Objective 1: Characterize dietary factors, such as variation in nutrient composition and nutrient-nutrient interactions, and non-dietary factors, such as age, genetics and hormone status, that contribute to the inter-individual variation in vitamin K and vitamin D metabolism. Sub-objective 1.A: Impact of processing on the vitamin K content of foods. Sub-objective 1.B: Relative absorption of menaquinone forms compared to phylloquinone. Objective 2: Determine role of nutrients including vitamin K and vitamin D on bone, muscle, and joint metabolism and function in older adults. Sub-objective 2.A: Effect of dried fruit intake on musculoskeletal health, weight, and body composition in community dwelling older adults – a feasibility study. Sub-objective 2.B: Effect of the disruption of the microbiome and associated vitamin K forms on bone tissue in rodents. Sub-objective 2.C: Association between circulating vitamin K, with or without vitamin D, and incident mobility limitation and disability in older adults. Objective 3: Determine the role(s) and underlying mechanisms of vitamin K and vitamin D, alone and in combination, and the acid-base balance of the diet in age-related diseases, such as cardiometabolic and neurological diseases. Sub-objective 3.A: Association between vitamin D and K metabolites in the brain and cognitive impairment and neuropathology in older persons. Sub-objective 3.B: Associations of biomarkers of vitamin K status with clinical atherosclerotic cardiovascular disease and coronary artery calcification in adults with chronic renal disease. Objective 4: Assess oxylipins as a driver of cellular senescence and age-related pathologies. Objective 5: Develop HIV therapy-induced premature aging as a new model for nutritional intervention in aging and degenerative disease.
Our focus is to develop further understanding of the mechanisms by which fruits, vegetables, and vitamins K and D affect bone, muscle, and joint health and identify the benefits of increased dietary intake. We will utilize mouse models to study the metabolism of multiple vitamin K forms present in the diet and/or formed by gut bacteria and their impact on bone quantity and quality. Concurrently, we will use a variety of study designs, including clinical trials and observational studies, to examine the impact of dried fruit and leafy vegetables, and vitamins K and D, on bone, muscle and body composition in older adults. Cognitive decline and cardiovascular disease often co-exist with musculoskeletal disease, so we will conduct observational studies to characterize the contribution of low vitamin K and D levels to these conditions in older adults. Evidence gained from this project will provide scientific justification for more accurate dietary guidance for maintenance of musculoskeletal health and related health outcomes.
a) The main results of the DO-HEALTH trial were recently published in The Journal of the American Medical Association (JAMA). The main findings were that supplementation with vitamin D (2000 IU per day), marine omega-3s (1 g per day), and a home-based exercise program, either alone or in combination, had no significant effect on muscle performance or incident fractures in healthy older adults age 70 and older. Analysis of secondary outcomes is in progress. b) We led an analysis of data from the D2d vitamin D intervention trial to determine whether the serum 25-hydroxyvitamin D level achieved on supplementation with 4000 IU of vitamin D3 per day influenced the progression from prediabetes to type 2 diabetes in 2,423 adults treated for a median of 2.5 years. We found that participants achieving 25-hydroxyvitamin D levels of 100-124 nmol/L and =125 nmol/L had progressively greater reductions in incident diabetes compared with those achieving 50-74 nmol/L, the range considered to be sufficient by the National Academy of Medicine. This analysis was published recently in Diabetes Care. c) We performed a cross-calibration and precision study to transition studies from an old to a new DXA scanner. The cross-calibration equations will be used when, for a given study, some participants are measured on the old, and others are measured on the new DXA scanner. The cross-calibration equations were recently published in the Journal of Clinical Densitometry. d) We investigated the association of vitamin K status with atherosclerotic cardiovascular disease and all-cause mortality in 3066 older adults with chronic kidney disease. Vitamin K status was estimated using two blood measures: phylloquinone concentrations and uncarboxylated matrix gla protein (ucMGP) concentrations. Phylloquinone is the primary form of vitamin K in the blood. UcMGP is a measure of vitamin K function, and concentrations increase when vitamin K status is low. We found that those with low circulating phylloquinone or high ucMGP had a 20-28% higher risk for death from all causes than those with high circulating phylloquinone or low ucMGP. However, the risk of atherosclerotic cardiovascular disease did not differ according to vitamin K status. e) We fed mice either a vitamin K deficient diet or a vitamin K sufficient diet containing different forms of vitamin K. The vitamin K deficient diet significantly altered the gut microbiome compared to vitamin K sufficient diets in female mice. This was similar in male mice, but the effect was not as strong. To determine if the gut bacteria can use dietary vitamin K to make their menaquinones, we fed mice stable-isotope labeled forms of vitamin K. In mice, gut bacteria formed menaquinones that contained the menadione from the dietary form given, but with a substituted side chain. When we supplemented human gut microbes in culture with stable isotope-labeled vitamin K forms, human gut microbes could only transform menadione to menaquinones. These results suggest that vitamin K deficiency alters the gut microbiome. More research is needed to determine if menadione formed in intestinal tissue is an important intermediate in remodeling dietary vitamin K to bacterial menaquinones.
