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.
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.
Objective 1.B. There are multiple forms of vitamin K, including at least ten (10) menaquinones (MKn), present in the food system, with large dietary contributors being animal sources and fermented foods. MKn are bacterially-produced compounds, with the exception of MK4, which is converted from phylloquinone, the plant-based form of vitamin K, in mammalian tissues. Due to our limited understanding of MKn metabolism, and the relationship, if any, of dietary MKn to gut bacterial-produced MKn in terms of physiological function, purported benefits of high MKn intakes, which are abundant in the popular press, are speculative. To address this gap, in the last year we compared the absorption of equimolar amounts of phylloquinone, MK4, and MK9, alone and in combination, in C57BL/6 male and female mice, as measured by phylloquinone and MKn contents in tissues, feces and blood following intake of purified vitamin K forms for 4 weeks. To definitively identify the dietary source of the vitamin K forms present in tissue and feces, we then conducted a second 7-day study in which C57BL/6 mice were given equimolar doses of deuterium or C13-labeled phylloquinone, MK4, MK7 and MK9. Both studies are now completed and laboratory analysis is ongoing. Objective 2.A. 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. Research in this laboratory has confirmed that correcting acid-producing diets with potassium bicarbonate has favorable effects on bone and muscle, at least over the short term. This research provides a scientific rationale to determine whether achieving acid-base balance with diet modification rather than alkali pills will be effective over the long term. In the last year, we have exceeded the targeted enrollment of subjects into a clinical trial designed to determine whether consuming 100 g per day of dried fruit, when compared with no fruit, over a 1-year period will alter 24-hr urinary net acid excretion (NAE), a biomarker of acid base balance, and reduce the bone resorption biomarker, N-telopeptide, an indicator of bone loss in older adults with low usual fruit intake. Dietary protein is important for muscle health, but the benefit may be reduced by the fact that protein is acid-producing. A question related to Objective 2A is whether the impact of protein on muscle may be enhanced by concurrent use of the alkaline salt of potassium. In the last year, Drs. Ceglia and Dawson-Hughes acquired funding from the NIH to conduct a randomized controlled clinical trial to determine the impact of supplemental protein, with and without added alkali (potassium bicarbonate), on muscle function in older adults with low usual protein intake. Enrollment has begun. Ghrelin, the hunger hormone, stimulates appetite. It also stimulates the secretion of growth hormone which is anabolic to bone and muscle. In the last year, Drs. Dawson-Hughes and Ceglia attained funding from the NIH to conduct a clinical trial to assess the effect of the ghrelin receptor agonist, anamorelin, on short-term indicators of bone and muscle health in older adults with low bone mass and low muscle mass. Five subjects have been enrolled in this one-year study. This study is complementary to Objective 2. In the last year, we acquired a new dual-energy X-ray absorptiometry (DXA) scanner for measurement of bone mineral density and body composition. Forty-two subjects have completed measurements in a study designed to determine the precision of the new scanner and to cross-calibrate the old and new scanners. The cross-calibration will enable the researchers to transition current studies from the old to the new scanner, while maintaining integrity of the measurements. Objective 2.C. In addition to a role in bone health, we and others have reported that low vitamin K status was associated with more osteoarthritis (OA) and worse lower-extremity performance in older adults. Furthermore, our observational data indicate that both vitamin K and vitamin D are mutually important to lower-extremity function. Vitamin D alone does not reduce knee pain and functional impairment in OA. We posit that the null findings of vitamin D supplementation trials in OA may be due to lack of consideration for vitamin K, intakes of which are