Search

PURPOSE: To examine whether long-term fish oil (FO) supplementation is associated with a lower risk of mobility disability and enhances benefits of physical activity. METHODS: 1635 sedentary adults aged 70 to 89 years from the Lifestyle Interventions and Independence for Elders (LIFE) single-blinded randomized, multi-center clinical trial, which compared a structured physical activity (PA) program to a health education (HE) program. Primary outcome was incident major mobility disability (MMD), defined by loss of ability to walk 400m, measured every 6 months for an average of 2.6 years. Secondary outcomes included persistent mobility disability (PMD), Short Physical Performance Battery (SPPB), 400m walk speed, and grip strength. RESULTS: A third of participants reported using FO at baseline (456, 28%; mean age, 78.5 years; 70.5% women). MMD was experienced by 131 participants (28.7%) in the FO group and 405 (34.4%) participants in the nonuser group. After adjusting for confounders, FO supplementation was associated with a lower risk (hazard ratio [HR], 0.78; 95% CI, 0.64–0.96) of incident MMD. However, there was no interaction (P= .19) between FO supplementation and PA intervention for MMD. For the secondary outcome of PMD, the intervention association differed by supplementation (P= .002) with PA intervention associations of (HR, 1.36; 95% CI, 0.83–2.23) for users and (HR, 0.61; 95% CI, 0.46–0.81) for nonusers. Changes in physical performance outcomes were not modified by baseline FO supplementation or combination with PA. CONCLUSIONS: FO supplementation was associated with a lower risk of major mobility disability in low to moderate functioning older adults. However, supplementation did not enhance the benefit of physical activity on risk of mobility disability. These results are hypothesis generating and need to be confirmed in randomized trials. more...

Significant progress in defining the biology of aging, particularly in animal models, supports the geroscience hypothesis, which posits that by therapeutically targeting biological aging, the onset of multiple age-related diseases can be delayed "en suite". Geroscience investigators are preparing to test this hypothesis in humans for the first time. In this review, we describe development of large-scale clinical trials designed to determine if multiple age-related health conditions can be simultaneously alleviated with interventions targeting the underlying biology of aging. We describe the rationale and collaborative, consensus building approach used to design the first aging outcomes trial called Targeting Aging with Metformin (TAME). Through this case study, we outline features that could be more broadly extended to other geroscience-guided clinical trials, including a process for selecting biochemical and molecular markers of biologic age and we provide a perspective on the potential impact of clinical trials targeting aging. more...

Supplemental Digital Content is available in the text., Background: Physical capability, a key component of healthy aging, is associated with cardiovascular and other risk factors across life. We investigated whether midlife biomarkers of heart and kidney damage capturing the cumulative impact of long-term adverse exposures were associated with the level and decline in physical capability over 9 years of follow-up, taking account of systemic inflammatory biomarkers and conventional cardiovascular risk factors. Methods: We used data on 1736 men and women from the oldest British birth cohort study with walking speed, chair rise speed, balance time, and grip strength assessed at ages 60 to 64 and 69 years. We tested associations between logged and standardized measures of cystatin C, NT-proBNP (N-terminal pro-B-type natriuretic peptide), interleukin (IL)-6, and E-selectin at age 60 to 64 years with performance at age 69 years, adjusting for sex, height, and body mass index; then for performance at age 60 to 64 years. These biomarkers were mutually adjusted, and additionally adjusted for cardiovascular risk factors (pulse pressure, total/high density lipoprotein cholesterol, glycosylated hemoglobin), diabetes mellitus, cardiovascular and kidney disease, smoking status, and lifetime socioeconomic position. Results: Cystatin C, NT-proBNP, and IL-6 (but not E-selectin) were inversely associated with all outcomes, adjusted for sex, height, and body mass index. For example, a 1-SD increase in logged NT-proBNP was associated with weaker grip (−0.63 kg, 95% CI, −0.99 to −0.28); the equivalent association for cystatin C was −0.60 kg (95% CI, −0.94 to −0.25) and for IL-6 was −0.76 kg (95% CI, −1.11 to −0.41). Most associations remained, albeit attenuated, after adjustment for previous performance and mutual adjustment of the biomarkers. NT-proBNP and IL-6 (but not cystatin C) were more strongly associated with the outcomes than many of the conventional risk factors after mutual adjustment. Conclusions: Higher levels of NT-proBNP may identify those in midlife at risk of accelerated physical decline. Before considering the use of NT-proBNP for risk stratification, further research should untangle whether these associations exist because the biomarker is an integrated measure of cumulative exposures to relevant stressors across life, or whether it is marking additional risk pathways. Randomized trials to reduce the rate of decline in physical capability or delay incident disability could benefit from including middle-aged adults and adding NT-proBNP and IL-6 as intermediate outcomes. more...

