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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #436095

Research Project: Nutrient Metabolism and Musculoskeletal Health in Older Adults

Location: Jean Mayer Human Nutrition Research Center On Aging

2023 Annual Report

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.

Progress Report
a) Based on evidence that natural metabolites produced by the intestinal microbiome, such as menaquinones, may influence joint health, we evaluated the association of intestinally produced menaquinones with obesity-related osteoarthritis (OA) in 52 obese adults with hand and knee OA and 42 age- and sex-matched obese adults without OA who participated in the Johnston County Osteoarthritis Study. Menaquinones were variable and abundant in the human gut, but the fecal menaquinone clusters did not differ between those with and without OA. We found the relative abundance of specific bacterial taxa differed among fecal menaquinone clusters, but the relevance of these differences with respect to vitamin K status and human health is uncertain. b) We determined no association of vitamin K status with coronary artery calcification (CAC) and arterial stiffness in adults with mild to moderate chronic kidney disease (CKD) – a group more likely to develop arterial calcification and stiffness. Vitamin K status was estimated using two blood measures: phylloquinone concentrations and (dp)ucMGP concentrations. Phylloquinone is the primary form of vitamin K in blood. (Dp)ucMGP is a measure of vitamin K function, and concentrations increase when vitamin K status is low. However, we did not find any consistent associations between vitamin K status biomarker with CAC and arterial stiffness in adults with mild-to-moderate CKD. c) Several previous studies reported low circulating 25(OH)D was associated with more cognitive decline and dementia. However, little is known about vitamin D in the human brain and the association with dementia or neuropathology. We measured vitamin D concentrations in four brain regions of 290 decedents of the Rush Memory and Aging Project and determined the associations with cognitive and neuropathological outcomes. The main form of vitamin D in all brain regions measured was 25(OH)D3. Higher brain 25(OH)D3 concentrations were associated with a 25% to 33% lower odds of dementia or mild cognitive impairment just before death. However, brain 25(OH)D concentrations were not associated with any post-mortem neuropathology outcome studied. Additional research is needed to clarify the specific mechanisms underlying this potentially protective relationship. d) We completed the randomized, controlled clinical trial to determine the effect of 100 g/d of dried fruit vs no dried fruit on net acid excretion (NAE), the bone resorption marker N-telopeptide, and on muscle performance. There was no significant effect of dried fruit on any outcome. This null finding may be attributable to the high day-to-day variability in consumption of foods affecting NAE in the group as a whole. However, change in NAE was positively associated with change in N-terminal telopeptide of type-I collagen (NTX), suggesting that neutralizing the dietary acid load may have a favorable effect on bone health. e) We are collaborating with colleagues in Zurich, Switzerland, on a clinical trial designed to determine the effect of vitamin D (2000 IU of vitamin D3 per day) and marine omega-3s (1 g per day), and a home-based exercise program on bone and muscle health over three years in 2152 older adults. The main findings have been published and secondary analyses are underway. In one secondary analysis, the number of prevalent chronic diseases at baseline was positively associated with the rates of incident falls and injurious falls. f) We led an analysis of data from the Boston Site Testing Osteoporosis Prevention/Intervention Treatment (STOP IT) study to determine whether the serum 25-hydroxyvitamin D level achieved during the trial was related to muscle strength. We found no association of the 25-hydroxyvitamin D level with muscle strength. This suggests that the favorable effect of vitamin D in lowering risk of falling may be attributable to a favorable effect of vitamin D on balance and/or other factors. g) We have undertaken two clinical trials. In one, the team is testing the effect of the ghrelin receptor agonist, anamorelin, versus placebo on muscle mass, bone turnover markers, and muscle strength and performance in older adults. All measurements in the trial have been completed and data are currently being analyzed. The second trial will determine the effect of supplemental protein with and without the alkaline compound, potassium bicarbonate, on muscle mass and function in older adults with low usual protein intakes. This trial is now fully enrolled, and participants are being followed for 6 months each. h) In collaboration with the University of Massachusetts in Lowell, we are carrying out an observational study that involved the recall of up to 500 older Puerto Rican men and women for follow up bone mineral density and first-time bone material strength measurements. These participants had bone mineral density measured 8 years ago at the Jean Mayer Human Nutrition Research Center (HNRCA). The objective is to determine whether participants with type two diabetes have altered bone material strength and whether bone mineral density declines more or less in participants with diabetes than in those without diabetes. The study visits are nearly completed. Biochemical measurements, data review, and quality control measures have begun. i) In collaboration with a colleague at Tufts Medical Center, we completed a meta-analysis of three clinical trials testing the effect of supplemental vitamin D on risk of developing type 2 diabetes in adults with prediabetes. Supplementation significantly lowered risk of developing diabetes by 15% over a 3-year period. Further research is required to identify the level of 25-hydroxyvitamin D that will cause the greatest reduction in risk of developing type 2 diabetes.

