Research Project: Nutrient Metabolism and Musculoskeletal Health in Older Adults

Location: Jean Mayer Human Nutrition Research Center On Aging

2022 Annual Report

Objectives
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.

Approach
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) To investigate the origins of distinct fecal vitamin K profiles consistently observed in adults, fecal and breastmilk samples were measured for multiple vitamin K forms at six weeks postpartum in breastfeeding or formula-feeding mother and infant dyads, delivered vaginally or by C-section. Feeding practice and delivery mode influenced bacterial vitamin K production in the infant gut whereas the mother's vitamin K status did not. High concentrations of unmetabolized vitamin K in feces of formula-fed infants suggests formula vitamin K content exceeds the absorptive capacity of the infant gut. b) Motivated by previous studies linking vitamin K status to cognitive decline, we evaluated the association of vitamin K status biomarkers with cognitive performance in adults with chronic kidney disease (CKD), a group at heightened risk for cognitive decline and vitamin K insufficiency. 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. Participants with low plasma ucMGP, reflecting higher vitamin K status, had better overall cognitive performance based on a composite score of six separate tests. However, plasma phylloquinone was not associated with global cognitive performance. Neither biomarker was significantly associated with performance on any individual cognitive tests. c) In an ongoing collaboration with Harvard investigators to evaluate the interrelationship of vitamin D and vitamin K on bone, we measured dephosphorylated un-carboxylated Matrix Gla protein [(dp)ucMGP], and undercarboxylated osteocalcin (ucOC), two biomarkers of vitamin K status, in 3238 and 1534 participants of the VITamin D and OmegA-3 Trial (VITAL), respectively. To transition our biomarker studies from the ELISA assay historically used to measure ucOC, but is no longer available, to an assay using the same automated system as (dp)ucMGP, we first conducted rigorous validation and quality assurance testing prior to sample analysis. Analysis of a third marker of vitamin K status in the samples of VITAL participants is also in progress. d) By 2060, the number of adults 65 y and older is expected to double and the =85 y segment of the population is expected to triple in the United States (US). US federal nutrition guidance is based on the premise that healthy diets contribute to delaying the onset and progression of many age-related diseases and disability, including cognitive decline. Yet, little is known about the dietary intakes or nutritional needs across the older adulthood age-span. We identified community-based longitudinal cohorts that collected information on dietary intake of adults =65 y in the US and summarized information on the cohorts' design, demographics, and diet assessment. We also identified key gaps in the existing databases that, if filled, could enhance their utility to address certain research questions. e) The main results of a large clinical trial based in Zurich, Switzerland were recently published and secondary analyses related to Objective 3 are ongoing. In one secondary analysis, there was a significant reduction in risk of invasive cancer with the individual and combined treatments of 2000 IU per day of vitamin D, 1 gm per day of marine omega-3 fatty acids, and a simple home-based exercise program. For all three treatments combined, the incidence of invasive cancer was reduced by 61%. In another secondary analysis of the same clinical trial, we determined the effect of the interventions on risk of falling. There were 3333 falls recorded over the follow-up period of 3 years. We found that supplemental omega-3s reduced falls modestly (by 10%), whilst daily dosing with 2000 IU of vitamin D and the simple home-based exercise program had no effect on fall risk among these generally healthy, active and vitamin D-replete older adults. 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 influenced risk of falling. In this trial, men and women aged 65 years and older were treated with 700 IU of vitamin D3 and 500 mg of calcium or with placebo for 3 years. Circulating 25-hydroxyvitamin D measurements and fall assessments were made every 6 months. We found that participants achieving intra-trial mean 25-hydroxyvitamin D levels in the range of 20-40 ng/ml had the lowest risk of falling whereas participants with levels both below and above this range had significantly greater risk of falling. g) Two clinical trials are ongoing in the Bone Research team at the Human Nutrition Research Center on Aging (HNRCA). In one trial we are testing the effect of the ghrelin receptor agonist, anamorelin, versus placebo on muscle mass in older adults. The study is fully enrolled and final study visits are due to begin in July 2022 and be completed in July 2023. Also, in relation to Objective 3, a trial examining the effects of supplemental protein with and without the alkaline compound, potassium bicarbonate, on muscle mass and function, is ongoing. Approximately one third of the needed participants have been enrolled in this study. h) In collaboration with the University of Massachusetts in Lowell, the Bone research team is carrying out an observational study that involves 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 in the Bone Lab. 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.

