Progress 05/16/19 to 03/11/24
Outputs
PROGRESS REPORT Objectives (from AD-416): 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 (from AD-416): 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. As part of our research characterizing factors that contribute to the inter-individual variation in vitamins D and K (Objective 1), we compared relative absorption of different forms of vitamin K. All vitamin K forms share a biochemical structure called menadione, but have different sidechains. Phylloquinone is the vitamin K form produced by plants, and menaquinones are the different vitamin K forms produced by bacteria, including gut bacteria. Not much is known about how dietary vitamin K influences the gut microbiota or the vitamin K forms it produces. We fed mice either a vitamin K deficient diet or vitamin K sufficient diets 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 own 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, and more research is needed to determine if menadione that is formed in intestinal tissue is an important intermediate in the remodeling of dietary vitamin K to bacterial menaquinones. As part of our research on the role of nutrients on bone and muscle (Objective 2), we examined the roles of nutrient and food intakes on risk of falling and muscle strength. 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. Data were 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. Participants achieving intra-trial mean 25- hydroxyvitamin D levels in the range of 20-40 ng/ml had the lowest risk of falling. Participants with levels both below and above this range had significantly greater risk of falling. Circulating 25-hydroxyvitamin D levels are a useful indicator of fall risk in older adults. To minimize risk of falling, one may need to supplement with vitamin D to bring the 25-hydroxyvitamin D level into the range of 20 ⿿ 40 ng/ml. An elevated dietary acid load is a risk factor for reduced muscle mass; however, the relationship between dietary acid load and muscle strength is unknown. This research gap needs to be addressed because muscle strength, when compared with muscle mass, has a stronger relationship to physical function and to related adverse health outcomes, including falls, fractures, and hospitalization. The dietary acid load reflects the balance of intake of acid-producing foods, grains and protein, and alkali- producing foods, fruits and vegetables. We examined the association between the dietary acid load and grip strength in a nationally representative sample of U.S adults 50 years of age and older. Two measures of the dietary acid load, the potential renal acid load (PRAL) and the net endogenous acid production (NEAP), were calculated from self- reported food intake in 4,059 men and women aged 50 years and older who participated in the 2011-2014 NHANES survey cycles. As expected, grip strength was lower in the women than in the men (26.8 +/- 0.2 kg vs 43.0 +/- 0.4 kg). Consistent with our hypothesis, grip strength was significantly lower in women consuming higher dietary acid loads. In contrast, we identified no association between grip strength and dietary acid load in the men. We conclude that higher fruit and vegetable intake may contribute to higher grip strength in women. More research is needed to understand why the same association was not observed in the men. As part of our research examining the roles of vitamins D and K in brain and heart health (Objective 3), we analyzed postmortem brain concentrations of vitamins D and K and their related metabolites in decedents of the Rush Memory and Aging Project (MAP) to determine the association of these different forms with antemortem measures of cognitive function and Alzheimer's disease and related dementias (ADRD) neuropathologies. The 25(OH)D was the primary form of vitamin D in all brain regions evaluated. The odds of having dementia or mild cognitive impairment at the last visit before death were 25% - 33% lower per doubling of 25(OH)D in the brain. However, brain 25(OH)D concentrations were not associated with any post-mortem neuropathology outcome studied. MK4 was the main form of vitamin K in all brain regions evaluated. The odds of having dementia or mild cognitive impairment at the last visit before death were up to 20% lower per doubling of MK4 in the brain. Further investigation of neuropathologically-defined outcomes revealed that higher brain MK4 concentrations were associated with lower global ADRD pathology, including fewer neurofibrillary tangles. These data will inform the design of future studies in both animal models and observational studies on this topic. Low amounts of vitamin K have been implicated in an increased risk of cardiovascular disease in older adults; however, this has not been studied in a diverse population with an extended follow-up. To address this gap, a vitamin K biomarker was measured in 2663 older adults participating in the Multi-Ethnic Study of Atherosclerosis who were followed for 10 years. Higher vitamin K status was associated with less progression of heart disease. These data provide justification for future clinical studies focused on vitamin K intake and heart disease risk. ACCOMPLISHMENTS 01 Differences in dietary intakes across older adulthood. Dietary guidance is set based on age and life stage and defines older adults as 60 years or older. Yet, little is known about if or how diet quality differs beyond age 60. To address this gap, ARS funded-researchers at Boston, Massachusetts, compared diet quality and dietary intakes of older adults by decade of life using data from the National Health and Nutrition Examination Survey. Compared to the 60-69-year-olds, men and women in their eighties had markedly lower energy intakes, which was accompanied by a lower intake of nutrient dense food and a higher intake of snacks and sweets. This analysis provides justification for considering defining older adults by decade of life rather than grouping them as 60 years and older when setting dietary guidance.
