Leukocyte telomere length is associated with MRI-thigh fat-free muscle volume: data from 16 356 UK Biobank adults.

BACKGROUND: Telomere attrition may share common biological mechanisms with bone and muscle loss with aging. Here, we investigated the association between these hallmarks of aging using data from UK Biobank, a large observational study. METHODS: Leukocyte telomere length (LTL as T/S ratio) was measured using a multiplex qPCR assay at baseline (2006-2010). Bone mineral density (whole body and regional; via dual-energy X-ray absorptiometry), trabecular bone score (via lumbar-spine dual-energy X-ray absorptiometry images), fat-free muscle volume (thighs; via magnetic resonance imaging), and muscle fat infiltration (thighs; via magnetic resonance imaging) were measured during the imaging visit (2014-2018). Regression models were used to model LTL against a muscle or bone outcome, unadjusted and adjusted for covariates. RESULTS: A total of 16 356 adults (mean age: 62.8 ± 7.5 years, 50.5% women) were included. In the fully adjusted model, thigh fat-free muscle volume was associated with LTL in the overall sample (adjusted standardized ß (aß) = 0.017, 95% CI 0.009 to 0.026, P < 0.001, per SD increase in LTL), with stronger associations in men (aß = 0.022, 95% CI 0.010 to 0.034, P < 0.001) than in women (aß = 0.013, 95% CI 0.000 to 0.025, P = 0.041) (sex-LTL P = 0.028). The adjusted odds ratio (aOR) for low thigh fat-free muscle volume (body mass index-adjusted, sex-specific bottom 20%) was 0.93 per SD increase in LTL (95% CI 0.89 to 0.96, P < 0.001) in the overall sample, with stronger associations in men (aOR = 0.92, 95% CI 0.87 to 0.99, P = 0.008) than women (aOR = 0.93, 95% CI 0.88 to 0.98, P = 0.009), although the sex difference was not statistically significant in this model (sex-LTL P = 0.37). LTL was not associated with bone mineral density, trabecular bone score, or muscle fat infiltration in the overall or subgroup analyses (P > 0.05). CONCLUSIONS: LTL was consistently associated with thigh fat-free muscle volume in men and women. Future research should investigate moderating effects of lifestyle factors (e.g., physical activity, nutrition, or chronic diseases) in the association between LTL and muscle volume.

Dynamic model assuming mutually inhibitory biomarkers of frailty suggests bistability with contrasting mobility phenotypes.

Bistability is a fundamental biological phenomenon associated with "switch-like" behavior reflecting the capacity of a system to exist in either of two stable states. It plays a role in gene regulation, cell fate switch, signal transduction and cell oscillation, with relevance for cognition, hearing, vision, sleep, gait and voiding. Here we consider a potential role for bistability in the existence of specific frailty states or phenotypes as part of disablement pathways. We use mathematical modeling with two frailty biomarkers (insulin growth factor-1, IGF-1 and interleukin-6, IL-6), which mutually inhibit each other. In our model, we demonstrate that small variations around critical IGF-1 or IL-6 blood levels lead to strikingly different mobility outcomes. We employ deterministic modeling of mobility outcomes, calculating the average trends in population health. Our model predicts the bistability of clinical outcomes: the deterministically-computed likelihood of an individual remaining mobile, becoming less mobile, or dying over time either increases to almost 100% or decreases to almost zero. Contrary to statistical models that attempt to estimate the likelihood of final outcomes based on probabilities and correlations, our model predicts functional outcomes over time based on specific hypothesized molecular mechanisms. Instead of estimating probabilities based on stochastic distributions and arbitrary priors, we deterministically simulate model outcomes over a wide range of physiological parameter values within experimentally derived boundaries. Our study is "a proof of principle" as it is based on a major assumption about mutual inhibition of pathways that is oversimplified. However, by making such an assumption, interesting effects can be described qualitatively. As our understanding of molecular mechanisms involved in aging deepens, we believe that such modeling will not only lead to more accurate predictions, but also help move the field from using mostly studies of associations to mechanistically guided approaches.

