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.
BONE METABOLISM LAB: This is the final report for the project 8050-51000-092-01S. Several large clinical trials assessing health effects of vitamin D were completed over the 5 years of the project. They have added substantially to current understanding of the impact of vitamin D in muscle performance and on risk of developing type 2 diabetes. Daily supplementation with a modest dose of vitamin D did not improve muscle performance in healthy older men and women with initial low-normal circulating vitamin D levels. Similarly, supplementation with 4,000 IU per day of vitamin D did not alter the risk of progressing from prediabetes to type 2 diabetes in a clinical trial in 2,423 adults. In the subset of the study population that had low circulating 25-hydroxyvitamin D levels, supplementation was associated with a lower risk of progression. High dose vitamin D is not an effective approach to preventing diabetes; however, it is important to prevent vitamin D deficiency for bone health and possibly also to reduce risk of developing type 2 diabetes. Our studies of dietary factors that influence vitamin D absorption revealed that absorption is greater when vitamin D supplements are taken with a meal that contains some fat than when taken with a fat-free meal or with no meal. This research affects recommendations for how to take vitamin D supplements. The impact of this work is that health care workers and the public now know how to take vitamin D supplements in order to maximize their absorption and effectiveness. The large majority of adults in the general population consume acid-producing diets, and these diets may contribute to bone and muscle losses that occur with aging. The last 5 years have been productive in terms of establishing that neutralizing acid-producing diets with potassium bicarbonate pills over the short term reduces muscle loss, assessed by nitrogen excretion, and reduces the rate at which bone is resorbed, an indicator of bone loss. A major objective over the last 5 years was to establish the optimal amount of potassium bicarbonate needed to protect bone and muscle. We accomplished this objective in a 3-month dose-finding potassium bicarbonate intervention trial. The impact of this research is that it confirms that correcting acid-producing diets has favorable effects on bone and muscle, at least over the short term. The research also provides the scientific justification for a larger, longer-term study to determine whether benefits seen at 3 months would persist and whether bone loss would be reduced with continued neutralization of acid stemming from the diet. It also provides a strong scientific rationale to determine whether achieving acid-base balance with diet modification rather than alkali pills will be effective over the long term. This research lays the groundwork for our next 5-year project in which we will determine the musculoskeletal effects of achieving acid-base balance by increasing fruit intake over a one-year period. VITAMIN K LAB: This is the final report for the project 8050-51000-092-02S. Significant progress was made on both objectives that fall under National Program 107. Current dietary recommendations for vitamin K are based on usual dietary intakes as estimated from surveys conducted in the 1990s. In collaboration with the Nutrient Data Laboratory at the Beltsville Human Nutrition Research Center (BHNRC) in Beltsville, Maryland, we have systematically analyzed the vitamin K content of common foods in the U.S. food supply. These data were then used to estimate average self-reported vitamin K intakes obtained from data collected as part of the 2011-2012 National Health and Nutrition Examination Survey. Our analysis indicated that the elderly self-report the lowest vitamin K intakes among adults, with only one-third of men over the age of 71 years meeting the current adequate intake. Vegetables continue to be the primary dietary source of phylloquinone in the U.S. diet. These data identify subgroups of the population who would benefit from increased consumption of vitamin K to meet current dietary recommendations. 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 BHNRC, we analyzed all known forms of vitamin K in dairy and meat products obtained through USDA’s National Food and Nutrition Analysis Program. We also partnered with commodity boards to extend the analysis to include different types of dairy, beef and pork products. Although low in phylloquinone, all full-fat dairy and meat products contained high amounts of multiple menaquinone forms. The relative biological activity of each of these menaquinone forms and their contribution to health now needs to be systematically evaluated before expanding the food composition database. While low vitamin K status has been associated with higher osteoarthritis prevalence and progression in observational studies, the mechanisms underlying dietary vitamin K’s role in reducing risk of osteoarthritis are poorly understood. We demonstrated that mice aged on a low vitamin K diet had significantly more articular cartilage proteoglycan loss compared to mice aged on a control diet, but there was no difference in the articular cartilage structural score or subarticular bone volume between the two groups. Articular cartilage proteoglycan loss is indicative of early stage osteoarthritis, so our findings suggest vitamin K may be important in reducing progression at the early stage of this disease. To the best of our knowledge, this is the first-time low vitamin K intake has been linked directly to a pathophysiological change in articular cartilage. In an observational study, we found older adults with low plasma vitamin K were more likely to have articular cartilage damage progression and meniscus damage progression over 3 years, compared to older adults with sufficient plasma vitamin K. Plasma vitamin K was not associated with structural outcomes related to subchondral bone damage, however. Because the meniscus is made of cartilage and proteoglycans these findings together suggest a potentially unique role for vitamin K in cartilage homeostasis. Epidemiological studies have shown osteoarthritis and arterial calcification occur together and have common underlying mechanisms. We demonstrated that low vitamin K status was associated with coronary artery calcification progression, a subclinical manifestation of cardiovascular disease (CVD), suggesting vitamin K-dependent mechanism are involved in both processes. We also found higher circulating vitamin K was associated cross-sectionally with lower concentrations of several inflammatory biomarkers. Inflammatory pathways are involved in osteoarthritis and CVD, so this finding suggests an alternate mechanism through which vitamin K may be involved in these age-related diseases.
