Location: Jean Mayer Human Nutrition Research Center On Aging
2017 Annual Report
Objectives
LAB Name: Bone Metabolism
1. Determine the effects of dietary and supplemental vitamin D and related nutrients in the prevention and progression of musculoskeletal performance and dysfunction, glucose homeostasis and type 2 diabetes, and other chronic diseases.
1.A. The impact of supplemental vitamin D on serum 25-hydroxyvitamin D (25OHD) levels and short-term indicators of physical function.
1.B. Determine the impact of vitamin D3-omega3-home exercise on aging.
1.C. Determine the effect of supplemental vitamin D on incident of diabetes in subjects with pre-diabetes.
1.D. Determine the effect of supplemental vitamin D on glucose tolerance in subjects with established diabetes.
2. Determine the effects of dietary acid-base balance on bone and muscle metabolism and function.
2.A. Conduct a dose-finding trial of the musculoskeletal benefits of bicarbonate in older adults.
3. Define the contributions of vitamin D absorption, metabolism, and genetic variation in regulating the circulating levels of 25-hydroxyvitamin D and other metabolites.
3.A. Conduct a pilot study of the effect of dietary fat type and amount on vitamin D3 absorption.
LAB NAME: Vitamin K
1: To characterize dietary factors, including food composition and nutrient-nutrient interactions, and non-dietary factors, such as genetics, that contribute to the inter-individual variation in vitamin K intake, bioavailability, and utilization and vitamin K metabolite production.
1.1: To study the influence of foods and single nutrients on the distribution, bioavailability and function of different forms of vitamin K and their metabolites.
1.2: To measure key foods to monitor changes in the food supply that affect vitamin K content
1.3: Identify genetic factors involved in vitamin K metabolism.
2: Determine the role(s) and mechanism(s) of action for vitamin K beyond its essential role in coagulation, including the role of vitamin K in the prevention of abnormal non-skeletal calcification and the mechanisms of vitamin K action not currently explained by its role as an enzyme cofactor.
2.1: Determine the effects of vitamin K in the prevention of abnormal non-skeletal calcification and other chronic diseases in older adults.
2.2: Identify potential mechanism(s) of vitamin K action that are not currently explained by its role as an enzyme cofactor.
Approach
LAB Name: Bone Metabolism
This laboratory uses a variety of approaches to carry out its clinical and translational research program, including cross-sectional and observational studies, randomized intervention trials, and small metabolic studies. This laboratory collaborates with the Nutrition, Exercise Physiology and Sarcopenia Laboratory to examine the impact of vitamin D and the acid-base balance of the diet on muscle performance and risk of falling. In collaboration with external laboratories, this laboratory seeks to determine the impact of vitamin D on risk of developing type 2 diabetes. These and other collaborations allow us access to basic research technologies, such as muscle tissue histology and gene array analysis, that enable us to identify mechanisms by which nutrients affect bone and muscle.
LAB NAME: Vitamin K
Our long-term objective is to study the determinants of vitamin K bioavailability, utilization, and metabolism in order to refine vitamin K intake recommendations. Expansion of the forms of vitamin K analyzed in a selected number of foods will enhance the USDA vitamin K database, and allow us to monitor changes in different forms of vitamin K in the food supply. To identify dietary and non-dietary factors that determine how much vitamin K obtained from foods is utilized, we will apply stable isotope techniques to established and novel measures of vitamin K metabolism. Data obtained from our completed metabolic study in younger and older adults, in addition to animal studies, have helped to refine the study designs that will be used in this project plan. We will initiate a series of studies that compare the metabolism of different forms of vitamin K, and identify the impact of other nutrients on different aspects of vitamin K metabolism. To expand our observations that vitamin K may have a role in the prevention of abnormal non-skeletal calcification, we will use observational data and biological samples collected from large on-going cohorts, as well as conduct animal studies, to examine potential mechanisms beyond that of an enzyme cofactor. We will then focus on the role(s) of different forms of vitamin K in insulin resistance and inflammation using a rodent model. This is a rapidly evolving field, and novel functions of vitamin K in other cells will be considered as new information becomes available.
Progress Report
BONE METABOLISM LAB: We have now recruited the needed 100 subjects into a randomized, double-blind placebo-controlled trial to determine whether supplementation with 800 to 1600 IU per day of vitamin D, when compared to placebo, improves leg strength and power in older men and women with low 25-hydroxyvitamin D levels. Study visits are ongoing. Over the course of a year, each subject comes to the Human Nutrition Research Center on Aging every 2 months for physical function and biochemical testing.
We had demonstrated earlier in a randomized placebo-controlled trial in 244 healthy older men and women that administration of potassium bicarbonate, an alkaline compound that neutralizes the acid load of the diet, has favorable effects on bone turnover markers over a 3-month period. In the same trial, we also measured urinary nitrogen excretion and estimated nitrogen intake by 24-hr diet recall. Urinary nitrogen excretion, when adjusted for same day nitrogen intake, is a good measure of muscle wasting. Recent analyses of data from this trial reveal that nitrogen excretion, adjusted for intake, declines with increasing intake of potassium bicarbonate. This finding is consistent with our hypothesis that neutralizing acid-producing diets may have favorable effects on muscle mass. Manuscript preparation is nearing completion.
