Project : USDA ARS

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Research Project: Nutrient Metabolism and Musculoskeletal Health in Older Adults

Location: Jean Mayer Human Nutrition Research Center On Aging

2024 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
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
1. 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.

U.S. DEPARTMENT OF AGRICULTURE

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