Relationship Between Plasma Homocysteine and Bone Density, Lean Mass, Muscle Strength and Physical Function in 1480 Middle-Aged and Older Adults: Data from NHANES.

Hyperhomocysteinemia induces oxidative stress and chronic inflammation (both of which are catabolic to bone and muscle); thus, we examined the association between homocysteine and body composition and physical function in middle-aged and older adults. Data from the National Health and Nutrition Examination Survey was used to build regression models. Plasma homocysteine (fluorescence immunoassay) was used as the exposure and bone mineral density (BMD; dual-energy X-ray absorptiometry; DXA), lean mass (DXA), knee extensor strength (isokinetic dynamometer; newtons) and gait speed (m/s) were used as outcomes. Regression models were adjusted for confounders (age, sex, race/Hispanic origin, height, fat mass %, physical activity, smoking status, alcohol intakes, cardiovascular disease, diabetes, cancer and vitamin B12). All models accounted for complex survey design by using sampling weights provided by NHANES. 1480 adults (median age: 64 years [IQR: 56, 73]; 50.3% men) were included. In multivariable models, homocysteine was inversely associated with knee extensor strength (ß = 0.98, 95% CI 0.96, 0.99, p = 0.012) and gait speed (ß = 0.85, 95% CI 0.78, 0.94, p = 0.003) and borderline inversely associated with femur BMD (ß = 0.84, 95% CI 0.69, 1.03, p = 0.086). In the sub-group analysis of older adults (≥ 65 years), homocysteine was inversely associated with gait speed and femur BMD (p < 0.05) and the slope for knee extensor strength and whole-body BMD were in the same direction. No significant associations were observed between homocysteine and total or appendicular lean mass in the full or sub-group analysis. We found inverse associations between plasma homocysteine and muscle strength/physical function, and borderline significant inverse associations for femur BMD.

Nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties: Targeting the biological mechanisms of aging to support musculoskeletal health.

Old age is associated with declines in bone density and muscle mass and function, which predisposes to mobility disability, falls, and fractures. Poor nutritional status, a risk factor for several age-related pathologies, becomes prevalent in old age and contributes to the structural and functional changes of the musculoskeletal system that increases the risk of osteoporosis, sarcopenia, osteosarcopenia, and physical frailty. The biological mechanisms underpinning these pathologies often overlap and include loss of proteostasis, impaired redox functioning, and chronic low-grade inflammation. Thus, provision of nutrients with anabolic/anticatabolic, antioxidant, and anti-inflammatory properties may be an effective strategy to offset these age-related pathologies. We searched PUBMED for pre-clinical and clinical work examining the effects of nutrients with a combined effect on muscle and bone. This review summarizes recent evidence on the mechanisms of action and potential clinical use of nutrients that concomitantly improve muscle and bone health in older persons.

Interaction Between Vitamin D and Interleukin 6 on Slow Gait Speed: 6-Year Follow-up Data of Older Adults From InCHIANTI.

BACKGROUND: Whereas the independent effects of biomarkers, including 25-hydroxy vitamin D (25(OH)D), insulin-like growth factor 1, C-reactive protein, and interleukin 6 (IL-6), on gait speed in older adults have been evaluated, their joint effects on gait speed are not well understood. METHODS: Study subjects aged at least 65 at baseline (N = 970) were enrolled in the population-based Invecchiare in Chianti (InCHIANTI) study from 1998 to 2000 and were followed up at 3 and 6 years. All above biomarkers and gait speed data were measured at each of the three time points. Using a generalized estimating equation approach, we determined if slow gait speed (<0.8 m/s) was associated with the biomarkers. Further investigation was conducted for interactions between high IL-6 (≥.87 pg/mL) and other biomarkers focusing on low 25(OH)D (<20 ng/mL). RESULTS: After controlling for other biomarkers and potential confounders, IL-6 emerged as the only biomarker independently associated with gait speed. The association between high IL-6 and slow gait speed was enhanced by low 25(OH)D, with significant interaction between high IL-6 and low 25(OH)D (p = .038). The odds ratio of slow gait speed for low 25(OH)D and high IL-6 was 1.63 (95% confidence interval [CI]: 1.15, 2.32) compared with the reference groups with both biomarker levels at the other ends. CONCLUSION: The association of low vitamin D with slow gait speed statistically interacts with high IL-6. Coexisting vitamin D insufficiency and inflammation may provide a better biomarker for identifying those at risk of developing impairments in gait speed than either factor alone.