1. BONE METABOLISM LAB: Vitamin D supplementation does not affect muscle performance. Vitamin D deficiency has been associated with decreased muscle strength in some studies but has no effect on strength in others. Reduced muscle performance in older adults is an important problem because it leads to falls, fractures, and other injuries, as well as loss of independence in older adults. Based on the hypothesis that individuals with low levels of vitamin D may benefit most from taking vitamin D supplements, ARS-funded researchers in Boston, Massachusetts, conducted a study in older men and women who had low-to-normal blood levels of vitamin D. Over the period of 12 months, participants were given either a dose of vitamin D (800-1600 IU per day) or a placebo. The researchers found that supplementation had no effect on muscle strength, muscle power, or on balance in this study population. Researchers conclude that in adults with vitamin D levels in the lower part of the normal range, added vitamin D had no effect on muscle performance. While vitamin D is not important for muscle strength, maintaining normal levels of vitamin D in the body is important for other reasons, including bone health.
2. VITAMIN K LAB: Vitamin D is present in human brain. Low blood levels of vitamin D have been associated with cognitive impairment in older adults. It has been assumed that blood levels of vitamin D reflects vitamin D action in the human brain. However, it is not known if vitamin D is present in the human brain, which challenges the validity of this assumption. ARS-funded researchers in Boston, Massachusetts, developed and validated a method to quantify vitamin D and its metabolites in the human brain. The method development stage was performed using pig brain and then was successfully applied to the simultaneous determination of the levels of three vitamin D forms in multiple sections of the human brain. This validated method establishes that three forms of vitamin D are present in the human brain. This method can be applied to post-mortem studies to obtain accurate information about the presence and role of vitamin D in human brain and neurodegenerative diseases, which affect older adults.
Ellis, J.L., Fu, X., Al Rajabi, A., Grusak, M.A., Shearer, M., Naumova, E., Saltzman, E., Barger, K., Booth, S.L. 2018. Plasma response to deuterium-labeled vitamin K intake varies by TG response, but not age or vitamin K status, in older and younger adults. Journal of Nutrition. 149(1):18-25. https://doi.org/10.1093/jn/nxy216.
Shea, K., Fielding, R.A., Dawson-Hughes, B. 2019. The effect of vitamin D supplementation on lower-extremity power and function in older adults: a randomized controlled trial. American Journal of Clinical Nutrition. 109(2):369-379. https://doi.org/10.1093/ajcn/nqy290.
Stemmle, J., Marzel, A., Chocano, P.O., Orav, E.J., Dawson-Hughes, B., Freystaetter, G., Egli, A., Theiler, R., Staehelin, H.B., Bischoff-Ferrari, H.A. 2018. Effect of 800 IU versus 2000 IU vitamin D3 with or without a simple home exercise program on functional recovery after hip fracture: a randomized controlled trial. Journal of the American Medical Directors Association - Post-Acute and Long Term Care Medicine. https://doi.org/10.1016/j.jamda.2018.10.013.
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Harshman, S., Shea, K., Fu, X., Grusak, M.A., Smith, D.E., Lamon-Fava, S., Kuliopulos, A., Greenberg, A., Booth, S.L. 2019. Atorvastatin decreases renal menaquinone-4 formation in C57BL/6 male mice. Journal of Nutrition. 149(3):416-421. https://doi.org/10.1093/jn/nxy290.
Zwakenberg, S.R., Remmelzwaal, S., Beulens, J.W., Booth, S.L., Burgess, S., Dashti, H.S., Imamura, F., Feskens, E.J., Van Der Schouw, Y.T., Sluijs, I. 2019. Circulating phylloquinone concentrations and risk of type 2 diabetes: a Mendelian randomization study. Diabetes. 68(1):220-225. https://doi.org/10.2337/db18-0543.