Safe and low cost strategies are urgently needed to curb the current epidemic of type 2 diabetes. We are currently conducting a multicenter randomized double-blind placebo-controlled trial to test the possibility that supplementation with 4000 IU per day of vitamin D, compared with placebo, will retard the progression to type 2 diabetes in high risk adults (adults with pre-diabetes.) The 2,382 needed participants were recruited at 20 sites around the United States between October, 2014 and November, 2016. This is an event driven trial which will continue until 700 participants have converted to type 2 diabetes. To date there have been over 250 conversions. Participants come to their respective clinical sites every 6 months for study visits. At the end of the trial, the numbers of participants meeting criteria for type 2 diabetes will be compared in the placebo and vitamin D treated groups.
Individuals with type 2 diabetes have increased fracture risk despite having normal bone density. This suggests that bone strength is altered in type 2 diabetes. We have recently received NIH (National Institute of Health) funding to assess bone strength and bone density in 200 older adults with a balanced spectrum of fasting blood sugar levels, including normal (glucose < 100 mg/dl,) prediabetes (100-125 mg/dl) and type 2 diabetes (>125 mg/dl.) Bone strength is being assessed at the shaft of the mid-tibia by reference point indentation, a direct measure of resistance to micro-fracture. Subject recruitment is now underway. If we observe that bone strength declines with increasing glycemia, then this measure may serve as a useful predictor of fracture risk in adults with type 2 diabetes.
VITAMIN K LAB: Vitamin K food composition data have historically been limited to plant-based phylloquinone. Menaquinones are vitamin K forms that have limited representation in food composition databases yet have been linked to unique heart health benefits. In collaboration with scientists at the ARS-Beltsville Human Nutrition Research Center (BHNRC) in Beltsville, Maryland, we analyzed 11 forms of vitamin K in dairy products obtained through USDA’s National Food and Nutrition Analysis Program or purchased from local retail outlets. Although low in phylloquinone, all full-fat dairy products contained high amounts of three menaquinone forms. Therefore, dairy products are a rich dietary source of menaquinones that are currently unaccounted for in assessment of vitamin K in the food supply. The relative biological activity of each of these menaquinone forms and their contribution to heart health now needs to be systematically evaluated.
Menaquinone-4 is a vitamin K metabolite produced in certain tissues and is thought to share a metabolic pathway with cholesterol. It has been suggested that increased use of lipid-lowering medications among the elderly reduces formation of menaquinone-4 in the kidney, which results in increased abnormal renal calcification. To understand the role of the cholesterol pathway in the formation of menaquinone-4, we examined the effects of lipid lowering medications on menaquinone-4 formation in younger and older mice. Both young and old mice given lipid-lowering medications had 40% less menaquinone-4 formation in the kidney compared to those that did not receive the lipid-lowering medications. Menaquinone-4 formation in other tissues did not appear to be affected. These data confirm that cholesterol metabolism is involved in the generation of menaquinone-4 in the kidney. The health implications of alterations in menaquinone-4 formation in the kidney require further study.
Emerging evidence suggests that menaquinone forms may contribute to vitamin K’s role in human health. However, the relevance of menaquinones produced by gut bacteria to vitamin K requirements is unknown. We conducted a study in men and post-menopausal women to determine the associations between fecal menaquinone concentrations, gut microbiota composition and biological markers of vitamin K status. Fecal menaquinone concentrations were highly variable and were associated with the gut microbiota composition but not with specific dietary patterns. Menaquinones were not detected in circulation. The health implications of menaquinones produced by the human gut remain unclear.
Accomplishments
1. BONE METABOLISM LAB: Vitamin D deficiency has been associated with an increased risk of falling. Vitamin D supplements are usually taken daily, but less frequent dosing would be more convenient for many elders. In this trial, ARS-funded researchers in Boston, Massachusetts, in collaboration with colleagues at the University of Zurich assessed the effectiveness of two monthly doses of vitamin D on risk of falling in older community-dwelling men and women. The higher monthly dose was equivalent to 2,000 IU per day, and the lower dose was equivalent to the standard dose of 800 IU per day. Over the one year follow-up period, there were significantly more falls in the high dose compared with the standard dose group. We conclude that high monthly doses of vitamin D are not warranted in seniors because of a potentially harmful effect on falls.
Review Publications
Binkley, N., Dawson-Hughes, B., Durazo-Arvizu, R., Thamm, M., Tian, L., Merkel, J., Jones, J.C., Carter, G.D., Sempos, C.T. 2016. Vitamin D measurement standardization: the way out of the chaos. The Journal of Steroid Biochemistry and Molecular Biology. doi: 10.1016/j.jsbmb.2016.12.002.