low in older adults. Vitamin D upregulates expression of multiple vitamin K-dependent proteins through its interaction with the vitamin D receptor. Matrix Gla Protein (MGP) is a vitamin K-dependent protein that functions as a calcification inhibitor in cartilage, vascular and other soft tissues. MGP is upregulated by vitamin D and is synthesized as uncarboxylated MGP (ucMGP). If there is not sufficient vitamin K intake to carboxylate the MGP, MGP remains non-functional and unable to inhibit soft-tissue calcification. We have initiated analysis of existing data from the Health, Aging, and Body Composition Study to determine the association of vitamin K status, with and without controlling for vitamin D status, with incident mobility limitation in community-dwelling older adults. This will determine if vitamin K and vitamin D are interdependent with respect to mobility limitation and disability. Objective 3.A. There is growing evidence that both vitamin D and vitamin K have biological roles in Alzheimer’s Disease (AD) etiology, based primarily on in vitro experiments and animal models. Translating the findings to humans is challenging because study designs required to directly link nutrient intake and brain function in humans are implausible. Instead, one needs to identify and validate suitable biomarkers of vitamins D and K to link to brain health and AD pathology. Low circulating 25(OH)D levels are associated with cognitive impairment and AD in observational studies. However, it is not known what vitamin D forms are present in the human brain or how these individual forms are linked to AD risk or circulating 25(OH)D. Similarly, low phylloquinone intakes are associated with poor memory. However, MK4 is the form in the mammalian brain, and it is not known if brain MK4 levels are linked to phylloquinone intake. In collaboration with Rush Medical Center, we obtained brain tissue samples from 500 deceased Memory and Aging Project (MAP) participants and analyzed them for concentrations of vitamin D, 25(OH)D, 1,25(OH)2D, phylloquinone and MK4. Based on our analyses, vitamin D and vitamin K appear to be stable in frozen human brain tissue stored for up to 6 and 9 years, respectively, after which their concentrations markedly decline. Now these laboratory analyses are completed, we will evaluate the association of vitamin D and vitamin K in four brain regions with AD neuropathology and cognitive impairment. We are also measuring the serum 25(OH)D and phylloquinone and MK4 concentrations in these same participants from samples obtained prior to death. We will also determine the associations of serum phylloquinone and 25(OH)D prior to death to determine if these measures are suitable biomarkers of these vitamins in the brain. These analyses will provide critical information regarding the contribution of non-dietary factors to the inter-individual variation in vitamin D brain levels, consistent with Objective 1.
Kanis, J.A., Harvey, N.C., Mccloskey, E., Bruyere, O., Veronese, N., Lorentzon, M., Cooper, C., Rizzoli, R., Adib, G., Al-Daghri, N., Campusano, C., Chandran, M., Dawson-Hughes, B., Javaid, K., Jiwa, F., Johansson, H., Lee, J.K., Liu, E., Messina, O.D., Mkinsi, O., Pinto, D., Prieto-Alhambra, D., Saag, K., Xia, W., Zakraoui, L., Reginster, J. 2019. Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporosis International. https://doi.org/10.1007/s00198-019-05176-3.
Noel, S.E., Arevalo, S.P., Mena, N.Z., Mangano, K., Velez, M., Dawson-Hughes, B., Tucker, K.L. 2019. Knowledge, attitudes, beliefs, and health behaviors of bone health among Caribbean Hispanic/Latino adults. Archives of Osteoporosis. 14:14. https://doi.org/10.1007/s11657-019-0566-5.
Kelly, J.M., Ordovas, J.M., Matuszek, G.H., Smith, C.E., Huggins, G.S., Dashti, H.S., Ichikawa, R., Booth, S.L. 2019. The contribution of lipids to the inter-individual response of vitamin K biomarkers to vitamin K supplementation. Molecular Nutrition and Food Research. https://doi.org/10.1002/mnfr.201900399.
Gugger, A., Marzel, A., Orav, E.J., Willett, W.C., Dawson-Hughes, B., Theiler, R., Freystatter, G., Egli, A., Bischoff-Ferrari, H.A. 2019. Effect of monthly high-dose vitamin D on mental health in older adults: Secondary analysis of a RCT. Journal of the American Geriatrics Society. 67(6):1211-1217. https://doi.org/10.1111/jgs.15808.