1. Inadequate intakes of vitamin K are common among the elderly, and there is growing evidence that vitamin K has a biological role in the risk of dementia. ARS-funded researchers in Boston, Massachusetts, demonstrated in the Rush Memory and Aging Project that higher postmortem brain levels of a vitamin K metabolite were associated with better cognitive function prior to death. They also found higher brain vitamin K concentrations were associated with lower odds of dementia or mild cognitive impairment. These findings provide new and compelling evidence implicating vitamin K in neuropathology underlying cognitive decline and dementia.

Review Publications
Shea, K., Barger, K., Dawson-Hughes, B., Leurgans, S.E., Fu, X., James, B.D., Holland, T.M., Agarwal, P., Wang, J., Matuszek, G.H., Heger, N., Schneider, J.A., Booth, S.L. 2022. Brain vitamin D forms, cognitive decline and neuropathology in community-dwelling older adults. Alzheimer's & Dementia.
Pittas, A.G., Kawahara, T., Jorde, R., Dawson-Hughes, B., Vickery, E.M., Angellotti, E., Nelson, J., Trikalinos, T.A., Balk, E.M. 2023. Vitamin D and risk for type 2 diabetes in people with prediabetes: a systematic review and meta-analysis of individual participant data from 3 randomized clinical trials. Annals of Internal Medicine.
Shea, K., Wang, J., Barger, K., Weiner, D.E., Townsend, R., Feldman, H.I., Rosas, S., Chen, J., He, J., Flack, J., Jaar, B., Kansal, M., Booth, S.L. 2022. Association of Vitamin K status with arterial calcification and stiffness in chronic kidney disease: The chronic renal insufficiency cohort. Current Developments in Nutrition.
Kanis, J.A., McCloskey, E.V., Harvey, N.C., Cooper, C., Rizzoli, R., Dawson-Hughes, B., Maggi, S., Reginster, J. 2022. The need to distinguish intervention thresholds and diagnostic thresholds in the management of osteoporosis. Osteoporosis International.
Huberty, S., Freystatter, G., Wieczorek, M., Dawson-Hughes, B., Kanis, J.A., Rizzoli, R., Kressig, R., Vellas, B., Da Silva, J., Armbrecht, G., Theiler, R., Egli, A.L., Orav, E., Bischoff-Ferrari, H.A. 2023. Association between multimorbidity and rate of falls: a 3-year 5-country prospective study in generally healthy and active community-dwelling adults aged 70+. Journal of the American Medical Directors Association - Post-Acute and Long Term Care Medicine.
Ceglia, L., Rivas, D.A., Schloegl, M., Fielding, G.B., Egli, A.L., Bischoff-Ferrari, H.A., Dawson-Hughes, B. 2022. Effect of vitamin D3 vs. calcifediol on VDR concentration and fiber size in skeletal muscle. Journal of Bone and Mineral Metabolism.
Faggioli, F., Velarde, M., Wiley, C. 2022. Cellular senescence, a novel area of investigation for metastatic diseases. Preprints.
Kuehnemann, C., Wiley, C. 2023. Cholesterol drives inflammatory senescence. Nature Metabolism.
Liu, M., Matuszek, G.H., Azacarate-Peril, A., Loeser, R., Shea, K. 2023. An exploratory case-control study on associations of bacterially derived vitamin K forms with the intestinal microbiome and obesity-related osteoarthritis. Current Developments in Nutrition.
