elderly.8 Along with vitamin D deficiency found in the centenarian population, investigators also observed elevated serum PTH concentration, and this is implicated in bone loss.9 Vitamin D can aid in reducing PTH synthesis and secretion as well as enhance fat breakdown, thus improving abnormal lipid metabolism.10 Another consideration as to why supplementing with vitamin D in the oldest-of-old population is important is its relation to cognitive function.11 Decreased plasma vitamin D concentrations were associated with an increase in risk of a decline in mini-mental state examination points.12 There is an association between decreased calcium concentrations and decreased vitamin D levels,13 which is why supplementing with both calcium and vitamin D in the oldest of old should be considered. Supplementing with vitamin D in the centenarian population can lead to an increase in physicality, with evidence showing that there is a dose-dependent correlation between higher vitamin D concentrations and physical function in centenarians.14 Another factor to consider with aging is metabolic interactions contributing to chronic diseases, starting as young as in the 4th decade of life; some of these relationships include decreased muscle mass, decreased bone density, increased abdominal obesity, hyperglycemia, and insulin resistance.

ABSTRACT & COMMENTARY

There have been data revealing the relationship between skeletal muscle and bone, with a focus on osteocalcin (OCN, also sometimes called bone Gla protein).15 OCN, largely secreted by mature osteoblasts and possibly also by immature osteocytes,16 is 1 of the most abundant noncollagenous pleiotropic proteins of the bone matrix.17 OCN requires a vitamin K dependent carboxylation, which can be stimulated by 1,25 Vitamin D, and has a strong affinity to the bone hydroxyapatite matrix.18 OCN can be used as a specific biomarker of bone turnover, and there are suggestions that it can be used as a screen for high bone turnover and possibly monitoring response to osteoporosis treatments.19 Current literature suggests OCN can be categorized in the group of compounds called bone-derived hormones, or “osteokines.” OCN is beneficial for bone and aids the deposition of calcium into the bone matrix.20 While a significant amount of this data is still in preclinical stages, there is compelling evidence that OCN, when undercarboxylated (UcOCN, also referred to as uncarboxylated), has an impact on muscle, adipose tissue, the pancreas, and metabolism, with preliminary research indicating that vitamin D is needed for UcOCN.21 Muscle, a highly metabolic tissue, and bone are intimately linked, with both tissues derived from the same progenitor cell type, mesenchymal stromal cells. Throughout life, both respond anabolically to exercise and mechanism stress, and tissue mass coincides.22 Preclinical data have shown that UcOCN promotes brain-derived neurotrophic factor (BDNF) expression when performing strenuous exercise,23 and increased adenosine monophosphate-activated protein kinase (AMPK) activation, favoring fatty acid oxidation in skeletal muscle.24 This suggests that UcOCN may have an effect in the regulation of insulin. There are data that support UcOCN increasing the expression and secretion of insulin and β-cell proliferation and mass from the pancreas.25 This may be due in part to the activity of vitamin K1, as shown in a double-blind, randomized, controlled clinical trial of 82 prediabetic women who 12

consumed 1,000 mcg of phylloquinone for 4 weeks, versus a soy oil placebo as the control. Results showed an increased serum level of OCN, with improvements seen in glycemic status and insulin sensitivity.26 There is more evidence of this metabolic activity of UcOCN in a 2021 study of 2,493 participants with an age range of 58 to 63 years, which showed that UcOCN was higher in people who had fewer signs and symptoms of metabolic syndrome, and serum osteocalcin levels are independently associated with measures of insulin resistance.27 In addition, some have speculated reproductive hormones may have a protective effect on the tissues and organs associated with aging, and that sex hormones later in life may be part of the path to longevity. Centenarians, especially if they have ovaries, have a significant decline of sex hormones after menopause and in advancing years. A surprising association in this study is that the group of centenarians had less abdominal obesity than their younger counterparts, but more progesterone and estradiol. The authors of the study theorize that the sex hormones may reduce the shift from muscles to fat and prevent nutritional accumulation and abdominal obesity, based on past research with testosterone. There may be enough circulating androgens from the ovary28 and adrenal glands for peripheral aromatization to estradiol. There have been associations seen in postmenopausal people revealing that higher plasma OCN correlated positively with dehydroepiandrosterone sulfate (DHEA-S) and androstenedione levels;29 these associations were not statistically significant in the centenarian group. Perhaps the neurosteroid activity of sex hormones should not be ignored, with progesterone involved. While progesterone production in a postmenopausal ovary is unpredictable, the ovary can still produce about ¹/³ to ½ the amount of androgens compared to the premenopausal ovary.30 However, progesterone has been shown to be synthesized locally in the brain from cholesterol by neuron and glial cells.31 Progesterone and the metabolite allopregnanolone have been shown to support neuroprotection by increasing neurogenesis, improved cognitive function, and memory and decreasing neuroinflammation and beta-amyloid accumulation.32

Several important interventions have evidence to support them slowing the aging process, especially in animal studies, such as calorie restriction and physical exercise.33 Those who are young to middle-aged can easily implement these interventions to support a normoglycemia metabolism. Looking at the bone tissue as a key endocrine factor in regulating metabolic pathways as we age could be supportive in a society where physical activity is not often obtained to the degree needed for health. These interventions, along with adequate micronutrients including supplementing with vitamins D and K, could support the intricate pathways necessary for physical resilience, adaptability, and greater longevity in the future.

