Project : USDA ARS

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Research Project: Nutrients, Aging, and Musculoskeletal Function

Location: Jean Mayer Human Nutrition Research Center On Aging

2018 Annual Report

Objectives
LAB Name: Bone Metabolism 1. Determine the effects of dietary and supplemental vitamin D and related nutrients in the prevention and progression of musculoskeletal performance and dysfunction, glucose homeostasis and type 2 diabetes, and other chronic diseases. 1.A. The impact of supplemental vitamin D on serum 25-hydroxyvitamin D (25OHD) levels and short-term indicators of physical function. 1.B. Determine the impact of vitamin D3-omega3-home exercise on aging. 1.C. Determine the effect of supplemental vitamin D on incident of diabetes in subjects with pre-diabetes. 1.D. Determine the effect of supplemental vitamin D on glucose tolerance in subjects with established diabetes. 2. Determine the effects of dietary acid-base balance on bone and muscle metabolism and function. 2.A. Conduct a dose-finding trial of the musculoskeletal benefits of bicarbonate in older adults. 3. Define the contributions of vitamin D absorption, metabolism, and genetic variation in regulating the circulating levels of 25-hydroxyvitamin D and other metabolites. 3.A. Conduct a pilot study of the effect of dietary fat type and amount on vitamin D3 absorption. LAB NAME: Vitamin K 1: To characterize dietary factors, including food composition and nutrient-nutrient interactions, and non-dietary factors, such as genetics, that contribute to the inter-individual variation in vitamin K intake, bioavailability, and utilization and vitamin K metabolite production. 1.1: To study the influence of foods and single nutrients on the distribution, bioavailability and function of different forms of vitamin K and their metabolites. 1.2: To measure key foods to monitor changes in the food supply that affect vitamin K content 1.3: Identify genetic factors involved in vitamin K metabolism. 2: Determine the role(s) and mechanism(s) of action for vitamin K beyond its essential role in coagulation, including the role of vitamin K in the prevention of abnormal non-skeletal calcification and the mechanisms of vitamin K action not currently explained by its role as an enzyme cofactor. 2.1: Determine the effects of vitamin K in the prevention of abnormal non-skeletal calcification and other chronic diseases in older adults. 2.2: Identify potential mechanism(s) of vitamin K action that are not currently explained by its role as an enzyme cofactor.

Approach
LAB Name: Bone Metabolism This laboratory uses a variety of approaches to carry out its clinical and translational research program, including cross-sectional and observational studies, randomized intervention trials, and small metabolic studies. This laboratory collaborates with the Nutrition, Exercise Physiology and Sarcopenia Laboratory to examine the impact of vitamin D and the acid-base balance of the diet on muscle performance and risk of falling. In collaboration with external laboratories, this laboratory seeks to determine the impact of vitamin D on risk of developing type 2 diabetes. These and other collaborations allow us access to basic research technologies, such as muscle tissue histology and gene array analysis, that enable us to identify mechanisms by which nutrients affect bone and muscle. LAB NAME: Vitamin K Our long-term objective is to study the determinants of vitamin K bioavailability, utilization, and metabolism in order to refine vitamin K intake recommendations. Expansion of the forms of vitamin K analyzed in a selected number of foods will enhance the USDA vitamin K database, and allow us to monitor changes in different forms of vitamin K in the food supply. To identify dietary and non-dietary factors that determine how much vitamin K obtained from foods is utilized, we will apply stable isotope techniques to established and novel measures of vitamin K metabolism. Data obtained from our completed metabolic study in younger and older adults, in addition to animal studies, have helped to refine the study designs that will be used in this project plan. We will initiate a series of studies that compare the metabolism of different forms of vitamin K, and identify the impact of other nutrients on different aspects of vitamin K metabolism. To expand our observations that vitamin K may have a role in the prevention of abnormal non-skeletal calcification, we will use observational data and biological samples collected from large on-going cohorts, as well as conduct animal studies, to examine potential mechanisms beyond that of an enzyme cofactor. We will then focus on the role(s) of different forms of vitamin K in insulin resistance and inflammation using a rodent model. This is a rapidly evolving field, and novel functions of vitamin K in other cells will be considered as new information becomes available.