OBJECTIVE: To characterize change in physical performance and differential prevalence of low skeletal muscle mass and strength (sarcopenia) and lower 25-hydroxyvitamin D concentrations among older women when they develop urinary incontinence (UI) symptoms. METHODS: This is a secondary analysis of the Health, Aging, and Body Composition Study. Urinary incontinence symptoms were assessed using validated questions. The Short Physical Performance Battery (SPPB) measured physical performance. Sarcopenia, defined by low muscle mass and strength, was determined using validated cut-offs for gait speed, grip strength, and appendicular skeletal muscle mass. All parameters were evaluated at baseline and year 4. Serum 25-hydroxyvitamin D concentrations were assessed at year 2. The primary outcome was the change in SPPB total scores. Sarcopenia and lower serum 25-hydroxyvitamin D concentrations have been independently associated with poor physical performance and UI, therefore included as secondary outcomes. Univariate and multivariate analyses were used to characterize the associations of change in physical performance from baseline to year 4, incidence of sarcopenia, and lower serum 25-hydroxyvitamin D on the development of UI symptoms. RESULTS: Of the 1,583 women enrolled, 910 were excluded (730 had baseline UI; 180 with missing data). Six hundred seventy-three women were continent at baseline; 223 (33%) developed UI symptoms at year 4. Short Physical Performance Battery total scores had a significant decline in among women with incident UI compared to continent women [mean difference [95% CI] continent – incident UI 0.32 [0.04, 0.60], p=0.02. Of subscale measures, standing balance showed the greatest decline at 0.20 [0.05, 0.36], continent - incident UI respectively; p=0.009]. Sarcopenia developed at a higher rate with incident UI (adjusted OR 95% CI: 1.7 [1.0, 2.9]). Low 25-hydroxyvitamin D was not associated with incident UI. [adjusted OR (95% CI) 1.1 (0.7–1.6) and 1.1 (0.7–1.6) for deficient or insufficient compared with sufficient status, respectively]. CONCLUSIONS: We observed a significant decline in standing balance among older women who developed UI symptoms. This decline may be associated with coinciding development of sarcopenia. more...

CKD appears to be a condition of soluble klotho deficiency. Despite known associations between low soluble klotho levels and conditions that promote kidney damage, such as oxidative stress and fibrosis, little information exists regarding the longitudinal association between soluble klotho levels and change in kidney function. We assayed serum soluble α-klotho in 2496 participants within the Health Aging and Body Composition study, a cohort of older adults. The associations between soluble klotho levels and decline in kidney function (relative decline: eGFR decline ≥30%; absolute decline: eGFR decline >3 ml/min per year) and incident CKD (incident eGFR 1 ml/min per year decline) were evaluated. We adjusted models for demographics, baseline eGFR, urine albumin-to-creatinine ratio, comorbidity, and measures of mineral metabolism. Among participants, the mean (SD) age was 75 (3) years, 52% were women, and 38% were black. Median (25th, 75th percentiles) klotho level was 630 (477, 817) pg/ml. In fully adjusted models, each two-fold higher level of klotho associated with lower odds of decline in kidney function (odds ratio, 0.78 [95% confidence interval, 0.66 to 0.93] for 30% decline in eGFR, and 0.85 [95% confidence interval, 0.73 to 0.98] for >3 ml/min per year decline in eGFR), but not of incident CKD (incident rate ratio, 0.90 [95% confidence interval, 0.78 to 1.04]). Overall, a higher soluble klotho level independently associated with a lower risk of decline in kidney function. Future studies should attempt to replicate these results in other cohorts and evaluate the underlying mechanism. more...