18 Wen L, Chen J, Duan L, Li S. Vitamin K dependent proteins involved in bone and cardiovascular health (review). Mol Med Rep. 2018;18(1):3-15.

REFERENCES

27 Saleem U, Mosley TH Jr, Kullo IJ. Serum osteocalcin is associated with measures of insulin resistance, adipokine levels, and the presence of metabolic syndrome. Arterioscler Thromb Vasc Biol. 2010;30(7):1474-1478.

Older Americans 2020: key indicators of well-being. Federal Interagency Forum on Aging-Related Statistics website. https://agingstats.gov/docs/LatestReport/ OA20_508_10142020.pdf. Accessed March 15, 2022.

Retooling for an aging America: building the health care workforce. Institute of Medicine (US) Committee on the Future Health Care Workforce for Older Americans. Washington (DC): National Academies Press (US); 2008.

Borras C, Ingles M, Mas-Bargues C, et al. Centenarians: an excellent example of resilience for successful ageing. Mech Ageing Dev. 2020;186:111199.

Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):362-371. Review. Erratum in: Am J Clin Nutr. 2004;79(5):890.

Gussago C, Arosio B, Guerini FR, et al. Impact of vitamin D receptor polymorphisms in centenarians. Endocrine. 2016;53(2):558-564.

Passeri G, Pini G, Troiano L, et al. Low vitamin D status, high bone turnover, and bone fractures in centenarians. J Clin Endocrinol Metab. 2003;88(11):5109-5115.

Passeri G, Vescovini R, Sansoni P, et al. Calcium metabolism and vitamin D in the extreme longevity. Exp Gerontol. 2008;43(2):79-87.

10 Liu L, Cao Z, Lu F, et al. Vitamin D deficiency and metabolic syndrome in elderly Chinese individuals: evidence from CLHLS. Nutr Metab (Lond). 2020;17:58. 11 Lv Y, Mao C, Yin Z, Li F, Wu X, Shi X. Healthy Ageing and Biomarkers Cohort Study (HABCS): a cohort profile. BMJ Open. 2019;9(10):e026513.

19 Neustadt J. Making sense of osteoporosis testing. Natural Medicine Journal website. https://www.naturalmedicinejournal.com/journal/2021-05/making-sense-osteoporosis-testing. Accessed May 2, 2022. 20 Manolagas SC. Osteocalcin promotes bone mineralization but is not a hormone. PLoS Genet. 2020;16(6):e1008714. 21 Buranasinsup S, Bunyaratavej N. The intriguing correlation between undercarboxylated osteocalcin and vitamin D. J Med Assoc Thai. 2015;98 Suppl 8:S16-S20. 22 Moser SC, van der Eerden BCJ. Osteocalcin-A versatile bone-derived hormone. Front Endocrinol (Lausanne). 2019;9:794. 23 Stephan JS, Sleiman SF. Exercise factors released by the liver, muscle, and bones have promising therapeutic potential for stroke. Front Neurol. 2021;12:600365.

24 Mera P, Laue K, Ferron M, et al. Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise [published correction appears in Cell Metab. 2017;25(1):218]. Cell Metab. 2016;23(6):1078-1092. 25 Karsenty G, Mera P. Molecular bases of the crosstalk between bone and muscle. Bone. 2018;115:43-49.

26 Rasekhi H, Karandish M, Jalali MT, et al. The effect of vitamin K1 supplementation on sensitivity and insulin resistance via osteocalcin in prediabetic women: a doubleblind randomized controlled clinical trial. Eur J Clin Nutr. 2015;69(8):891-895.