Impacts
(N/A)
Publications
- Dawson-Hughes, B., Bischoff-Ferrari, H.A. 2023. Adult vitamin D deficiency: fracture & fall prevention. In: Feldman and Pike's Vitamin D. 5th edition. Elsevier. https://doi.org/10.1016/B978-0-323-91338-6.00021-5.
- Greenblatt, D.J., Bruno, C.D., Harmatz, J.S., Dawson-Hughes, B., Zhang, Q., Li, C., Chow, C.R. 2023. Estimation of absolute and relative body fat content using non-invasive surrogates: Can DXA be bypassed? Journal of Clinical Pharmacology. https://doi.org/10.1002/jcph.2306.
- Dawson-Hughes, B., Barger, K., Reitshamer, E., Fielding, R.A., Evans, W., Ceglia, L. 2023. Effect of anamorelin, a ghrelin receptor agonist, on muscle and bone in adults with osteosarcopenia. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgad702.
- Shea, K., Barger, K., Rogers, G., Talegawkar, S., Eicher-Miller, H., Booth, S.L. 2024. Dietary intakes of community-dwelling adults in the United States across older adulthood: NHANES 2015-March 2020. Journal of Nutrition. https://doi.org/10.1016/j.tjnut.2023.12.014.
- Vanderput, L., Johansson, H., McCloskey, E.V., Liu, E., Schini, M., Akesson, K.E., Anderson, F.A., Azagra, R., Bager, C.L., Beaudart, C., Bischoff-Ferrara, H., Biver, E., Bruyere, O., Cauley, J.A., Center, J.R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C.J., Cummings, S., da Silva, J.A., Dawson-Hughes, B., Diez-Perez, A., Dufour, A.B., Eisman, J. A., Elders, P., Ferrari, S., Fujita, Y., Fujiwara, S., Gluer, C.C., Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R.J., Huisman, M., Iki, M., Shalom, S.I., Jones, G., Karlsson, M., Khosla, S., Kiel, D., Koh, W., Koromani, F., Kotowicz, M., Kroger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., Mcguigan, F.E., Mellstrom, D., Merlijn, T., Nguyen, T.V., Nordstrom, A., Nordstrom, P., O'Neill, T.W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E.S., Pasco, J., Rivadeneira, F., Schott, A., Shiroma, E.J., Siggeirsdottir, K., Simonsick, E.M., Sornay-Rendu, E., Sund, R., Swart, K.M., Szulc, P., Tamaki, J., Torgerson, D., van Schoor, N.C., 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. 2024. A meta- analysis of previous falls and subsequent fracture risk in cohort studies. Osteoporosis International. https://doi.org/10.1007/s00198-023-07012-1.
- Dawson-Hughes, B., Konieczynski, E.M., Reitshamer, E., Ceglia, L. 2024. Effect of a GH secretagogue, anamorelin, on serum irisin and inflammation levels in osteosarcopenic adults. Journal of the Endocrine Society. https:/ /doi.org/10.1210/jendso/bvae028.
- Mogck, B., Jezak, S., Wiley, C. 2024. Mitochondria-targeted catalase does not suppress development of cellular senescence during aging. Biomedicines. https://doi.org/10.3390/biomedicines12020414.
- Shea, K., Strath, L., Kim, M., Doan, L., Booth, S.L., Brinkley, T., Kritchevsky, S. 2024. Promoting healthy aging through nutrition: A research centers collaborative network workshop report. Advances in Nutrition. https://doi.org/10.1016/j.advnut.2024.100199.
- Stuck, A.K., Tsai, L., Freystatter, G., Vellas, B., Kanis, J.A., Rizzoli, R., Kressig, R., Armbrecht, G., da Silva, J.A., Dawson-Hughes, B., Egli, A. A., Bischoff-Ferrari, H.A. 2023. Prevalence of sarcopenia among generally healthy community-dwelling adults in a large multinational European population: Baseline data of the DO-HEALTH trial. Journal of Nutrition Health and Aging. https://doi.org/10.1007/s12603-023-1888-y.
- Paquette, A., Carbone, B.E., Vogel, S., Israel, E., Maria, S.D., Labhart, B., Morrow, A.L., Phillips, S.C., Kuang, C., Hondmann, D., Pandey, N., Biederer, T. 2023. The human milk component myo-inositol promotes neuronal connectivity. Proceedings of the National Academy of Sciences (PNAS). https://doi.org/10.1073/pnas.2221413120.