BackgroundSpecific geriatric assessment tools may complement traditional perioperative risk stratification. The aim of this study was to evaluate whether self-reported mobility is predictive of postoperative outcomes in older patients undergoing elective noncardiac surgery.MethodsPatients aged 69 yr or older (n = 197) underwent (1) traditional risk assessments (American Society of Anesthesiologists physical status classification and Revised Cardiac Risk Index), (2) five-point frailty evaluation, (3) self-reported mobility assessment using the Mobility Assessment Tool–short form (range, 30.21 [poor] to 69.76 [excellent]), and (4) measurements of high-sensitivity C-reactive protein. Outcomes were postoperative complications, time to discharge, and nursing home placement (NHP).ResultsIn the sample of this study (mean age, 75 ± 5 yr; 51% women), 72% had intermediate- or high-risk surgery. Median time to discharge was 3 days (interquartile range, 1 to 4 days). Thirty patients (15%) developed postoperative complications, and 27 (13%) required NHP. After controlling for age, sex, body mass index, pain score, Revised Cardiac Risk Index, American Society of Anesthesiologist physical status, surgical risk, and high-sensitivity C-reactive protein, worse self-reported mobility (per 10-point decrease in Mobility Assessment Tool, which is equivalent to 1 SD) was associated with more postoperative complications (odds ratio [OR], 1.69; 95% CI, 1.05 to 2.73), later time to discharge (hazards ratio, 0.81; 95% CI, 0.68 to 0.96), and increased NHP (OR, 2.01; 95% CI, 1.13 to 3.56). By using the same model, intermediate frailty or frailty increased NHP (OR, 3.11; 95% CI, 1.02 to 9.54) but was not related to either postoperative complications or time to discharge.ConclusionsPreoperative self-reported mobility using a novel and brief assessment may help identify elderly patients at risk for adverse postoperative events. more...

Background and objectives CKD is associated with mortality. Accurate prediction tools for mortality may guide clinical decision-making, particularly among elderly persons with CKD. Design, setting, participants, & measurements A prediction equation was developed for 5-year risk of mortality among participants with CKD in the Cardiovascular Health Study. Sixteen candidate predictor variables were explored, which included demographics, physical examination measures, comorbidity, medication use, and kidney function measures (eGFR calculated from serum creatinine and the CKD Epidemiology Collaboration equation and the urine albumin-to-creatinine ratio). Models were developed using Cox regression and evaluated using c statistics. A final parsimonious model was externally validated in an independent cohort of community-living elders with CKD in the Health, Aging, and Body Composition Study. Results The development cohort included 828 participants who had a mean age of 80 (±5.6) years and an eGFR of 47 (±11) ml/min per 1.73 m2, and median albumin-to-creatinine ratio of 13 (interquartile range 6–51) mg/g. The validation cohort included 789 participants who had a mean age of 74 (±2.8) years and an eGFR of 50 (±9) ml/min per 1.73 m2, and median albumin-to-creatinine ratio of 13 (interquartile range 6–42) mg/g. The final model for 5-year mortality risk included age, sex, race, eGFR, urine albumin-to-creatinine ratio, smoking, diabetes mellitus, and history of heart failure and stroke (c statistic=0.72; 95% confidence interval, 0.68 to 0.74). When a point-based system was assigned for each of nine variables in the equation, the estimated risk of death within 5 years ranged from 3.8% among participants with the lowest scores to 83.6% among participants with nine points. The model performed fair in external validation (c statistic=0.69; 95% confidence interval, 0.64 to 0.74). Conclusions A simple prediction tool using nine readily available clinical variables can assist in predicting 5-year mortality risk in elderly patients with CKD, which may be useful in counseling patients and guiding clinical decision making. more...