28 Strauss J, Williams C. Yen & Jaffe’s Reproductive Endocrinology, 8th ed. Elsevier; 2019: Chapter 8 Ovarian Life Cycle. 29 Czajkowska M, Plinta R, Owczarek A, Olszanecka-Glinianowicz M, Skrzypulec-Plinta V. Circulating sclerostin levels in relation to nutritional status, sex hormones and selected bone turnover biochemical markers levels in peri- and postmenopausal women. Ginekol Pol. 2019;90(7):371-375. 30 Shifren JL, Schiff I. The aging ovary. J Womens Health Gend Based Med. 2000;9 Suppl 1:S3-S7. 31 Kapur J, Joshi S. Progesterone modulates neuronal excitability bidirectionally. Neurosci Lett. 2021;744:135619. 32 Guennoun R. Progesterone in the brain: hormone, neurosteroid and neuroprotectant. Int J Mol Sci. 2020;21(15):5271. 33 Zia A, Pourbagher-Shahri AM, Farkhondeh T, Samarghandian S. Molecular and cellular pathways contributing to brain aging. Behav Brain Funct. 2021;17(1):6.

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12 Lv Y, Mao C, Yin Z, Li F, Wu X, Shi X. Healthy Ageing and Biomarkers Cohort Study (HABCS): a cohort profile. BMJ Open. 2019;9(10):e026513. 13 Kupisz-Urbańska M, Broczek K, Galus K, Mossakowska M, Marcinowska-Suchowierska E. Age-related differences in vitamin D status in Polish centenarians compared with 65-year-olds. Pol Arch Intern Med. 2020;130(10):853-859. 14 Ferri E, Casati M, Cesari M, Vitale G, Arosio B. Vitamin D in physiological and pathological aging: Lesson from centenarians. Rev Endocr Metab Disord. 2019;20(3):273-282. 15 de Paula FJ, Rosen CJ. Bone remodeling and energy metabolism: new perspectives. Bone Res. 2013;1(1):72-84. 16 Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell ... and more. Endocr Rev. 2013;34(5):658-690.

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17 Komori T. What is the function of osteocalcin? J Oral Biosci. 2020;62(3):223-227.

ABSTRACT & COMMENTARY

Fighting Urinary Tract Infections with Cranberry Results from a meta-analysis REFERENCE

Xia JY, Yang C, Xu DF, Xia H, Yang LG, Sun GJ. Consumption of cranberry as adjuvant therapy for urinary tract infections in susceptible populations: a systematic review and meta-analysis with trial sequential analysis. PLoS One. 2021;16(9):e0256992. STUDY OBJECTIVE

To synthesize the data from studies involving the use of cranberry-containing products in the prevention of recurrent urinary tract infections (UTIs). KEY TAKEAWAY

Supplementing with cranberry preparations in patients suffering from recurrent UTIs can play a significant role in reducing recurrence and, thus, reduce overprescription of antibiotics. DESIGN

Systematic review, meta-analysis containing randomized trials PARTICIPANTS

Inclusion criteria: The study was limited to only randomized controlled trials. For the intervention used, the authors included only trials that: • Compared cranberry-containing products to a placebo or nonplacebo control group; • Had outcomes that can be calculated or reported as the number of participants experiencing a UTI; and • Included nonheterogenous at-risk populations, including those experiencing recurrent UTIs, elderly men and women, pregnant women, children, participants with indwelling catheter, and participants with neuropathic bladder. 14

By Adam Rinde, ND Exclusion criteria: Trials whose intervention contained cranberry in combination with another bioactive compound, animal studies, case reports, reviews, conference papers, editorials, and studies with insufficient data. INTERVENTIONS

Interventions ranged and varied in the studies. Investigators included 15 trials: 2 administered cranberry juice, whereas 1 trial used both cranberry juice and cranberry tablets, and 12 trials used cranberry capsules. Eleven trials used cranberry-based products from the manufacturer Ocean Spray. Daily cranberry amount ranged from 0.4 to 194.4 g. The actual cranberry amount was not reported in the 11 trials. Twenty-three trials used a formula placebo, whereas 5 trials did not use a placebo. Also, some studies used capsules or tablets based on cranberry amount (g/d; in proanthocyanidin [PAC] content, mg/d). This ranged from 0.2 g per day to 2 g per day. Note: The clinical criteria of UTI threshold varied in the studies. Clinical symptoms to define UTI were required in most trials (eg, frequent micturition), and baseline bacteriuria were not excluded in 18 trials. In addition, the thresholds of bacteriuria ranged from 10,000 to 100,000 colony forming units (CFU)/mL. The presence of UTI symptoms was not required in 11 trials.