Xu, J., Bartz, T.M., Chittoor, G., Eiriksdottir, G., Manichaikul, A.W., Sun, F., Terzikhan, N., Zhou, X., Booth, S.L., Brusselle, G.G., de Boer, I.H., Fornage, M., Frazier-Wood, A.C., Graff, M., Gudnason, V., Harris, T.B., Hofman, A., Hou, R., Houston, D.K., Jacobs Jr, D.R., Kritchevsky, S.B., Latourelle, J., Lamaitre, R.N., Lutsey, P.L., O'Connor, G., Oelsner, E.C., Pankow, J.S., Psaty, B.M., Rohde, R.R., Rich, S.S., Rotter, J.I., Smith, L.J., Stricker, B.H., Voruganti, V., Wang, T.J., Zillikens, M., Barr, R., Dupuis, J., Gharib, S.A., Lahousse, L., London, S.J., North, K.E., Smith, A.V., Steffen, L.M., Hancock, D.B., Cassano, P.A. 2018. Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function. British Journal of Nutrition. 120(10):1159-1170. https://doi.org/10.1017/S0007114518002180.
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Holden, R.M., Booth, S., Day, A.G., Clase, C.M., Zimmerman, D., Moist, L., Shea, K., McCabe, K.M., Jamal, S.A., Tobe, S., Weinstein, J., Madhumathi, R., Adams, M.A., Heyland, D.K. 2015. Inhibiting the progression of arterial calcification with vitamin K in hemodialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease. Canadian Journal of Kidney Health and Disease. 2:17. https://doi.org/10.1186/s40697-015-0053-x.
Karl, J.P., Fu, X., Wang, X., Zhao, Y., Shen, J., Zhang, C., Wolfe, B.E., Saltzman, E., Zhao, L., Booth, S.L. 2015. Fecal menaquinone profiles of overweight adults are associated with gut microbiota composition during a gut microbiota-targeted dietary intervention. American Journal of Clinical Nutrition. 102:84-93. https://doi.org/10.3945/ajcn.115.109496.
Angellotti, E., D'Alessio, D., Dawson-Hughes, B., Nelson, J., Cohen, R., Gastaldelli, A., Pittas, A.G. 2018. Vitamin D supplementation in patients with type 2 diabetes: the vitamin D for established type 2 diabetes (DDM2) study. Journal of the Endocrine Society. 2(4):310-321. https://doi.org/10.1210/js.2018-00015.
Shea, K., Booth, S.L. 2019. Vitamin E: interactions with vitamin K and other bioactive compounds. In: Weber P, Birringer M, Blumberg JB, Eggersdorfer M., Frank J., editors. Vitamin E in Human Health. Humana Press, Switzerland. p. 261-269.
Shea, M., Kritchevsky, S.B., Loeser, R.F., Booth, S.L. 2019. Vitamin K status and mobility limitation and disability in older adults: the health, aging, and body composition study. Journal of Gerontology Medical Science. https://doi.org/10.1093/gerona/glz108.
Bischoff-Ferrari, H., Dawson-Hughes, B., Willett, W.C. 2018. Issues of trial selection and subgroup considerations in the recent meta-analysis of Zhao and colleagues on fracture reduction by calcium and vitamin D supplementation in community-dwelling older adults. Osteoporosis International. https://doi.org/10.1007/s00198-018-4587-5.
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Fu, X., Dolnikowski, G.G., Patterson, W.B., Dawson-Hughes, B., Zheng, T., Morris, M.C., Holland, T.M., Booth, S.L. 2019. Determination of vitamin D and its metabolites in human brain using an ultra pressure LC-tandem mass spectra method. Current Developments in Nutrition. 3(7):nzz074. https://doi.org/10.1093/cdn/nzz074.
Shea, M., Booth, S.L. 2019. Vitamin K, vascular calcification, and chronic kidney disease: current evidence and unanswered questions. Current Developments in Nutrition. https://doi.org/10.1093/cdn/nzz077.
Guss, J.D., Taylor, E., Rouse, Z., Roubert, S., Higgins, C.H., Thomas, C.J., Baker, S.P., Van Der Meulen, M.C., Vashishth, D., Donnelly, E., Shea, K., Booth, S.L., Bicalho, R.C., Hernandez, C.J. 2019. The microbial metagenome and bone tissue composition in mice with microbiome-induced reductions in bone strength. Bone. 127:146-154. https://doi.org/10.1016/j.bone.2019.06.010.