ObjectiveThe objective of this study was to evaluate whether increased serum 25-hydroxyvitamin D3 (25OHD3) concentrations, in response to calcium/vitamin D (CaD) supplementation, are associated with improved lipids in postmenopausal women.MethodsThe parent trial was a double-blind, randomize more...

Background— The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model. Methods and Results— Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the 20% 5-year risk categories, respectively. The Hosmer-Lemeshow χ 2 was 14.72 (degrees of freedom, 10; P =0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results. Conclusions— The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts. more...

Objective— Resistin is associated with inflammation and insulin resistance and exerts direct effects on myocardial cells including hypertrophy and altered contraction. We investigated the association of serum resistin concentrations with risk for incident heart failure (HF) in humans. Methods and Results— We studied 2902 older persons without prevalent HF (age, 73.6±2.9 years; 48.1% men; 58.8% white) enrolled in the Health, Aging, and Body Composition (Health ABC) Study. Correlation between baseline serum resistin concentrations (20.3±10.0 ng/mL) and clinical variables, biochemistry panel, markers of inflammation and insulin resistance, adipocytokines, and measures of adiposity was weak (all rho P =0.003). Results were comparable across sex, race, diabetes mellitus, and prevalent and incident coronary heart disease subgroups. In participants with available left ventricular ejection fraction at HF diagnosis (265 of 341; 77.7%), association of resistin with HF risk was comparable for cases with reduced versus preserved ejection fraction. Conclusions— Serum resistin concentrations are independently associated with risk for incident HF in older persons. more...

The objective of this study is to determine the optimal timing for surgical antimicrobial prophylaxis (AMP).National AMP guidelines should be supported by evidence from large contemporary data sets.Twenty-nine hospitals prospectively obtained information on AMP from 4472 randomly selected cardiac, hip/knee arthroplasty, and hysterectomy cases. Surgical site infections (SSIs) were ascertained through routine surveillance, using National Nosocomial Infections Surveillance system methodology. The association between the prophylaxis timing and the occurrence of SSI was assessed using conditional logistic regression (conditioning on hospital).One-hundred thirteen SSI were detected in 109 patients. SSI risk increased incrementally as the interval of time between antibiotic infusion and the incision increased (overall association between timing and infection risk P = 0.04). When antibiotics requiring long infusion times (vancomycin and fluoroquinolones) were excluded, the infection risk following administration of antibiotic within 30 minutes prior to incision was 1.6% compared with 2.4% associated with administration of antibiotic between 31 to 60 minutes prior to surgery (OR: 1.74; 95% confidence interval, 0.98-3.04). The infection risk increased as the time interval between preoperative antibiotic and incision increased or if the antibiotic was first infused after incision. Intraoperative redosing (performed in only 21% of long operations) appeared to reduce SSI risk in operations lasting more than 4 hours (OR of 3.08 with no redosing; 95% confidence interval 0.74-12.90), but only when the preoperative dose was given correctly.These data from a large multicenter collaborative study confirm and extend previous observations and show a consistent relationship between the timing of AMP and SSI risk with a trend toward lower risk occurring when AMP with cephalosporins and other antibiotics with short infusion times were given within 30 minutes prior to incision. more...