Accomplishments
1. High doses of vitamin D may actually increase risk of falling. Vitamin D insufficiency has been associated with increased risk of falling in older adults. Recent evidence indicates that high doses of vitamin D may increase risk of falling, but the minimum dose that causes increased falls has not been identified. ARS researchers in Boston, Massachusetts, conducted an analysis of data collected in the Boston Site Testing Osteoporosis Prevention/Intervention Treatment (STOP IT) study that included older men and women being treated with 700 IU of vitamin D3 and 500 mg of calcium or with placebo for 3 years.. Researchers conclude that the circulating level of 25-hydroxyvitamin D level is a useful indicator of fall risk in older adults. Vitamin D supplementation needed to bring the 25-hydroxyvitamin D level into the range of 20 – 40 ng/ml is desirable and doses resulting in levels below and above this range should be avoided, in order to minimize risk of falling.

Review Publications
Wiley, C., Campisi, J. 2021. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nature Metabolism. 3:1290-1301. https://doi.org/10.1038/s42255-021-00483-8.
Ellis, J.L., Fu, X., Karl, P.J., Hernandez, C.J., Mason, J.B., Debose-Boyd, R.A., Booth, S. 2021. Multiple dietary vitamin K forms are converted to tissue menaquinone-4 in mice. Journal of Nutrition. https://doi.org/10.1093/jn/nxab332.
Shea, K., Booth, S.L. 2021. Vitamin K. Advances in Nutrition. https://doi.org/10.1093/advances/nmab133.
Dawson-Hughes, B., Wang, J., Barger, K., Bischoff-Ferrari, H.A., Sempos, C.T., Durazo-Arvizu, R.A., Ceglia, L. 2022. Intra-trial mean 25(OH)D and PTH levels and risk of falling in older men and women in the Boston STOP IT trial. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgac012.
Mazess, R., Bischoff-Ferrari, H., Dawson-Hughes, B. 2021. Vitamin D: bolus is bogus--a narrative review. JBMR Plus. 5(12): e10567. https://doi.org/10.1002/jbm4.10567.
Luna, M., Guss, J., Vasquez-Bolanos, L., Castaneda, M., Vargas Rojas, M., Strong, J.M., Alabi, D.A., Dornevil, S., Nixon, J.C., Taylor, E.A., Donnelly, E., Fu, X., Shea, K., Booth, S.L., Bicalho, R.C., Hernandez, C.J. 2021. Components of the gut microbiome that influence bone tissue-level strength. Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.4341.
Ellis, J.L., Wang, M., Fu, X., Fields, C.J., Donovan, S.M., Booth, S.L. 2022. Feeding practice and delivery mode are determinants of vitamin K in the infant gut: An exploratory analysis. Current Developments in Nutrition. 6(3):nzac019. https://doi.org/10.1093/cdn/nzac019.
Booth, S., Shea, K., Barger, K., Leurgans, S.E., James, B.D., Holland, T.M., Agarwal, P., Fu, X., Wang, J., Matuszek, G., Schneider, J. 2022. Association of vitamin k with cognitive decline and neuropathology in community-dwelling older persons. Alzheimer's & Dementia. https://doi.org/10.1002/trc2.12255.
Shea, K., Barger, K., Booth, S.L., Wang, J., Feldman, H.I., Townsend, R.R., Chen, J., Flack, J., He, J., Jaar, B.G., Kansal, M., Rosas, S.E., Weiner, D.E. 2022. Vitamin K status, all-cause mortality, and cardiovascular disease in adults with chronic kidney disease: the chronic renal insufficiency cohort. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqab375.
Geerinck, A., Dawson-Hughes, B., Beaudart, C., Locquet, M., Reginster, J., Bruyer, O. 2021. Assessment of the performance of the SarQol questionnaire in screening for sarcopenia in older people. Aging Clinical Experimental Research. https://doi.org/10.1007/s40520-021-01913-z.
Mangano, K.M., Noel, S.E., Dawson-Hughes, B., Tucker, K.L. 2021. Sufficient plasma vitamin C is related to greater bone mineral density among postmenopausal women from the Boston Puerto Rican health study. Journal of Nutrition. https://doi.org/10.1093/jn/nxab291.
Zhang, Y., Shea, K., Judd, S., D'Alton, M., Kahe, K. 2021. Issues related to the research on vitamin K supplementation and bone mineral density. European Journal of Clinical Nutrition. 76:335-339. https://doi.org/10.1038/s41430-021-00941-2.
Dawson-Hughes, B. 2020. Acid-base balance of the diet-implications for bone and muscle. European Journal of Clinical Nutrition. 74:7-13. https://doi.org/10.1038/s41430-020-0691-7.