Vitamin D insufficiency and abnormal hemoglobin a1c in black and white older persons.

BACKGROUND: Although vitamin D has been mechanistically linked to insulin secretion and sensitivity, it remains unclear whether low 25-hydroxyvitamin D levels confer an increased risk of impaired glucose metabolism. We evaluated the relationship between vitamin D insufficiency (25-hydroxyvitamin D < 20ng/mL) and abnormal hemoglobin A1c (A1c) (≥6.5%) in community-dwelling older persons and examined whether this relationship differed according to race. METHODS: Participants were 2,193 persons of age 70-79 years at Year 1 (52% women; 37% black) in the Health, Aging, and Body Composition study who had clinic visits at Years 2 and 4. Logistic regression analyses, adjusted for potential confounders, were used to evaluate the association between vitamin D insufficiency and abnormal A1c 2 years later. Interaction of race and vitamin D insufficiency was tested. RESULTS: A total of 665 (30%) and 301 (14%) of the participants had vitamin D insufficiency at Year 2 and abnormal A1c at Year 4, respectively. After controlling for demographics, other potential confounders, and diabetes status at Year 4 (n = 477 diabetics), we found that vitamin D insufficiency was associated with an increased likelihood of having abnormal A1c (odds ratio = 1.56; 95% CI: 1.03-2.37). We also found that this relationship persisted among the 1,765 participants without diabetes in Year 2 (odds ratio = 2.33; 95% CI: 1.00-5.40). Findings did not differ by race. CONCLUSIONS: Vitamin D insufficiency was associated with abnormal A1c levels among black and white older persons independent of diabetes status. Future studies are needed to establish the temporal relationship between vitamin D and A1c in diverse samples of older persons.

C-reactive protein, vitamin D deficiency, and slow gait speed.

OBJECTIVES: To evaluate the independent and joint effects of C-reactive protein (CRP) and 25-OH vitamin D (25(OH)D) levels on mobility disability in older persons. DESIGN: U.S. population-based cross-sectional study. SETTING: National Health and Nutrition Examination Surveys (2001-2002). PARTICIPANTS: Individuals aged 50 and older (N = 1,826). MEASUREMENTS: C-reactive protein (mg/dL), with high CRP defined as ≥ 0.2 mg/dL, and 25(OH)D levels (ng/mL) operationalized as severe deficiency (<10 ng/mL), deficiency (10-19.9 ng/mL), insufficiency (20-29.9 ng/mL), and normal (≥ 30 ng/mL). Mobility disability was operationalized as gait speed of <0.8 m/s while completing a 20-foot walk (6.1 m). RESULTS: High CRP and low 25(OH)D levels were associated with slow gait speed. Individuals with high CRP levels and severe vitamin D deficiency were more likely to have slow gait speed than were those with neither risk factor (odds ratio = 3.54, 95% confidence interval = 1.42-8.84, P = .007). A significant positive association between vitamin D level and gait speed was found only in those with high CRP in stratified analyses. Whites and blacks showed similar findings as the overall population. CONCLUSION: These findings provide evidence of a potential joint effect of vitamin D and CRP on gait speed, suggesting that evaluation and correction of vitamin D levels may be especially important in individuals with high CRP levels.

Vitamin C and A1c relationship in the National Health and Nutrition Examination Survey (NHANES) 2003-2006.