The studies tracked frequency of UTIs by varied definitions over a period of time ranging from 1 month to 1 year. STUDY PARAMETERS ASSESSED

Investigators used the Cochrane risk-of-bias tool covering 7 domains of bias, including: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. Each item was scored as “high risk,” “low risk,” or “unclear” for all selected studies. KEY FINDINGS

Supplementing cranberry may be beneficial in preventing and treating UTIs in susceptible populations, particularly for women with recurrent UTIs (RR=0.68; 95% CI: 0.56 – 0.81), children (RR=0.55; 95% CI: 0.31 – 0.97) and patients using indwelling catheters (RR=0.49; 95% CI: 0.33). Overall, the meta-analysis results revealed a 30% reduction in the risk of developing a UTI in susceptible populations who consumed cranberry-containing products than those who did not (RR=0.70; 95% CI: 0.59 – 0.83; I2=48%). The daily recommended intake of PACs, to decrease the number of recurrent UTIs, is not lower than 36 mg, and inconsistent dosages among different studies may cause different outcomes. TRANSPARENCY

There were no conflicts of interests reported by study authors, but it is concerning that 1 trial that had quite a bit of quantitative power in the study (Maki, et al) was funded by Ocean Spray, and the authors did not point this out.

PRACTICE IMPLICATIONS & LIMITATIONS Cranberry-based supplements and/or juice are a welcome alternative for patients and health care providers alike, especially with growing concerns of antibiotic resistance against uropathogenic Escherichia coli strains (UPEC).1 Confidence in the form, dosage, and setting for cranberry use in chronic recurrent UTIs is needed. While cranberry preparations in UTI prevention have been studied in individual controlled trials, Xia et al (2021) conducted a helpful systematic review and meta-analysis of the research to further synthesize research data. There are 150 million cases of UTIs worldwide, and they are responsible for 130,000 deaths per year. Women are particularly susceptible to infection, largely due to the short length of the urethra in females. It is estimated that 20% to

30% of adult women will experience a recurrent UTI in their lifetime.2 Other populations at risk for recurrent UTIs are pregnant women, children, elderly, those with a neuropathic bladder disorder, and those with indwelling urinary catheters. The classic symptoms of a lower UTI are frequent micturition, dysuria, suprapubic tenderness, and sometimes low back or flank pain. Given their distinct and somewhat unmistakable symptoms, UTIs have a high rate of self-diagnosis. Some people will purchase over-the-counter screening tests to confirm suspected infections (yet these tests lack culture and sensitivity testing). This high level of self-treatment/ self-diagnosis has both the potential for improving outcomes with early intervention, and also the potential for increased harm if the infection is not controlled early. In some studies, up to 94% of self-diagnosed UTI patients ended up getting

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ABSTRACT & COMMENTARY

treated with antibiotics for their UTIs.4 Here it is important to mention that a great deal of self-diagnosis might be being made for asymptomatic bacteriuria (ASB) where there is a lack of classic UTI symptoms, but the patient may be experiencing an odor in their urine or urine cloudiness and may contact their provider. There is no evidence supporting treatment of ASB with antibiotics, except in pregnant women.5 While it may appear on the surface to make a clinician’s job easier if a patient has good self-diagnosis probability, the grave possibility of an unresolved lower UTI progressing into a kidney infection (acute pyelonephritis) is the counterbalance to this. The potential consequences of acute pyelonephritis, including sepsis, shock, and death, are well-documented and engraved in every clinician’s mind when confronted with a patient who has a UTI. While the classic clinical presentation of acute pyelonephritis includes bladder symptoms (micturition, dysuria, urinary urgency, suprapubic pain) and systemic inflammation (fever, malaise, chills, flank pain), it’s vital to note that over 20% of pyelonephritis patients do not present any bladder symptoms and would only be caught by urinalysis or through clinical acumen of other symptoms. It is also essential to note that 3% or less of cases of lower UTIs/cystitis and asymptomatic bacteriuria progress to pyelonephritis.6 Many guidelines for clinicians involve initiating treatment at the earliest symptoms of UTI and obtaining a urine culture and antibiotic sensitivity test of the urine as soon as possible. So, it’s understandable that the use of antibiotics has been deployed as a catchall treatment for anyone presenting with UTI symptoms. Yet, many lower UTIs will resolve untreated or with limited intervention (eg, hydration). This provides some opportunity to reduce the overuse of antibiotics and the potential resistance that ensues by using less-aggressive but proven-effective natural alternatives like cranberry preparations. Antibiotic resistance is increasing in the treatment of recurrent UTIs. The most common microbial species causing UTIs is uropathogenic Escherichia coli (UPEC), which accounts for 80% of complicated urinary tract infections, 95% of community-acquired infections, and 50% of hospital-acquired infections.3 16