Holden, R.M., Booth, S.L., Zimmerman, D., Moist, L., Norman, P., Day, A.G., Menard, A., Fu, X., Shea, K., Babiolakis, C.S., Nolan, R., Turner, M.E., Ward, E., Kaufmann, M., Adams, M.A., Heyland, D.K. 2022. Inhibit progression of coronary artery calcification with vitamin K in hemodialysis patients (The iPACK-HD Study): A randomized, placebo-controlled multi-centre, pilot trial. Nephrology Dialysis Transplantation.
Shea, K., Wang, J., Barger, K., Weiner, D.R., Booth, S.L., Seliger, S., Anderson, A.H., Deo, R., Feldman, H.I., Go, A., He, J., Ricardo, A.C., Tamura, M.K. 2022. Vitamin K status and cognitive function in adults with chronic kidney disease: The Chronic Renal Insufficiency Cohort. Current Developments in Nutrition.
Bischoff-Ferrari, H.A., Willett, W.C., Manson, J.E., Dawson-Hughes, B., Manz, M.G., Theiler, R., Brandle, K., Vellas, B., Rizzoli, R., Kressig, R.W., Staehelin, H.B., Da Silva, J.A., Ambrecht, G., Egli, A., Kanis, J., Orav, E.J., Gangler, S. 2022. Combined vitamin D, omega-3 fatty acids, and a simple home exercise program may reduce cancer risk among active adults aged 70 and older: a randomized clinical trial. British Medical Journal. 3:852643.
Kuehnemann, C., Hu, K., Butera, K., Patel, S.K., Bons, J., Schilling, B., Aguayo-Mazzucato, C., Wiley, C. 2022. Extracellular nicotinamide phosphoribosyltransferase is a component of the senescence-associated secretory phenotype. Frontiers in Endocrinology. 13:Article 935106.
Panda, A., Booth, S.L. 2022. Nutritional aspects of healthy aging. Medical Clinics of North America. 106(5): 853-864.
Pittas, A.G., Jorde, R., Kawahara, T., Dawson-Hughes, B. 2020. Vitamin D supplementation for prevention of type 2 diabetes mellitus. To D or not to D? Journal of Clinical Endocrinology and Metabolism. 105(12):3721-3733.
Shea, K., Ardisson Korat, A., Jacques, P., Sebastiani, P., Cohen, R., Lavertu, A., Booth, S.L. 2022. Leveraging observational cohorts to study diet and nutrition in older adults: Opportunities and obstacles. Advances in Nutrition.
Ceglia, L., Shea, K., Rasmussen, H., Gilhooly, C., Dawson-Hughes, B. 2022. A randomized study on the effect of dried fruit on acid-base balance, diet quality, and markers of musculoskeletal health in community dwelling adults. Journal of the American Nutrition Association.
Dawson-Hughes, B., Wang, J., Barger, K., Ceglia, L. 2022. Effects of vitamin D with calcium and associations of mean 25-hydroxyvitamin D levels with 3-year change in muscle performance in healthy older adults in the Boston STOP IT trial. Calcified Tissues International.
Bischoff-Ferrari, H.A., Freystatter, G., Vellas, B., Dawson-Hughes, B., Kressig, R.W., Kanis, J.A., Willett, W.C., Manson, J.E., Rizzoli, R., Theiler, R., Hofbauer, L., Ambrecht, G., Da Silva, J., Blauth, M., De Godoi Rezende, C., Lang, W., Siebert, U., Egli, A., Orav, E., Wieczorek, M. 2022. Effects of vitamin D, omega-3 fatty acids and a simple home strength exercise program on fall prevention: the DO-HEALTH randomized clinical trial. Lancet.
Holland, T.M., Agarwal, P., Wang, Y., Dhana, K., Leurgans, S.E., Shea, K., Booth, S.L., Rajan, K.B., Schneider, J.A., Barnes, L.L. 2023. Dietary intake of flavonols associated with global cognitive decline and multiple cognitive abilities. Neurology.
Giustina, A., Bouillon, R., Dawson-Hughes, B., Ebeling, P.R., Lazaretti-Castro, M., Lips, P., Marcocci, C., Bilezikian, J.P. 2022. Vitamin D in the older population: A consensus statement. Endocrine.