Schlogl, M., Chocano-Bedoya, P., Dawson-Hughes, B., Orav, E.J., Freystaetter, G., Theiler, R., Kressig, R.W., Egli, A., Bischoff-Ferrari, H. 2019. Effect of monthly vitamin D on chronic pain among community-dwelling seniors: a randomized, double-blind controlled trial. Journal of the American Medical Directors Association - Post-Acute and Long Term Care Medicine. 20(3):356-361. https://doi.org/10.1016/j.jamda.2018.09.004.
Renerts, K., Fischer, K., Dawson-Hughes, B., Orav, E.J., Freystaetter, G., Simmen, H., Pape, H., Egli, A., Theiler, R., Bischoff-Ferrari, H. 2019. Effects of a simple home exercise program and vitamin D supplementation on health-related quality of life after a hip fracture: a randomized controlled trial. Quality of Life Research. 28(5):1377-1386. https://doi.org/10.1007/s11136-019-02100-4.
Quinn, L., Sheh, A., Ellis, J.L., Smith, D., Booth, S.L., Fu, X., Muthupalani, S., Ge, Z., Puglisi, D.A., Wang, T.C., Gonda, T.A., Holcombe, H., Fox, J.G. 2020. Helicobacter pylori antibiotic eradication coupled with a chemically defined diet in INS-GAS mice triggers dysbiosis and vitamin K deficiency resulting in gastric hemorrhage. Gut Microbes. https://doi.org/10.1080/19490976.2019.1710092.
Dawson-Hughes, B., Bouxsein, M., Shea, K. 2019. Bone material strength in normoglycemic and hyperglycemic black and white older adults. Osteoporosis International. 30:2429-2435. https://doi.org/10.1007/s00198-019-05140-1.
McCann, A., Jeffery, I.B., Ouliass, B., Ferland, G., Fu, X., Booth, S.L., Tran, T.T., O'Toole, P.W., O'Connor, E.M. 2019. Exploratory analysis of covariation of microbiota-derived vitamin K and cognition in older adults. American Journal of Clinical Nutrition. 110(6):1404-1415. https://doi.org/10.1093/ajcn/nqz220.
Abderhalden, L.A., Meyer, S., Dawson-Hughes, B., Orav, E.J., Meyer, U., De Godoi Rezenda, C.C., Theiler, R., Stahelin, H.B., Ruschitzka, F., Egli, A., Forman, J.P., Willett, W.C., Bischoff-Ferrari, H.A. 2020. Effect of daily 2000 IU versus 800 IU vitamin D on blood pressure among adults age 60 years and older: a randomized clinical trial. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqaa145.
Kelly, J.M., Matuszek, G., Van Den Broek, T.J., Huggins, G.S., Smith, C.E., Ordovas, J.M., Wopereis, S., Booth, S.L. 2020. Associations between circulating lipids and fat-soluble vitamins and carotenoids in healthy overweight and obese men. Current Developments in Nutrition. 4(6). https://doi.org/10.1093/cdn/nzaa089.
Shea, M., Barger, K., Booth, S.L., Matuszek, G., Cushman, M., Benjamin, E.J., Kritchevsky, S.B., Weiner, D.E. 2020. Vitamin K status, cardiovascular disease and all-cause mortality: a participant-level meta-analysis of 3 US cohorts. American Journal of Clinical Nutrition. 111(6):1170-1177. https://doi.org/10.1093/ajcn/nqaa082.
Sabrina, N.E., Mangano, K.M., Mattei, J., Griffith, J.L., Dawson-Hughes, B., Bigornia, S., Tucker, K.L. 2020. DASH, mediterranean and alternative healthy eating indices are associated with bone health among Puerto Rican adults from the Boston Puerto Rican osteoporosis study. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqaa090.
Holland, T.M., Agarwal, P., Wang, Y., Leurgans, S.E., Bennett, D.E., Booth, S.L., Morris, M. 2020. Dietary flavonols and risk of Alzheimer's dementia. Neurology. 94(16):e1749-1756. https://doi.org/10.1212/WNL.0000000000008981.