Other species that can cause UTIs include Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus saprophyticus, Enterococcus faecalis, Streptococcus bovis, and the fungus Candida albicans.3 UPEC is part of an extraintestinal pathogenic E coli (EXPEC) that seems to originate from the gut. This is clearly elicited in children (especially female) who have chronic constipation and/or encopresis, as both groups suffer from recurrent UTIs. UPEC has growing resistance to commonly used antibiotics, such as amoxicillin-clavulanic acid, worldwide. In the United States, the resistance of UPEC to amoxicillin-clavulanic acid is between 3.1% and 40%, and it is worse in developing countries. For example, in Jordan it is 83%. Moreover trimethoprim-sulfamethoxazole, another frequently prescribed UPEC antibiotic, has resistance in the United States of 17.4%; this is as high as 82% in Pakistan. Finally, ciprofloxacin, a commonly prescribed broad-spectrum fluoroquinolone antibiotic with well-documented side effects (ie, tendinopathy, Clostridium difficile infection), has growing resistance in developed countries, such as in the United States, with 5.1% to 12.1% resistance rates and an amazingly high rate of 85.5% in Ethiopia.7 Not to despair, the first line therapies of fosfomycin or nitrofurantoin still have largely low resistance rates. Fosfomycin has an overall resistance to UPEC of <1.5% worldwide, and nitrofurantoin has an overall resistance of <1.5% to 15.5% worldwide.7 One of the key risk factors of UTIs is dehydration. Most people quickly blame recurrent UTIs on postintercourse practices such as not voiding after vaginal intercourse, but lack of hydration is actually a greater risk factor. In a high-quality randomized trial in 2018 by Hooten et al, premenopausal women with recurrent UTIs and low-volume fluid intake were intervened to increase their water intake by at least 1.5 liters daily. This trial showed that the improved hydration reduced UTIs and the frequency of antibiotic use during UTIs.8 The importance of hydration likely has something to do with reducing the adherence of UPEC to the bladder/urethra wall. The manual flushing of bacteria is, thus, preventative. Just a word of caution that it is also important to be mindful of overhydration as a possibility

in our most compliant patients, which can lead to hyponatremia. Lastly, there is some evidence that voiding within 15 minutes of vaginal intercourse may lower the risk of getting a UTI, especially in those without any history of past UTIs.9 Cranberry likely reduces UTIs due to its PAC content. The proanthocyanidins may reduce the adherence of UPEC to the bladder wall, thereby reducing infection risk. The study by Xia’s group showed that cranberry-containing capsules or tablets in 10 studies led to a relative risk (RR) of 0.8, meaning the relative risk of UTI was reduced by 20%. Cranberry juice had a RR of 0.65, meaning the relative risk of UTI was reduced by 35% and suggesting that juice is the better form for risk reduction. In certain subpopulations such as children with recurrent UTIs, there was a 45% risk reduction taking cranberry products. And women with recurrent UTIs had a 32% risk reduction of UTIs taking cranberry products. Patients with indwelling catheters taking cranberry products to prevent recurrent UTIs had a 51% risk reduction of recurrent UTIs. Investigators analyzed the dosing, frequency, and type of cranberry preparation (juice or tablet). The key factor in dosing seemed related to PAC content within the preparations. The recommended intake of PACs to decrease the number of recurrent UTIs, based on this review, is not lower than 36 mg daily regardless of type of preparation (ie, juice, tablet, capsule). The appeal of cranberry juice is 2-fold. Its PAC content can be coupled with its hydration effect, thus possibly helping on both fronts of increasing hydration and reducing adhesion of UPEC. In reality, however, drinking daily cranberry juice might not be as fun as Mr. Nathan Apodaca made it seem in his famous viral TikTok video during the height of the Covid-19 pandemic.10 So capsules or tablets may be more practical for some. The limitations of the study are the wide variety of dosing that the comparison studies used and also that in real-world settings cranberry is not often used as a monotherapy but rather in conjunction with other therapies. In addition, the lack of uniformity of what constitutes a UTI also added a limitation to the quality of the evidence.

Early education on preventing recurrent UTIs is essential, as the risk of recurrence in women is 27% within 6 months of having their first UTI.11 For example, education on reducing exposure of colon flora to vaginal regions, improving hydration, increasing perineal hydration and moisture, lubricating, and addressing other factors would help prevent recurrence. This study was very helpful in solidifying dosing (>36 mg proanthocyanidins daily) and supplement selection for daily cranberry consumption in populations at risk of recurrent UTIs. It also highlights the appeal of studying more integrative protocols containing other proven UTI prevention treatments such as D-mannose, Arctostaphylos uva-ursi, Zea Mays (corn silk), and probiotics. What also needs to be looked into (and which the researchers did not mention) is the role of biofilm in the recurrence of UTIs. Last but not least, this study shone light on the importance of prudent antibiotic prescribing, especially in the era of telehealth. We must use all our tools and be precise with antibiotic prescribing, or refer out for this if needed. REFERENCES

Zhang S. The patient who finally knows why her UTIs won’t go away. The Atlantic website. https://www.theatlantic.com/science/archive/2019/09/woman-recurringutis-for-48-years/597199/. Accessed April 22, 2022.

Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am. 2003;17(2):227-241.