Arterial stiffness is a prominent feature of vascular aging and is strongly related to cardiovascular disease. Oxidized low-density lipoprotein (ox-LDL), a key player in the pathogenesis of atherosclerosis, may also play a role in arterial stiffening, but this relationship has not been well studied. Thus, we examined the cross-sectional association between ox-LDL and aortic pulse wave velocity (aPWV), a marker of arterial stiffness, in community-dwelling older adults. Plasma ox-LDL levels and aPWV were measured in 2295 participants (mean age: 74 years; 52% female; 40% black) from the Health, Aging, and Body Composition Study. Mean aPWV significantly increased across tertiles of ox-LDL (tertile 1: 869±376 cm/s; tertile 2: 901±394 cm/s; tertile 3: 938±415 cm/s; P =0.002). In multivariate analyses, ox-LDL remained associated with aPWV after adjustment for demographics and traditional cardiovascular disease risk factors ( P =0.008). After further adjustment for hemoglobin A1c, abdominal visceral fat, antihypertensive and antilipemic medications, and C-reactive protein, the association with ox-LDL was attenuated but remained significant ( P =0.01). Results were similar when ox-LDL was expressed in absolute (milligrams per deciliter) or relative amounts (percentage of low-density lipoprotein). Moreover, individuals in the highest ox-LDL tertile were 30% to 55% more likely to have high arterial stiffness, defined as aPWV >75th percentile ( P ≤0.02). In conclusion, we found that, among elderly persons, elevated plasma ox-LDL levels were associated with higher arterial stiffness, independent of cardiovascular disease risk factors. These data suggest that ox-LDL may be related to the pathogenesis of arterial stiffness. more...

Background and objectives: Although physical function is a major determinant of health outcomes and quality of life in older adults, standard tools for its assessment have not been routinely applied to the fastest growing segment of the kidney transplant candidate population, which is at high risk of comorbidity and disability—people over age 60. The objective of this study was to describe the baseline physical function in older adults with renal failure referred for transplantation and compare them with older adults with other significant comorbidity. Design, setting, participants, & measurements: An observational sample comparing physical performance in renal transplant candidates over age 60 (Renal Failure) to older people with diastolic heart failure (Heart Failure), chronic obstructive pulmonary disease (COPD), or at high risk for cardiovascular disease (High CV Risk) was studied. Results: Older people with Renal Failure were significantly impaired by objective measures of physical function, including lower Short Physical Performance Battery, slower gait speed, and lower grip strength. Conclusions: Older people referred for renal transplantation had poorer physical performance than older adults with other common chronic diseases and may be at high risk for disability while awaiting transplantation. more...

Higher forebrain myoinositol (mIns), a marker of glial inflammation/proliferation as detected by proton magnetic resonance spectroscopy (MRS), correlates with systemic inflammation. Elevated circulating markers of inflammation are associated with lower baroreceptor reflex sensitivity (BRS) and heart rate variability (HRV) as well as visceral fat or central obesity. To determine whether transmitters/metabolites in a cardiovascularly (CV) relevant brain region correlate with age-related declines in BRS and HRV and markers of abdominal fat, autonomic profiles were determined by spectral and sequence analysis from continuous blood pressure and HR values in the supine position of healthy subjects 22 - 76 yrs old (12F, 4M); subjects later underwent a single voxel (10 x 7 x 20mm) proton MRS scan of dorsal medulla on a 3T magnet (n = 11; 9F, 2M) and measures of abdominal fat by computerized tomography (CT) (n = 9; 7F,2M). The mean arterial pressure was 88 ± 3 mm Hg, HR 64 ± 3 beats/min and BMI 27 ± 1 kg/m 2 . Glutamate (Glu) correlated directly with vagal (HF RRI r = 0.72, p < 0.02) and inversely with sympathetic (LF RRI r = -0.72, p < 0.02) control of HR. Markers of Glu metabolism and neuronal integrity/activity, N-acetyl-aspartate acid (NAA) + N-acetyl aspartyl glutamate (NAAG), did not correlate with age, but did correlate inversely with BRS (Seq ALL: r = -0.69, P < 0.02), HRV (rMSSD: r = -0.76, p < 0.008) and directly with HR (r = 0.68, p < 0.03). Total visceral fat had a negative correlation with BRS (Seq Up: r = -0.70, p < 0.02). mIns and markers of demyelination and reduced axonal integrity such as Glycerophosphocholine (GPC) and total choline containing compounds (GPC+PCh) exhibited striking positive correlations with percent visceral fat (r = 0.97, 0.81 and 0.82, P < 0.02). BMI and GPC correlated with HR (r = 0.55, 0.72, p < 0.04), but neither these nor mIns or choline compounds correlated with autonomic function. Thus, in healthy adults, Glu concentration in dorsal medulla directly correlates with cardiac vagal function, whereas markers of Glu metabolism inversely correlate with BRS and HRV. In contrast, markers of glial inflammation directly associate with increases in visceral adiposity, but not autonomic dysfunction. P30-AG21332, Farley Hudson, Hypertension & Vasc Res Ctr more...