- 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 supplementation on glycemia: A secondary analysis from the vitamin D and type 2 diabetes (D2d) study. Diabetes Research and Clinical Practice. https://doi.org/10.1016/j.diabres.2023.110792.
- Kanis, J.A., Johansson, H., McKloskey, E.V., Liu, E., Akesson, K., Anderson, F.A., Axagra, 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. A., Dawson-Hughes, B., Diez-Perez, A., Dufour, A.B., Eisman, J.A., Elders, P.J., Ferrari, S.J., Fujita, Y., Fujiwara, S., Gluer, C.C., Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R.J., Huisman, M., Iki, M., Ish-Shalom, S., Joens, G., Karlsson, M.K., Khosla, S. , Kiel, D., 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., Rivadeneira, F., Schott, A., Shiroma, E.J., Siggeirsdottir, K., Simonsick, E., Sornay-Rendu, E., Sund, R., Swart, K., Szulc, P., Tamaki, J., Torgerson, 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., Vandenput, L., Harvey, N.C., Lorentzon, M., Leslie, W.D. 2023. Previous fracture and subsequent fracture risk: A meta- analysis to update FRAX. Osteoporosis International. https://doi.org/10. 1007/s00198-023-06870-z.
- Chatterjee, R., Davenport, C.A., Vickery, E.M., Johnson, K.C., Kashyap, S. R., Leblanc, E.S., Nelson, J., Dagogo-Jack, S., Pittas, A.G., Dawson- Hughes, B. 2023. Effect of intra-trial mean 25(OH)D level on diabetes risk, by race and weight: An ancillary analysis in the D2d study. The American Journal of Clinical Nutrition. https://doi.org/10.1016/j.ajcnut.2023.03. 021.
- Fouhy, L.E., Mangano, K.M., Zhang, X., Dawson-Hughes, B., Tucker, K.L., Noel, S.E. 2023. Association between a calcium to magnesium ratio and osteoporosis among Puerto Rican older adults. Journal of Bone and Mineral Research. https://doi.org/10.1016/j.tjnut.2023.05.009.
- Kuehnemann, C., Wiley, C. 2023. Senescent cells at the crossroads of aging, disease, and tissue homeostasis. Aging Cell. https://doi.org/10.1111/acel. 13988.
- Kistler-Fischbacher, M., Armbrecht, G., Gangler, S., Theiler, R., Rizzoli, R., Dawson-Hughes, B., Kanis, J.A., Hofbauer, L.C., Schimmer, R.C., Vellas, B., Da Silva, J.A., Orav, J.E., Kressig, R.W., Egli, A., Lang, W., Wanner, G.A., Bischoff-Ferrari, H. 2024. Effects of vitamin D3, omega-3s and a simple strength training exercise program on bone health: the Do-Health randomized controlled trial. Journal of Bone and Mineral Research. https:// doi.org/10.1093/jbmr/zjae054.
- Bischoff-Ferrari, H.A., Kisttler-Fischbacher, M., Gaengler, S., Munzer, T., Dawson-Hughes, B., Lang, W., Theiler, R., Egli, A., Orav, J.E., Freystetter, G. 2024. Effects of testosterone and vitamin D on fall risk in pre-frail hypogonadal men: A factorial design RCT. Journal of Nutrition Health and Aging. https://doi.org/10.1016/j.jnha.2024.100217.
- Wieczorek, M., Isler, M., Landau, K., Becker, M.D., Dawson-Hughes, B., Kressig, R.W., Vellas, B., Orav, E.J., Rizzoli, R., Kanis, J.A., Armbrecht, G., da Silva, J.A., Egli, A., Freystatter, G., Bischoff-Ferrari, H. 2024. Association between visual acuity and prospective fall risk in generally healthy and active older adults: the 3-year DO-HEALTH study. Journal of the American Medical Directors Association - Post-Acute and Long Term Care Medicine. https://doi.org/10.1016/j.jamda.2024.03.005.
- Berlot, A.A., Fu, X., Shea, K., Tracy, R., Budoff, M., Kim, R.S., Naveed, M., Booth, S.L., Kizer, J.R., Bortnick, A.E. 2024. Matrix Gla protein and the long-term incidence and progression of coronary artery and aortic calcification in the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2024.117505.