Progress Report
BONE METABOLISM LAB: We have now completed all study visits in 100 older adults who participated in a randomized, double-blind placebo-controlled trial to determine whether supplementation with 800 to 1600 IU per day of vitamin D, when compared with placebo, improved leg strength and power in older men and women with low serum 25-hydroxyvitamin D levels. Over the course of a year, participants came to the Human Nutrition Research Center on Aging every 2 months for physical function and biochemical testing. The biochemical measurements have been made, the data have been quality controlled, and files are ready for data analyses. We had demonstrated earlier in two large randomized, placebo-controlled trials in healthy older men and women that administration of potassium bicarbonate, an alkaline compound that neutralizes the acid load of the diet, has favorable effects on markers of bone turnover and muscle mass and function over a 3-month period. The greatest benefit was seen in participants who consumed the most acid-producing diets. Recent analyses of data from these trials were used to determine whether we could develop a short food intake questionnaire that would identify participants with high dietary acid loads. We found in data from the first trial that simply asking “How many servings of fruit do you consume each day?” was effective. We then validated this approach with use of data from our second trial. We now have a quick and inexpensive tool to identify adults who have acid-producing diets and who are therefore likely to benefit from increasing their intake of alkali, either through potassium bicarbonate supplementation or by increasing their intake of fruit and vegetables. Safe and low cost strategies are urgently needed to curb the current epidemic of type 2 diabetes. We are conducting a multicenter randomized double-blind placebo-controlled trial to test the possibility that supplementation with 4000 IU per day of vitamin D, compared with placebo, will retard the progression to type 2 diabetes in high risk adults (adults with pre-diabetes.) The 2,382 needed participants were recruited at 20 sites around the United States between October, 2014 and November, 2016. This is an event driven trial designed to continue until 508 participants converted to type 2 diabetes. This number of converters was reached in April, 2018, at which point final study visits began. After approximately 5 months, these final visits will be completed and data analyses will begin. The numbers of participants meeting criteria for type 2 diabetes will be compared in the placebo and vitamin D treated groups. Individuals with type 2 diabetes have increased fracture risk despite having normal bone density. This suggests that bone strength is reduced in type 2 diabetes. We have recently completed enrollment of 200 older adults into a cross-sectional study designed to measure their bone strength and bone density. These participants had a balanced spectrum of fasting blood sugar levels, including normal (glucose < 100 mg/dl,) prediabetes (100-125 mg/dl) and type 2 diabetes (>125 mg/dl). Bone strength was assessed at the shaft of the mid-tibia by reference point indentation, a direct measure of resistance to micro-fracture. Bone density was measured by dual-energy x-ray absorptiometry. The data are now undergoing quality control procedures, and data analysis will soon begin. If we observe that bone strength declines with increasing glycemia, then this bone strength measure may serve as a useful predictor of fracture risk in adults with type 2 diabetes. VITAMIN K LAB: A better understanding of the factors that influence vitamin K metabolism is needed. In a secondary analysis of data from a meta-analysis of Genome Wide Association Studies of circulating phylloquinone, triglyceride-specific single nucleotide polymorphism (SNPs) were significantly associated with circulating phylloquinone, both individually and when combined in a genetic risk score. This was an expected finding given that phylloquinone is transported by triglycerides in circulation. The SNPs associated with total and the LDL (low-density lipoprotein) fraction of cholesterol were not associated with phylloquinone concentrations, as expected. The associations with HDL-C (high-density lipoprotein-Cholesterol) require additional study as currently there is no biological underpinning for observed associations with phylloquinone concentrations. To compare plasma phylloquinone response to phylloquinone intake in older and younger adults following dietary phylloquinone depletion and repletion, 21 older and 21 younger adults were maintained on sequential 28-day phylloquinone depletion and 28-day phylloquinone repletion diets. On the 23rd day of each diet phase, participants were fed deuterium-labeled phylloquinone-rich collard greens and blood samples were obtained over 72 hours. Liquid chromatography-mass spectrometry was used to measure labeled and unlabeled phylloquinone in plasma. The plasma labeled phylloquinone area under the curve (AUC) did not differ in response to phylloquinone depletion or repletion, but was significantly higher in older adults than younger adults. However, plasma phylloquinone AUC was highly correlated with the serum triglyceride AUC. After adjustment for the serum triglyceride response, there was no significant difference in the plasma labeled phylloquinone response between younger and older adults. Plasma response to phylloquinone intake, therefore, seems to be predominantly triglyceride-driven and not dependent on existing vitamin K status or non-dietary factors, such as age. There is currently no known cure for osteoarthritis, the leading cause of lower-extremity disability in older adults. Vitamin D has been proposed as a nutritional strategy to reduce osteoarthritis progression, but has not yet been demonstrated to be effective in clinical trials. However, none of the trials conducted to date considered participant vitamin K status. Using data obtained from two independent observational knee osteoarthritis studies, lower-extremity function in older adults with vitamin K sufficiency combined with vitamin D sufficiency was compared to those with sufficient status of either nutrient alone. Older adults with vitamin K sufficiency combined with vitamin D sufficiency at baseline had faster walking speed and better performance in other measures of lower-extremity function over 4 to 5 years of follow-up than those with sufficient status of either nutrient alone. These findings indicate that higher vitamin K status combined with higher vitamin D status could be beneficial to lower-extremity function in older adults with knee osteoarthritis but further study is needed.

Accomplishments
1. Net acid excretion is still the gold standard measure for acid-base status for clinical research. Urinary citrate has been proposed as an effective means of assessing acid base balance in children. Citrate is a common clinical measure, and it is easy to assay when compared with the current gold standard measure, 24-hour urinary net acid excretion. To determine whether citrate might be a suitable indicator of acid-base status in adults, ARS-funded researchers in Boston, Massachusetts, measured urinary citrate in archived 24-hour urine samples from an earlier potassium bicarbonate intervention trial in which we had measured net acid excretion. A comparative analysis revealed that in older adults, urinary citrate was not a good indicator of net acid excretion. Therefore, net acid excretion remains the gold standard measure of acid-base status for clinical research.

2. Nutrients and bioactives in green leafy vegetables may help to slow cognitive decline. The prevalence of dementia and decline in cognitive abilities is sharply increasing as older adults continue to grow in number. To increase understanding of the biological mechanisms underlying reported associations between green leafy vegetable intake and cognitive abilities, ARS researchers in Boston, Massachusetts investigated the associations of the primary nutrients and bioactives in green leafy vegetables to cognitive decline. Baseline food intakes were estimated using standardized questionnaires in 960 older community-based adults who then had multiple cognitive assessments over an average period of five years. Higher intakes of phylloquinone, lutein, nitrate, folate, a-tocopherol, and kaempferol were individually associated with slower cognitive decline. Consumption of approximately one serving per day of green leafy vegetables and foods rich in these nutrients may help to slow cognitive decline with aging.

U.S. DEPARTMENT OF AGRICULTURE

Jean Mayer Human Nutrition Research Center On Aging: Boston, MA