1. All dietary forms of vitamin K transform to the same metabolite. There is considerable debate about the superiority of fermented food-based forms of vitamin K compared to the plant-based vitamin K form in terms of their function, yet little is known about their relative absorption and metabolism. ARS-funded researchers in Boston, Massachusetts, conducted two studies in which similar amounts of plant-based and the fermented-food-based vitamin K forms were fed to mice. Regardless of the dietary form provided, most tissues contained the same amount of a single vitamin K metabolite. These data challenge claims of the biological superiority of fermented food-based vitamin K forms and support the revision of current dietary vitamin K recommendations to combine plant-based and fermented food-based forms of vitamin K.
Shea, K., Berkner, K., Ferland, G., Fu, X., Holden, R., Booth, S.L. 2021. Evidence before enthusiasm: A critical review of the potential cardiovascular benefits of vitamin K. Advances in Nutrition. https://doi.org/10.1093/advances/nmab004.
Kratz, M., Zelnick, L.R., Trenchevska, O., Jeffs, J.W., Borges, C.R., Tseng, H., Booth, S.L., Kestenbaum, B.R., Utzschneider, K.M., De Boer, I.H. 2020. Relationship between chronic kidney disease, glucose homeostasis, and plasma osteocalcin carboxylation and fragmentation. Journal of Renal Nutrition. 31(3):248-256. https://doi.org/10.1053/j.jrn.2020.05.013.
Fu, X., Shea, K., Dolnikowski, G.G., Patterson, W.B., Dawson-Hughes, B., Holland, T.M., Schneider, J.A., Booth, S.L. 2020. Vitamin D and Vitamin K concentrations in human brain tissue are influenced by freezer storage time: the memory and aging project. Journal of Nutrition. https://doi.org/10.1093/jn/nxaa336.
Reitshamer, E., Viera, K.B., Shea, K., Dawson-Hughes, B. 2021. Cross-calibration of prodigy and horizon a densitometers and precision of the horizon a densitometer. Journal of Clinical Densitometry. https://doi.org/10.1016/j.jocd.2021.02.003.
Ellis, J.L., Karl, J., Oliverio, A.M., Fu, X., Soares, J.W., Wolfe, B.E., Hernandez, C.J., Mason, J.L., Booth, S.L. 2021. Dietary vitamin K is remodeled by gut microbiota and influences community composition. Gut Microbes. 13(1):1-16. https://doi.org/10.1080/19490976.2021.1887721.
Dawson-Hughes, B., Staten, M.A., Knowler, W.C., Nelson, J., Vickery, E.M., LeBlanc, E.S., Neff, L.M., Park, J., Pittas, A.G. 2020. Intratrial exposure to vitamin D and new-onset diabetes among adults with prediabetes: a secondary analysis from the vitamin D and type 2 diabetes (D2d) study. Diabetes Care. https://doi.org/10.2337/dc20-1765.
Bischoff-Ferrara, H.A., De Godoi Rezende Costa Caroline, Rival, S., Vellas, B., Rizzoli, R., Kressig, R.W., Kanis, J.A., Manson, J.E., Dawson-Hughes, B., Orav, E.J., Da Silva, J.A., Blauth, M., Felsenberg, D., Ferrari, S.M., Theiler, R., Egli, A. 2020. DO-HEALTH: vitamin D3 - omega3 - home exercise - healthy aging and longevity trial - design of a multinational clinical trial on healthy aging among european seniors. Contemporary Clinical Trials. 100(2021):106124. https://doi.org/10.1016/j.cct.2020.106124.
Bischoff-Ferrari, H.A., Vellas, B., Rizzoli, R., Kressig, R.W., da Silva, J., Blauth, M., Felson, D.T., McCloskey, E., Watzl, B., Hofbauer, L., Felsenberg, D., Willett, W.C., Dawson-Hughes, B., Manson, J.E., Siebert, U., Theiler, R., Stahelin, H.B., de Godoi Rezende Costa, C., Chocano-Bedoya, P.O., Abderhalden, L.A., Egli, A., Kanis, J.A., Orav, J. 2020. Effect of vitamin D supplementation, omega-3 fatty acid supplementation, or a strength-training exercise program on clinical outcomes in older adults: the DO-HEALTH randomized clinical trial. Journal of the American Medical Association. 324(18):1855-1868. https://doi.org/10.1001/jama.2020.16909.