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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #426446

Research Project: Nutrients, Aging, and Musculoskeletal Function

Location: Jean Mayer Human Nutrition Research Center On Aging

2016 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 continue to recruit subjects into a randomized, double-blind placebo-controlled trial to determine whether supplementation with vitamin D improves leg strength and power in older men and women with low 25-hydroxyvitamin D levels. We plan to enroll up to 100 subjects in order to have 88 completers. To date we have enrolled 70 subjects. Over the course of a year, each subject comes to the Human Nutrition Research Center on Aging (HNRCA) every 2 months for physical function and biochemical testing. We had demonstrated earlier that administration of the 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. We have now completed and published the main results of a randomized, placebo-controlled dose-finding trial to identify the dose of potassium bicarbonate that is most favorable to short-term indicators of bone health in 244 older men and women. We found that a dose of 81 mmol per day of potassium bicarbonate maximally lowered the biochemical marker of bone turnover, urinary N-telopeptide. We have submitted a National Institutes of Health (NIH) application for funding to conduct a 3-year dietary intervention trial to determine the long-term effect of neutralizing acid-producing diets with a dietary intervention (dried fruit equivalent to 81 mmol/d) on rates of bone loss and on bone architecture in healthy older men and women. 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 vitamin D, compared with placebo, will retard the progression to type 2 diabetes in high risk adults (adults with pre-diabetes). Subject recruitment began in October 2014 and will continue until 2,382 men and women from 20 centers around the US are enrolled. As of end of June 1, 2016, over 1,900 subjects have been enrolled. Subjects take either 4,000 IU of vitamin D or placebo daily for up to 4 years. The numbers of subjects meeting our criteria for type 2 diabetes will be compared in the placebo and vitamin D treated subjects. Individuals with type 2 diabetes have increased fracture risk, despite having normal bone density. This suggests that bone architecture is altered in type 2 diabetes. We have been notified that we will receive NIH funding to assess and compare bone architecture 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). This cross-sectional study will take 3 years. 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 Beltsville Human Nutrition Research Center (BHNRC), we expanded our analysis of 11 forms of vitamin K in processed and fresh-cut pork products obtained through USDA’s National Food and Nutrition Analysis Program or purchased from local retail outlets. Although low in phylloquinone, all processed pork products and fresh pork cuts contained high amounts of three menaquinone forms. Therefore, processed and fresh-cut pork 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. Various biological and environmental factors have been implicated in their effect on vitamin K status, but have not been systematically studied in rodent models used to study the role of dietary vitamin K in health outcomes. In a series of pilot studies using a mouse model, we observed significant differences between male and female mice in how they respond to different amounts of vitamin K in the diet. The magnitude of these differences varied among tissues. We then determined that use of a more stressful housing environment that is advocated for vitamin K nutrition studies conferred no benefit compared to use of standardized rodent housing that minimizes stress for the animal. Based on these findings, it is important to consider sex-specific differences that vary by tissue when using rodent models for vitamin K nutrition studies. Use of standard rodent housing reduces stress to the animal while maintaining the integrity of the study design as it relates to vitamin K metabolism. Previous studies found lower vitamin K nutritional status was associated with more osteoarthritis progression. We determined the association between vitamin K nutritional status and lower extremity function in older adults participating in the Healthy Aging and Body Composition Study because knee osteoarthritis is the leading cause of lower extremity disability in older age. We found older adults who had higher levels of vitamin K in their blood had better performance scores and faster walking speed over 4-5 years of follow-up. More studies are needed to determine if vitamin K supplementation could benefit older adults at risk for disability, such as those with osteoarthritis.


Accomplishments
1. BONE METABOLISM LAB: Supplementation with alkali lowers bone resorption. The acid/base balance of the diet appears to be important for bone health. Tufts University researchers at USDA in Boston, Massachusetts, recently published the main results of a 3-month clinical trial in 244 men and women age 60 years and older, in which we examined the impact of different doses of alkali, as potassium bicarbonate, and placebo on biochemical markers of bone turnover. We found that the dose of 81 mmol per day was most effective and it lowered the biochemical marker of bone turnover, urinary N-telopeptide, significantly by 18%. In subsequent analyses of the extensive diet data from this trial, we have determined that the addition of 81 mmol per day of alkali can be achieved by diet modification, specifically, by consuming one-half cup of dried fruit per day. If long-term benefit from maintaining dietary acid-base balance can be demonstrated, this research may lead to a more effective strategy to preserve bone health in older men and women.