OBJECTIVE: The scope of the diabetes epidemic stresses the critical need for primary prevention. The consumption of foods high in vitamin C has been associated with lower risk of diabetes. The aim of this study was to analyze the relation between vitamin C concentration and glycemic control index in a large sample of U.S. adults without a history of diabetes. METHODS: We analyzed data collected from 7697 adult participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2006 who did not report a history of diabetes. Multivariate linear regression analyzed the association of vitamin C and hemoglobin A1c (A1c) levels after accounting for potential confounders. We also conducted stratified analyses based on race/ethnicity, gender, age group, body mass index, and vitamin D status. RESULTS: Vitamin C concentrations were inversely associated with A1c (p = 0.0202). Stronger inverse associations were observed in subjects 18-44 years of age (p = 0.0017), as well as in female (p = 0.0035) and Mexican American (p = 0.0149) subgroups. Evidence of a significant interaction between vitamin C and vitamin D was noted in subjects aged 18-44 years and in females (p = 0.0073 and 0.0095 respectively), with the inverse association tending to be evident at lower levels of vitamin D. CONCLUSIONS: Vitamin C status may influence glycemic control. Investigators should be cognizant of the interaction of vitamins C and D and should take this into consideration in planning future studies.

Screening for vitamin D deficiency in the elderly.

The importance of vitamin D to normal physiologic function is well established. With deficiency becoming increasingly frequent, the potential for preventing and treating diseases through vitamin D supplementation is gaining in appreciation. Deficiency is particularly common in the geriatric population based on both behavioral and biologic factors, and has been associated with increased risk of musculoskeletal, neuropsychiatric, cardiovascular, endocrine and oncologic disease. Although some experts recommend empiric supplementation for all elderly persons, a strategy of routine screening and documented adequacy of replacement in deficient patients appears superior.

Association of A1C levels with vitamin D status in U.S. adults: data from the National Health and Nutrition Examination Survey.

OBJECTIVE: Data relating vitamin D status with indices of glucose homeostasis as manifested by A1C in the U.S. adult population are few. RESEARCH DESIGN AND METHODS: We examined the association between serum 25 hydroxyvitamin D [25(OH)D] and A1C levels in 9,773 adults (age >or=18 years old) participating in the 2003-2006 National Health and Nutrition Examination Survey. Multivariate linear regression analyzed the association after accounting for potential confounders. RESULTS Serum 25(OH)D levels were inversely associated with A1C levels in subjects age 35-74 years (P = 0.0045) and those who did not report a history of diabetes (P = 0.0282). CONCLUSIONS: These findings support a mechanistic link between serum vitamin D concentrations, glucose homeostasis, and the evolution of diabetes in a large segment of the U.S. adult population. Screening people with elevated A1C levels for vitamin D insufficiency should be considered.

The ratio of oleic-to-stearic acid in the prostate predicts biochemical failure after radical prostatectomy for localized prostate cancer.

PURPOSE: To identify lifestyle related factors that may influence the prognosis of clinically localized prostate cancer we evaluated the relative impact of obesity and prostatic fatty acid concentrations at diagnosis on the risk of biochemical failure following radical prostatectomy. MATERIALS AND METHODS: Height and weight were measured in 195 men scheduled for radical prostatectomy for clinically localized prostate cancer. Fatty acids were measured in nonmalignant prostate tissue collected at surgery. Biochemical failure was defined as detectable serum prostate specific antigen (0.1 ng/ml or greater). Cox proportional hazards models and logistic regression, respectively, were used to analyze the association of obesity (body mass index 30 kg/m2 or greater) and prostatic fatty acid concentrations with time to biochemical failure and the relative odds of biochemical failure at different time points after accounting for prostate specific antigen at diagnosis, surgical margin status, pathological stage, Gleason sum, patient age, race/ethnicity and other factors. RESULTS: During an average followup of 56 months the oleic-to-stearic acid ratio predicted the risk of biochemical failure (multivariate HR 1.50, 95% CI 1.17-1.91, p = 0.001 per 1 standard deviation increase). Obesity did not correlate with biochemical failure during the entire study period. However, obesity tended to be associated with biochemical failure within the first 2 years (multivariate OR 2.55, 95% CI 0.84-7.77, p = 0.10). CONCLUSIONS: The oleic-to-stearic acid ratio in the prostate predicts the risk of biochemical failure following radical prostatectomy for clinically localized prostate cancer. This observation and the tendency of obesity to be associated with biochemical failure during the first 2 years in our cohort suggest that lifestyle related factors influence the prognosis of clinically early stage prostate cancer.