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.
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.
This report documents research conducted under 2 projects in a Non-Assistance Cooperative Agreement between ARS and TUFTS UNIVERSITY. Additional details for the research are associated with projects 8050-51000-092-01S, Musculoskeletal Health and Metabolism in Elderly Adults and 8050-51000-092-02S Vitamin K: Food Composition, Bioavailability and Human Health. LAB: Bone Metabolism - We have demonstrated that administration of potassium bicarbonate, a compound that neutralizes the acid load of the diet, has favorable effects on muscle performance and bone turnover markers over a 3-month period. However, the amount of potassium bicarbonate needed for maximal benefit is unknown. We have just completed 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. Initial analyses reveal that a dose of 81 mmol per day of potassium bicarbonate is the dose that maximally lowers the biochemical marker of bone turnover, urinary N-telopeptide. We are currently preparing an NIH application for funding to conduct a 3-year potassium bicarbonate versus placebo intervention trial to determine the long-term effect of the supplement on rates of bone loss and on newer measures of bone architecture. 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 United States (U.S.) are enrolled. As of end of May, 2015, over 1,125 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. We have recently started recruiting subjects into a 1-year randomized, 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. Over the next two years, we plan to enroll up to 100 subjects in order to have 88 completers. To date we have enrolled 20 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. LAB: Vitamin K - Recent reports from Europe attribute unique heart health benefits to certain forms of vitamin K obtained from the diet. However, these forms of vitamin K, called menaquinones, have not been systematically analyzed in U.S. foods, nor have their intakes been estimated in the U.S. population. Therefore, these observations have yet to be substantiated in the U.S. In collaboration with scientists at the Beltsville Human Nutrition Research Center (BHNRC), Beltsville, Maryland, we analyzed commonly-consumed foods for all 11 known individual forms of vitamin K as part of the USDA Nutrient and Food Analysis Program. We found that animal products and fermented foods, such as pork meat and dairy products, had high concentrations of menaquinones. A more comprehensive analysis of meats and dairy products will be conducted to more accurately reflect what vitamin K forms are in the U.S. food supply, and to determine if these forms have unique health-promoting properties. Menaquinones are also produced by gut bacteria, and may contribute to vitamin K status. However, gut menaquinone content and factors mediating menaquinone synthesis are not well characterized. In collaboration with scientists at the BHNRC, we examined the effect of a whole grain diet intervention expected to alter gut microbiota composition on fecal menaquinone content. Fecal vitamin K concentrations were measured in healthy adults randomly assigned to consume one of three diets differing only in grain content for six weeks. Fecal menaquinone concentrations generally increased over the six-week study, but did not differ among the three diets. In conclusion, consuming whole grains does not appear to alter fecal menaquinone concentrations. Osteoarthritis afflicts nearly one in five adults in the U.S., and there is currently no known therapy that delays its progression. Low vitamin K status has been associated with higher osteoarthritis prevalence and progression in observational studies. At this time, mechanisms underlying dietary vitamin K’s role in reducing risk of osteoarthritis are poorly understood because studies in this area are lacking. To address this gap in knowledge, we utilized a surgical model of knee osteoarthritis in rats. Whereas we were able to induce vitamin K deficiency in the rats, the surgical procedure appeared to not have been ideal for the hypothesis proposed. This was due, in part, to high variability in the response of the control group. Therefore we have now designed and initiated a new experiment using aging mice, which have been shown to develop knee osteoarthritis naturally with age. Use of an aging model is more translatable to humans as risk for osteoarthritis increases with age.
1. Meal composition affects vitamin D absorption. An issue that complicates the process of correcting vitamin D deficiency is that individual serum 25OHD responses to a given dose of the vitamin vary widely. ARS funded researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging in Boston, Massachusetts, found that supplemental vitamin D is absorbed more efficiently when the supplement is taken with a meal, rather than with no meal. They have recently published the results of a follow-up study in 50 healthy older adults to determine whether the presence of fat in the meal influenced vitamin D absorption. They found that absorption of vitamin D from a supplement was over 30% greater when the supplement was taken with a meal containing fat (in an amount commonly consumed) than with a fat-free meal. This research may lead to more effective strategies for older adults to achieve and maintain vitamin D repletion.
2. Supplementation with alkali lowers bone resorption. The acid/base balance of the diet appears to be important for bone and health. In a recently completed 3-month clinical trial in 244 men and women age 60 years and older, ARS funded researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging in Boston, Massachusetts, examined the impact of different doses of alkali, as potassium bicarbonate, and placebo on biochemical markers of bone turnover. They found that the lower dose administered, 81 mmol per day, was most effective and that it lowered the biochemical marker of bone turnover, urinary N-telopeptide, significantly by 18%. This dose was safe and well tolerated, and should now be tested in a long-term trial to determine its effect on rates of bone loss in community-dwelling older men and women. They also plan to characterize the food combinations that result in an acid-base balanced diet. 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.
3. Role of vitamin K and associated bone proteins in diabetes risk. Individuals with osteoporosis have a higher risk of diabetes. Osteocalcin, a protein which requires vitamin K for its function in bone formation, may be responsible for this crosstalk between the skeleton and glucose metabolism. To test this, ARS funded researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging in Boston, Massachusetts, measured the associations between vitamin K, osteocalcin, and insulin resistance in three independent human studies. Their research showed the importance of consuming higher amounts of dietary vitamin K to support function of bone proteins, such as osteocalcin, and reduce diabetes risk in older men. Carefully designed studies are now required to define the optimal amount of dietary vitamin K required for regulation of glucose metabolism in humans.