Ruditser, R., Fu, X., Booth, S.L., Liu, M., Shen, X., Shea, K. 2023. Lack of consensus between measurements of plasma phylloquinone by enzyme-linked immunoassays and a well-validated high performance liquid chromatographic method. Current Developments in Nutrition.
Bigman, G., Shea, K., Rusu, M., Ryan, A.S. 2023. Intake of dark green vegetables may benefit specific cognitive domains in US men and women aged 60 years or older. Journal of Nutrition Health and Aging.
Ceglia, L., Pittas, A.G., Dawson-Hughes, B. 2023. Effect of vitamin D supplementation on circulating fibroblast growth factor-23 concentration in adults with prediabetes. Aging Clinical Experimental Research.
Shea, M.K., Booth, S.L., 2023. Vitamin K. In: Caballero, B., editor. Encyclopedia of Human Nutrition, Vol. 1. Cambridge, MA: Elsevier, Academic Press. p. 569–576.
Vandenput, L., Johansson, H., McCloskey, E.V., Liu, E., Akesson, K.E., Anderson, F.A., Azagra, R., Bager, C.L., Beaudart, C., Bischoff-Ferrari, H.A., Biver, E., Bruyere, O., Cauley, J.A., Center, J.R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C.J., Cummings, S.R., Da Silva, J., Dawson-Hughes, B., Diez-Perez, A., Dufour, A.B., Eisman, J.A., Elders, P.J., Ferrari, S., Fujita, Y., Fujiwara, S., Gluer, C.C., Goldstein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R.J., Huisman, M., Iki, M., Ish-Shalom, S., Jones, G., Karlsson, M.K., Khosla, S., Kiel, D.P., Koh, W.P., Koromani, F., Kotowicz, M.A., Kroger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., Mellstrom, D., Merlijn, T., Nordstrom, A., Nordstrom, P., O'Neill, T.W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E.S., Pasco, J.A., Rivadeneira, F., Schei, B., Schott, A.M., Shiroma, E.J., Siggeirsdottir, K., Simonsick, E.M., Sornay-Rendu, E., Sund, R., Swart, K.M., Szulc, P., Tamaki, J., Torgenson, D.J., Van Schoor, N.M., Van Staa, T.P., Vila, J., Wareham, N.J., Wright, N.C., Yoshimura, N., Zillikens, M.C., Zwart, M., Harvey, N.C., Lorentzon, M., Leslie, W.D., Kanis, J.A. 2022. Update of the fracture risk prediction tool FRAX: a systematic review of potential cohorts and analysis plan. Osteoporosis International. 33:3103-2136.
Hsia, D.S., Nelson, J., Vickery, E.M., Rasouli, N., Leblanc, E.S., Kim, S., Brodsky, I., Pratley, R., Dawson-Hughes, B., Pittas, A.G. 2023. Effect of vitamin D on regression to normal glucose regulation and individual glycemic measures: A secondary analysis among participants adherent to the trial protocol in the randomized clinical trial vitamin D and type 2 diabetes (D2d) study. Diabetes Research and Clinical Practice.
Kuehnemann, C., Hughes, J.B., Desprez, P., Melov, S., Wiley, C., Campisi, J. 2022. Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal. Aging Cell.
Beaudart, C., Reginster, J., Smith, J., Bautmans, I., Bauer, J., Burlet, N., Cesare, M., Cherubini, A., Cooper, C., Cruz-Jentoft, A.J., Dawson-Hughes, B., Fielding, R.A., Harvey, N.C., Landi, F., Laslop, A., Maggi, S., Montero-Errasquin, B., Prieto Yerro, M., Rolland, Y., Rizzzoli, R., Visser, M. 2023. Measuring health-related quality of life in sarcopenia: summary of the SarQoL psychometric properties. Aging Clinical Experimental Research.