Kidney dysfunction is known to decrease life expectancy in the elderly. Cystatin C is a novel biomarker of kidney function that may have prognostic utility in older adults. The association of cystatin C with mortality was evaluated in a biracial cohort of black and white ambulatory elderly and compared with that of serum creatinine concentrations. The Health, Aging and Body Composition study is a cohort of well-functioning elderly that was designed to evaluate longitudinal changes in weight, body composition, and function. A total of 3075 participants who were aged 70 to 79 yr and had no disability were recruited at sites in Memphis, TN, and Pittsburgh, PA, between April 1997 and June 1998 with a follow-up of 6 yr. At entry, the mean cystatin C was 1.05 mg/L and the mean creatinine was 1.06 mg/dl. After 6 yr of follow-up, 557 participants had died. The mortality rates in each ascending cystatin C quintile were 1.7, 2.7, 2.9, 3.1, and 5.4%/yr. After adjustment for demographic risk factors, comorbid health conditions, and inflammatory biomarkers (C-reactive protein, IL-6. and TNF-alpha), each quintile of cystatin C was significantly associated with increased mortality risk compared with the lowest: Hazard ratios (HR; 95% confidence intervals) quintile 1, -1.0 (referent); quintile 2, -1.74 (1.21 to 2.50); quintile 3, -1.51 (1.05 to 2.18); quintile 4, -1.49 (1.04 to 2.13); and quintile 5, -2.18 (1.53 to 3.10). These associations did not differ by gender or race. Results were consistent for cardiovascular and other-cause mortality, but not cancer mortality. Creatinine quintiles were not associated with mortality after multivariate adjustment (HR: 1.0 [referent], 1.00 [0.72 to 1.39], 0.95 [0.68 to 1.32], 1.11 [0.79 to 1.57], 1.16 [0.86 to 1.58]). Cystatin C is a strong, independent risk factor for mortality in the elderly. Future studies should investigate whether cystatin C has a role in clinical medicine. more...

Background— Aging results in vascular stiffening and an increase in the velocity of the pressure wave as it travels down the aorta. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. The objective of this investigation was to determine whether aPWV is associated with total and cardiovascular (CV) mortality and CV events in a community-dwelling sample of older adults. Methods and Results— aPWV was measured at baseline in 2488 participants from the Health, Aging and Body Composition (Health ABC) study. Vital status, cause of death and coronary heart disease (CHD), stroke, and congestive heart failure were determined from medical records. Over 4.6 years, 265 deaths occurred, 111 as a result of cardiovascular causes. There were 341 CHD events, 94 stroke events, and 181 cases of congestive heart failure. Results are presented by quartiles because of a threshold effect between the first and second aPWV quartiles. Higher aPWV was associated with both total mortality (relative risk, 1.5, 1.6, and 1.7 for aPWV quartiles 2, 3, and 4 versus 1; P =0.019) and cardiovascular mortality (relative risk, 2.1, 3.0, and 2.3 for quartiles 2, 3, and 4 versus 1; P =0.004). aPWV quartile was also significantly associated with CHD ( P =0.007) and stroke ( P =0.001). These associations remained after adjustment for age, gender, race, systolic blood pressure, known CV disease, and other variables related to events. Conclusions— Among generally healthy, community-dwelling older adults, aPWV, a marker of arterial stiffness, is associated with higher CV mortality, CHD, and stroke. more...