Bischoff-Ferrari, H., Fischer, K., Orav, E.J., Dawson-Hughes, B., Meyer, U., Chocano-Bedoya, P.O., Meyer, O.W., Ernst, R., Schietzel, S., Eberli, F., Stahelin, H.B., Freystatter, G., Roas, S., Theiler, R., Egli, A., Wilson, N.M. 2017. Statin use and 25-hydroxyvitamin D blood level response to vitamin D treatment of older adults. Journal of American Geriatric Society. doi: 10.1111/jgs.14784.
Durazo-Arvizu, R.A., Dawson-Hughes, B., Kramer, H., Cao, G., Merkel, J., Coates, P.M., Sempos, C.T. 2017. The reverse J shaped association between serum total 25- hydroxyvitamin D and all-cause mortality: The impact of assay standardization. American Journal of Epidemiology. doi: 10.1093/aje/kww244.
Shea, K., Booth, S.L., Weiner, D.E., Brinkley, T.E., Kanaya, A.A., Murphy, R.A., Simonsick, E.M., Wassel, C.L., Vermeer, C., Kritchevsky, S.B. 2017. Circulating vitamin K is inversely associated with incident cardiovascular disease risk among those treated for hypertension in the Health, Aging, and Body Composition Study (Health ABC). Journal of Nutrition. 32(2):243-249. doi: 10.3945/jn.117.249375.
Chambers, J.D., Anderson, J.E., Salem, M.N., Bugel, S.G., Fenech, M., Mason, J.B., Weber, P., West, K.P., Wilde, P., Booth, S.L. 2017. The decline in vitamin research funding: a missed opportunity? Current Developments in Nutrition. doi: 10.3945/cdn.117.000430.
Shea, K., Dawson-Hughes, B., Gunberg, C., Booth, S.L. 2017. Reducing undercarboxylated osteocalcin with vitamin K supplementation does not promote lean tissue loss or fat gain over three years in older women and men: a randomized controlled trial. Journal of Bone and Mineral Research. 32(2):243-249. doi: 10.1002/jbmr.2989.
Nigwekar, S.U., Bloch, D.B., Nazarian, R.M., Vermeer, C., Booth, S.L., Thadhani, R.I., Malhotra, R. 2017. Vitamin K-dependent carboxylation of matrix gla protein influences the risk of calciphylaxis. Journal of the American Society of Nephrology. doi: 10.1681/asn.2016060651.
Harshman, S.C., Fu, X., Philip, K.J., Lamon-Fava, S., Kuliopulos, A., Greenberg, A., Smith, D.E., Shen, X., Booth, S.L. 2016. Tissue concentrations of vitamin K and expression of key enzymes of vitamin K metabolism are influenced by sex and diet but not housing in C57Bl6 mice. Journal of Nutrition. doi: 10.3945/jn.116.233130.
Dawson-Hughes, B. 2016. Acid-base balance of the diet: implications for bone. In: Weaver, C.M. et al, editors. Nutritional Influences on Bone Health. Switzerland: Springer International. doi: 10.1007/978-3-319-32417-3_9.
Cooper, C., Schneider, M.C., Javaid, K., Akesson, K., Dawson-Hughes, B., Rizzoli, R., Kanis, J.A., Reginster, J. 2016. How to implement a fracture liaison service. Orthogeriatrics. doi: 10.1007/978-3-319-43249-6_12.
Shea, K., Booth, S.L. 2017. Vitamin K, osteoarthritis, and joint pain. In: Watson, R.R. and Zibadi, S., editors. Nutritional Modulators of Pain in the Aging Population. Kidlington, Oxford, United Kingdom: Elsevier Inc. p. 225-233. doi: 10.1016/B978-0-12-805186-3.00019-9.
Wright, N.C., Saag, K.G., Dawson-Hughes, B., Khosla, S., Siris, E.S. 2016. The impact of the new National Bone Health Alliance (NBHA) diagnostic criteria on the prevalence of osteoporosis in the USA. Osteoporosis International. doi: 10.1007/s00198-016-3865-3.
Harvey, N.C., Biver, E., Kaufman, J., Bauer, J., Branco, J., Brandi, M.L., Bruyère, O., Coxam, V., Cruz-Jentoft, A., Czerwinski, E., Dimai, H., Fardellone, F., Reginster, J., Dawson-Hughes, B., Kanis, J.A., Rizzoli, R., Cooper, C. 2016. The role of calcium supplementation in healthy musculoskeletal aging: an expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF). Osteoporosis International. doi: 10.1007/s00198-016-3773-6.
Harshman, S.G., Shea, K. 2016. The role of vitamin K in chronic aging diseases: inflammation, cardiovascular disease and osteoarthritis. Current Nutrition Reports. 5:90-98.
McCabe, K.M., Booth, S.L., Fu, X., Ward, E., Adams, M.A., Holden, R.M. 2016. Vitamin K metabolism in a rat model of chronic kidney disease. The American Journal of Nephrology. 45:4-13. doi: 10.1159/000451068.