2. VITAMIN K LAB: Food sources and intakes of vitamin K among U.S. adults. Current dietary recommendations for vitamin K are based on dietary data obtained from older surveys. Tufts University researchers at USDA in Boston, Massachusetts, working with ARS researchers in Beltsville, Maryland, have systematically analyzed the vitamin K content of common foods in the US food supply. These data were used to estimate average vitamin K intakes obtained from a recent national survey. Vitamin K intake on any given day varies significantly by age, race/ethnicity, education, income, and vegetable intake, with the elderly reporting the lowest intakes among adults. Vitamin K-containing oils and animal products in mixed dishes and restaurant foods contributed substantially to a person’s total daily vitamin K intake. These data identify subgroups of the population who would benefit from increased consumption of vitamin K to meet current dietary recommendations.



Review Publications
Bischoff-Ferrari, H.A., Dawson-Hughes, B., Orav, E.J., Stahelin, H.B., Meyer, O., Theiler, R., Dick, W., Willett, W.C., Egli, A. 2016. Monthly high dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. Journal of the American Medical Association. 176(2):175-183.
Niu, J., Sahni, S., Liao, S., Tucker, K.L., Dawson-Hughes, B., Gao, X. 2015. Association between sleep duration, insomnia symptoms and bone mineral density in older Puerto Rican adults. PLoS One. 10(7):e0132342. doi: 10.1371/journal.pone.0132342.
Mitchell, P., Cooper, C., Dawson-Hughes, B., Gordon, C.M., Rizzoli, R. 2015. Life-course approach to nutrition. Osteoporosis International. 26(12):2723-2742. doi:10.1007/s00198-015-3288-6.
Ceglia, L., Neslon, J., Ware, J., Alysandratos, K., Bray, G., Garganta, C., Nathan, D.M., Hu, F.B., Dawson-Hughes, B., Pittas, A. 2015. Association between body weight and composition and plasma 25 hydroxyvitamin D level in the diabetes prevention program. European Journal of Nutrition. doi: 10.1007/s00394-015-1066-z.
Shea, K., Booth, S.L. 2016. Concepts and controversies in estimating vitamin K status in population based studies. Nutrients.(8):8. doi: 10.3390/nu8010008.
Centi, A., Booth, S.L., Gundberg, C., Saltzman, E., Nicklas, B., Shea, K. 2015. Osteocalcin carboxylation is not associated with body weight or percent fat changes during weight loss in post menopausal women. Endocrine Journal. 50(3):627-632.
Dawson-Hughes, B., Harris, S.S., Palermo, N.J., Gilhooly, C.H., Shea, K., Fielding, R.A., Ceglia, L. 2015. Potassium bicarbonate supplementation lowers bone turnover and calcium excretion in older men and women a randomized dose-finding trial. Journal of Bone and Mineral Research. 30(11):2103-2111. doi: 10.1002/jbmr.25.
Weaver, C.M., Alexander, D.D., Boushey, C.J., Dawson-Hughes, B., Lappe, J.M., Leboff, M.S., Looker, A.C., Wallace, T.C., Liu, S., Wang, D.D. 2015. Calcium plus vitamin D supplementation and risk of fractures: an updated meta analysis from the National Osteoporosis Foundation. Annals Of Internal Medicine. 27(1):367-376.
Bischoff-Ferrari, H.A., Orav, J., Kanis, J.A., Rizzoli, R., Schloegl, M., Staehelin, H.B., Willett, W.C., Dawson-Hughes, B. 2015. Comparative performance of current definitions of sarcopenia against the prospective incidence of falls among community dwelling seniors age 65 and older. Osteoporosis International. 26:2793–2802.
Danziger, J., Young, R.L., Shea, K., Tracy, R.P., Ix, J.H., Jenny, N.S., Mukamal, K.J. 2016. Vitamin K dependent protein activity and incident ischemic cardiovascular disease: The multi ethnic study of atherosclerosis. Arteriosclerosis Thrombosis and Vascular Biology. 36(5):1037-1042.
Centi, A., Booth, S.L., Gundberg, C., Saltzman, E., Nicklas, B., Shea, K. 2015. Osteocalcin carboxylation is not associated with body weight or percent fat changes during weight loss in post menopausal women. Endocrine Journal. 50(3):627-632.