Background— Increased levels of acute-phase reactants predict the onset of poor health outcomes. A U-shaped association has been reported between alcohol intake and health outcomes, which suggests that alcohol intake may modify levels of acute-phase reactants. We investigated the relationship between weekly alcohol intake and interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1). Methods and Results— Data are from year 1 of the Health, Aging, and Body Composition study, a biracial cohort of 3075 well-functioning men and women aged 70 to 79 years, living in Memphis, Tenn, and Pittsburgh, Pa. The analysis included 2574 persons (51.2% women; 40.1% black) with complete data. After adjustment for age, race, smoking status, history of diabetes, history of cardiovascular disease, physical activity, high-density lipoprotein cholesterol, antiinflammatory medications, statins, and total fat mass, alcohol intake showed a J-shaped relationship with mean IL-6 ( P for quadratic term P =0.014) levels. The association was consistent in both men and women. Compared with subjects who consumed 1 to 7 drinks per week, those who never drank had an increased likelihood of having high levels of both IL-6 and CRP, as did those who drank 8 or more drinks per week. We found no relationship between alcohol intake and levels of TNF-α and PAI-1 ( P =0.137 and 0.08, respectively). Conclusions— In well-functioning older persons, light alcohol consumption is associated with lower levels of IL-6 and CRP. These results might suggest an additional biological explanation to the epidemiological link between moderate alcohol consumption and cardiovascular events. more...

Objective— Although circulating oxidized LDL (oxLDL) is elevated in persons with coronary heart disease (CHD), whether oxLDL is elevated in persons with high CHD risk before any events is unknown. Therefore, we studied the association between high, predicted CHD risk and oxLDL in the Health ABC cohort. Methods and Results— This cohort included 385 persons with CHD and 1183 persons at high risk; the latter were all persons with CHD risk equivalents: noncoronary forms of clinical atherosclerotic disease, diabetes, and a 10-year risk for CHD >20% by Framingham scoring. The remaining 1535 participants were at low risk. Levels of oxLDL were 1.18±0.61 mg/dL for low-risk persons, 1.50±0.81 mg/dL for high-risk persons without diagnosed CHD, and 1.32±0.83 mg/dL for persons with CHD ( P P Conclusion— The odds ratio for elevated oxLDL among persons with high CHD risk before any CHD events was higher than that among persons with established CHD. A likely explanation is that once CHD is diagnosed, individuals are frequently treated with a statin, which is associated with lowering of LDL cholesterol and oxLDL levels. more...

Summary Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z -score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10 −109 for rs2282679, in GC ); 11q12 (p=2·1×10 −27 for rs12785878, near DHCR7 ); and 11p15 (p=3·3×10 −20 for rs10741657, near CYP2R1 ). Variants at an additional locus (20q13, CYP24A1 ) were genome-wide significant in the pooled sample (p=6·0×10 −10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10 −48 ) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10 −26 ) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Funding Full funding sources listed at end of paper (see Acknowledgments). more...