3 4 5

Rastogi R, Martinez KA, Gupta N, Rood M, Rothberg MB. Management of urinary tract infections in direct to consumer telemedicine. J Gen Intern Med. 2020;35(3):643-648. Henderson JT, Webber EM, Bean SI. Screening for Asymptomatic bacteriuria in adults: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2019;322(12):1195-1205. Johnson JR, Russo TA. Acute pyelonephritis in adults. N Engl J Med. 2018;378(1):48-59.

Kot B. Antibiotic resistance among uropathogenic Escherichia coli. 2019;68(4):403415.

Mccollum BJ, Garigan T, Earwood J. Can drinking more water prevent urinary tract infections? J Fam Pract. 2020;69(3):e19-e20.

Harris LM. Does urinating after intercourse reduce the risk of urinary tract infections among women? Evid-Based Pract. 2013;16(5):6.

10 Apodaca N. Dreams (2004 Remaster) - Fleetwood Mac. @420doggface20. https:// www.tiktok.com/@420doggface208/video/6876424179084709126. Accessed April 22, 2022. 11 Medina M, Castillo-Pino E. An introduction to the epidemiology and burden of urinary tract infections. Ther Adv Urol. 2019;11:1756287219832172.

EXPERT INTERVIEW

Can We Slow Aging at the Cellular Level? An interview with Kara Fitzgerald, ND, IFMCP

Natural Medicine Journal’s Editor-in-Chief, Tina Kaczor, ND, FABNO, recently had the opportunity to sit down with Kara Fitzgerald, ND, IFMCP. Fitzgerald is the coauthor of a peer-reviewed paper on antiaging epigenetic effects of a naturopathic protocol. In this interview, Fitzgerald discusses how epigenetics is involved in cellular aging, details of the protocol used in the study, and talks about where we are headed in the future. This interview was published as a podcast in December 2021 and is being reprised here as a Q&A for our Healthy Aging special issue.

Listen to the full interview here. Approximate listening time: 45 minutes

Tina Kaczor: You’re the lead author of a first-of-its-kind study on a diet and lifestyle intervention that has a measurable effect on the aging process. What was so interesting about the study is that it combined the latest in assessment using DNA, epigenetics, and methylation patterns with what I would call an old-school natural medicine approach. I was excited to see you didn’t use the nutraceuticals. You used basic, good, foundational medicine. How did your background lead you here? Kara Fitzgerald: We’re in a real scientific medical revolution right now. Our technologies are advancing at a breakneck pace. We’re learning, though, that going back to old-school interventions is still the way we’re going to get the best outcomes.

I saw this when I worked at the first clinical lab to release a DNA stool analysis (ie, a PCR stool analysis) during my postdoc training. It was this amazing, stratospheric blast of technology. But the kinds of interventions that were ultimately landed on were chew your food, rest and digest, and eat a whole-food diet. The interventions got simpler and simpler.

Flash forward, and we can now look at DNA methylation, which is one of the main epigenetic markers that determines whether genes are turned on or off. At the time of our study in 2017, it was only available in the research setting, but now slowly labs are making epigenetic testing more broadly available. In our world, we talk about nutrigenomics all the time. We put a lot of attention into assuming that what we’re doing is influencing genetic expression, and rightly so. So I finally started to really tussle with the epigenetic research. It was mostly in cancer, which is where the best science was coming out around 2013. So I was aware of epigenetics and that it was getting big. It really expanded after the genome was fully mapped in the early 2000s and we realized this idea of one gene driving one disease was in fact a misconception. We’ve got 23,000 genes. It’s remarkably simple. Epigenetics, which regulates genetic expression, controlling genes that are on or turning genes off, is as complex as DNA is simple. Mapping the genome wasn’t going to provide the ticket to all the complex diseases we are facing.

I’m somewhat of a geeky, biochemistry-inclined naturopathic physician. I was hoping we would have pinpoint probiotic prescriptions. Not that the complexity would just be so expansive, and that we would see that a whole-foods diet ultimately changed things. 18

“

There’s a clear need for abundance of methylation support. It’s happening in every cell of the body, basically all of the time.

One of the things that interested me was the methylation cycle. Hypermethylation on the genome—which turns a gene off when there are a lot of little methyl groups hanging out, usually in the promoter region of a gene—is going to shut that gene down. Conversely, hypomethylation also happens on different genes. Hyper- and hypo-, this tension, is happening all the time. In cancer, the tumor microenvironment can very effectively hijack our epigenetic machinery and turn genes on and off—to hyper- and hypomethylate concurrently—for its own growth process.

KF: My clinic has a strong nutrition team. Our nutrition director was Romilly Hodges. She and I began to really talk about this, and I said, “Let’s build out a nutrition-forward methylation program.”