- Harvey, N.C., Ward, K.A., Agnusdei, D., Binkley, N., Biver, E., Campusano, C., Cavalier, E., Clark, P., Diaz-Curiel, M., El-Hajj Fuleihan, G., Khashayer, P., Lane, N.E., Messina, O.D., Mithal, A., Rizzoli, R., Sempos, C., Dawson-Hughes, B. 2024. Optimization of vitamin D status in global populations. Osteoporosis International. https://doi.org/10.1007/s00198- 024-07127-z.
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Progress 10/01/22 to 09/30/23
Outputs
PROGRESS REPORT Objectives (from AD-416): 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 (from AD-416): 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) 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. ACCOMPLISHMENTS 01 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.
Impacts
(N/A)
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. https://doi.org/10.1002/alz.12836.
- 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. https://doi.org/10.7326/M22- 3018.
- 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. https://doi.org/10.1016/j.cdnut. 2022.100008.
- 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. https://doi.org/10.1007/s00198- 022-06567-9.
- 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. https://doi.org/10.1016/j.jamda. 2022.12.011.
- 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. https://doi.org/10.1007/s00774-022- 01374-y.
- Faggioli, F., Velarde, M., Wiley, C. 2022. Cellular senescence, a novel area of investigation for metastatic diseases. Preprints. https://doi.org/ 10.20944/preprints202211.0564.v1.
- Kuehnemann, C., Wiley, C. 2023. Cholesterol drives inflammatory senescence. Nature Metabolism. https://doi.org/10.1038/s42255-023-00758-2.
- 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. https://doi.org/10.1016/ j.cdnut.2023.100049.
- 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. https://doi.org/10.1093/ndt/gfac191.
- 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. https://doi.org/10.1093/cdn/nzac111.
- 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. https://doi.org/10.3389/fragi.2022.852643.
- 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. https:/ /doi.org/10.3389/fendo.2022.935106.
- Panda, A., Booth, S.L. 2022. Nutritional aspects of healthy aging. Medical Clinics of North America. 106(5): 853-864. https://doi.org/10.1016/j.mcna. 2022.04.008.
- 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. https://doi.org/10.1210/clinem/dgaa594.
- 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. https://doi.org/10.1093/advances/nmac031.
- 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. https://doi.org/10. 1080/27697061.2022.2082599.
- 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. https://doi.org/10. 1007/s00223-022-01024-5.
- 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. https://doi.org/10.1093/ajcn/nqac022.
- 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. https://doi.org/10.1212/WNL. 0000000000201541.
- 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. https://doi.org/10. 1007/s12020-022-03208-3.
- 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. https://doi.org/10.1016/j.cdnut. 2023.101959.
- 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. https://doi.org/ 10.3233/NHA-220193.
- 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. https:// doi.org/10.1007/s40520-022-02338-y.
- 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. https://doi.org/10.1016/B978-0-12-821848-8.00139-6.
- 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. https://doi.org/ 10.1007/s00198-022-06435-6.
- 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. https://doi. org/10.1016/j.diabres.2023.110792.
- 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. https://doi. org/10.1111/acel.13750.
- 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. https://doi.org/10.1007/s40520-023-02438-3.
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Progress 10/01/21 to 09/30/22
Outputs
PROGRESS REPORT Objectives (from AD-416): 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 (from AD-416): 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) 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 01 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.
Impacts
(N/A)
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.
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Progress 10/01/20 to 09/30/21
Outputs
PROGRESS REPORT Objectives (from AD-416): 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 (from AD-416): 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. Record of Any Impact of Maximized Teleworking Requirement: The laboratory⿿s maximized telework posture due to COVID-19 hindered our capability to make progress toward Subobjective 2a as we could not collect any new data on human study participants during this time. We had been enrolling ahead of schedule, and at the transition to teleworking, 75 participants had had their 6-month study visit, and few had had their final visit in this 12-month study. We had to discontinue all study activities because we could no longer provide the intervention or make study outcome or safety measurements. We are currently analyzing the baseline, 3-month, and 6-month laboratory data in the 75 participants. We will learn from the smaller sample size and shorter intervention period and plan subsequent work accordingly. Being unable to perform human studies allowed more time for manuscript writing. ACCOMPLISHMENTS 01 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.
Impacts
(N/A)
Publications
- 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.
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Progress 10/01/19 to 09/30/20
Outputs
Progress Report Objectives (from AD-416): 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. Approach (from AD-416): 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.
Impacts
(N/A)
Publications
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. Contributions of lipids to variances in circulating fat-soluble vitamins and carotenoids. Current Developments in Nutrition. 4(6).
- 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.
- 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.
- 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.
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