The big aha for me was that we could possibly be doing harm to our patients by pushing aggressive amounts of B-12 and folate, natural or otherwise. Could our interventions be negatively influencing DNA methylation? Some literature suggests it’s possible.

There’s a clear need for an abundance of methylation support. It’s happening in every cell of the body, basically all of the time. So we need to support it. And we also need to perhaps be a little bit more nuanced in our approach. And that was our entry into the conversation.

One of the more famous studies was the B-PROOF trial, where they gave elderly individuals with elevated homocysteine 400 mcg of folic acid and maybe 500 of B12 to try to prevent fractures. It wasn’t a huge amount, but a small but significant subset of these individuals, particularly those who were older, had a statistically significant increased risk of colorectal cancer.

We built out this methylation diet and lifestyle program to use in our clinic practice. We also used it a lot with individuals who don’t tolerate B12. We had the capacity, and Romilly led the charge in building out a beautiful program that loaded up on natural folates from foods and betaine. We used lots of beets, and liver for folks who will eat liver. Liver is a multi vitamin of food matrix.

For me, it just shone a light on the U-curve. We know that if you don’t have enough methyl donors, there are big problems, including cancer risk, but there an also be too much. TK: How you come to develop your nutrition program?

THE STUDY INTERVENTION Diet Weekly • 3 servings of liver • 5-10 eggs

Daily • 2 cups dark leafy greens • 2 cups cruciferous vegetables • 3 additional cups colorful vegetables • 1-2 medium beets • 4 tablespoons pumpkin seeds • 4 tablespoons sunflower seeds • 1+ servings of methylation adaptogens like berries, garlic, and some herbs • 6 ounces animal protein • 2 servings low-glycemic fruit

General guidelines • Stay hydrated • Don’t eat between 7 PM and 7 AM, • Include healthy oils in the diet • Avoid sugar, candy, dairy, grains, legumes, and beans • Minimize plastic food containers • Supplement exercise • Sleep 7 hours • Manage stress through breathing exercise

EXPERT INTERVIEW

Concurrently we also saw that exercise is associated with lowering homocysteine; it promotes balanced methylation. As do sleep and meditation. So we looked beyond just food and we looked at lifestyle components that had evidence behind them for healthy methylation. Another big aha for me on this journey was the fact that aging is the number one risk factor for all the chronic diseases we’re working with in practice. Some of the imbalances that drive aging epigenetically are the same as what’s happening in cancer, cardiovascular disease, or diabetes, or stem cell exhaustion. The imbalances that are happening in stem cell exhaustion look like the tumor microenvironment. TK: What’s your take on the term antiaging? KF: Everybody has their own idea around aging and what antiaging is. For many people it’s Botox and whatever else you can do to make yourself look young. I’m speaking about something very, very different—biological aging. It is different than chronological aging. TK: Yeah, it’s biological aging, this is not a calendar. This is more profound than most papers out there on antiaging. So tell us more about the study you conducted. KF: Romilly and I were thinking the whole time about whether we were actually influencing epigenetics. We put together a program that suggests yes. But we threw out all sorts of permutations of studies we might do, because measuring epigenetics at the time in practice in 2017 was not available. It’s only now just barely becoming available.

I was in conversation with Brent Eck, the CEO of Metagenics, and he very graciously gave me an unrestricted grant to conduct this study. We included their probiotic and greens powder in the study, but they didn’t pick those. We were allowed to do this and to manifest it ourselves, and we were in charge of design and everything. We used the largest available DNA methylation array, which measures a good portion of the methylone, which are those marks directly on DNA. Methylation tends to become 20

aberrant or disordered as we age. Anybody who’s measuring homocysteine sees that it tends to rise and other things become imbalanced. The study was a pilot and we needed to limit it to men since we didn’t have the resources to distinguish between pre-, periand post-menopausal influence. As a woman, it was difficult, but we had to make that choice. We also wanted a healthy cohort. We weren’t looking at epigenetic changes in diabetes or cardiovascular disease. We were specifically looking at whether or not we’re reversing biological age. We didn’t want to do that in a population who wasn’t healthy. To really push study adherence, our nutrition team volunteered their time and coached participants. Required nutrition meetings were built in. They weren’t cheerleading meetings; they were drab IRB-approved script meetings. They were not a typical encounter you would have with your patients, but adherence was very good. We had a modest exercise prescription, the relaxation response, and some basic breathing exercises, limited to 10 to 20 minutes twice per day. We included the probiotic Lactobacillus plantarum. The reason behind the probiotic is that it may increase folate production. We did end up significantly increasing full circulating methyl folate by 15% in our study population. And then included a greens powder. TK: It’s interesting that it worked in a healthy population, because to me that means it might have more profound effects in people with more evidence of biological aging. KF: I think that’s right, but as a counterpoint, an unwell population may require a longer intervention period. Though as a clinician I know we can turn around blood sugar, A1C, insulin in a short amount of time if you’ve got a motivated patient. So yes, I think unwell people might reverse aging faster and more profoundly than a healthy population. But we’ll have to see what kind of a timeframe that is.

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Horvath is a biostatistician and he created it with a massive dataset of individuals. The original clock was locked to chronological age and correlates with a 0.96-degree correlation coefficient. This one blows away any other biological age market out there. The next best at the time was telomeres, which are still used and can be useful. But the correlation coefficient is about 0.4, maybe. So this was just the most rigorous biological age assessment out there dialed in with chronological age.

If aging is a pre-programmed event and there’s some evidence that it is, and some evidence that at least a chunk of that role is played by changes to DNA methylation, then it looks like what we’re doing could be massaging that favorably.

One of the big questions we set out to answer was whether we could improve the biological aging patterns in our population. Being a naturopath and working with Romilly on orthomolecular nutrition, we wanted to see how we could massage the DNA methylone for optimal expression.

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In our healthy population, we lowered total cholesterol, even though it wasn’t elevated. It wasn’t too low, but we brought LDL and triglycerides down. Our diet is a little bit keto-leaning. It’s got a very gentle intermittent fasting structure (not eating from 7 PM to 7 AM). And again, we have the exercise prescription. I think the burning of the triglycerides suggests a little bit of ketosis. TK: Can you explain the tool that was used to measure biological aging on the DNA? KF: There is a predictable change in DNA methylation patterns, starting from conception. From embryogenesis to death, predictable changes occur across the lifespan. The clock that we used is the first biological age clock, which was released in 2013. There are subsequent clocks now and we’ll be looking at those. Second and even third generation clocks that track aging more closely associated with morbidity and mortality. There’s aging of skin and looking at the immune system, et cetera. There are ways to track organ-specific aging, and there are all sorts of cool aging questions we can answer now with DNA methylation patterns. But the very first and most utilized clock is the Horvath 2013 DNA methylation age clock.

One of the revolutions in thinking that I’ve experienced on this journey is that all of the massive timestamped movements we go through as human beings are regulated in significant part with changes to methylation, DNA methylation. This is both adding methylation, but subtracting demethylation too. In fact are 2 families of enzymes that are involved in here—DNA methyltransferase enzymes, and then a family of enzymes called Ten-eleven translocation enzymes that take methyl groups off. Over time these really influence the course of our life. There is probably a program to the aging journey that may be dictated by changes to DNA methylation. I think that’s where some of the science is really headed now. So if we put attention on optimizing DNA methylation, yes, we saw improvement in the standard biomarkers of our participants. But we also saw improvement in their DNA methylation patterns. So our proposal is that changing and optimizing DNA methylation patterns as it relates to biological aging isn’t just changing the surrogate marker of biological aging, it actually is changing biological aging. TK: And the worst case is, you’re eating a healthy diet. You wake up feeling good, your joint pain goes away. Best case is you feel good longer.

EXPERT INTERVIEW

KF: Well, and you live longer, you’ve got a longer health span. And we’re actually influencing sort of a pre-programmed clock. If aging is a pre-programmed event and there’s some evidence that it is, and some evidence that at least a chunk of that role is played by changes to DNA methylation, then it looks like what we’re doing could be massaging that favorably. When you think about things with an orthomolecular model, why wouldn’t we be able to do that, right? Why wouldn’t we be able to influence with the sweet spot of nutrients to ingest? TK: Was there a calorie count that these participants had to adhere to? KF: No. The cool thing about this program is you can layer it into whatever intervention you want. We’ve used it in clinical practice with FODMAP, or with people with allergies, or with cancer. We really want to massage methylation in a balanced, healthy way. We use this all of the time, but we might turn up the volume with ketosis or turn

down the volume on caloric intake. But if we had done caloric restriction and we’d achieved these findings, we wouldn’t be able to lean on our intervention, it would’ve been clear. TK: You recently published a book. Can you tell us a bit about that? KF: The book is called Younger You: Reduce Your Bio Age and Live Longer, Better. In it, I walk through this program with more nuance. I give more specific protein requirements for body size and age. I’ve also interpreted it for pregnancy. And I go into how to transition to other foods, since this not necessarily a forever diet. TK: I really appreciate your being at the forefront of combining the functional medicine and naturopathic medicine with integrity. Thank you for taking the time to share your research with us. KF: That means a lot. And right back at you. You’re blazing amazing trails as well.

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Natural Medicine Journal Healthy Aging Special Issue 2022

Articles inside

Can We Slow Aging at the Cellular Level?

Endocrine and Nutritional Relationships in Centenarians