Background: There is little clinical trial evidence that sustained physical activity can prevent cardiovascular disease (CVD) in older adults. The LIFE Study was a multi-center randomized trial comparing sustained, structured physical activity (PA) to health education/successful aging (SA) to prevent mobility disability in older sedentary men and women. Cardiovascular morbidity and mortality was a secondary endpoint. Methods: Eligible participants (N=1635, 67% women, aged 70-89 years) were randomized to PA vs. SA. Eligibility criteria included being sedentary with a score Results: Incident CVD occurred in 14.4% (n=118/818) of PA and 13.8% (113/817) of SA participants (HR=1.07, 95%CI=0.82-1.38. Using a narrower endpoint of MI, stroke or cardiovascular death, rates were 8.9% in PA and 8.7% in PA groups respectively with HR = 1.04 (95% CI=0.75-1.45). There were no significant differences in rates of incident vs. recurrent CVD. Among participants with SPPB Conclusions: Among participants in the LIFE Study, an aerobically-based, moderately intensive PA program did not reduce cardiovascular events overall. However, the intervention was more protective in lower functioning participants. Hypotheses to explain differences by functional status could be addressed with continued follow-up. more...

Background: We have shown previously that aging-induced cardiac dysfunction and β-adrenergic desensitization were prevented in β 3 -adrenergic receptor (AR) knockout (β 3 KO) aged mice. However, the molecular mechanism is unclear. We hypothesize that reversal of aging-induced alterations of cardiomyocyte SR Ca 2+ -ATPase (SERCA 2a) and inducible nitric oxide (NO) synthase by β 3 -AR deficiency may play a key role for the protective effect. Methods: We compared SERCA 2a, iNOS, β 1 - and β 3 -AR protein expression, myocyte contractile, and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to isoproterenol (ISO, 10 -8 M) in cardiomyocytes obtained from 2 young (Y) (~6 mo) and 2 aged (A) (~26-30 mo) groups (5/group) of wild-type (WT) and β 3 KO mice, respectively. Results: Compared with YWT, AWT myocytes had significantly decreased protein levels of SERCA 2a (AWT: 0.22 vs YWT: 0.61) and β 1 -AR (0.34 vs 0.56), but increased iNOS (0.49 vs 0.24) and β 3 -AR (0.29 vs 0.14). These changes were associated with reduced basal cell contraction (dL/dt max ) (84.3 vs 124.8 μm/s), relaxation (dR/dt max ) (-66.1 vs -98.8 μm/s), and [Ca 2+ ] iT (0.19 vs 0.23). This was accompanied by diminished ISO-stimulated inotropic response. In AWT myocytes, ISO caused significantly less increases in dL/dt max (34% vs 82%), dR/dt max (22% vs 60%), and [Ca 2+ ] iT (15% vs 35%). Compared with YWT, Yβ 3 KO did not alter basal myocyte contraction and relaxation and response to ISO stimulation, but had significantly increased protein levels of SERCA 2a (Yβ 3 KO: 1.3 vs YWT: 0.61) and reduced iNOS (0.17 vs 0.24) with relatively unchanged β 1 -AR (0.63 vs 0.60). Aβ 3 KO mice had similar alterations. Importantly, in contrast to AWT, in Aβ 3 KO myocytes, the increased SERCA 2a (1.1) and reduced iNOS (0.19) correlated with normal basal cell contraction and relaxation with preserved ISO-stimulated inotropic response. ISO caused similar increases in dL/dt max (82% vs 84%) and [Ca 2+ ] iT (31% vs 33%) compared to Yβ 3 KO mice. Conclusions: β 3 -AR deficiency prevents aging-caused downregulation of cardiac β 1 -ARs and reverses increased iNOS and decreased SERCA 2a, leading to the preservation of myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve in aged hearts. Thus, blocking β 3 -AR may provide a new strategy for myocardial aging. more...

Background Evidence that dietary antioxidants may prevent atherosclerotic disease is growing. The relationship between the intake of dietary and supplemental vitamin C, α-tocopherol, and provitamin A carotenoids and average carotid artery wall thickness was studied in 6318 female and 4989 male participants 45 to 64 years old in the Atherosclerosis Risk in Communities Study. Methods and Results Intake was assessed by use of a 66-item semiquantitative food-frequency questionnaire. Carotid artery intima-media wall thickness was measured as an indicator of atherosclerosis at multiple sites with B-mode ultrasound. Among men and women >55 years old who had not recently begun a special diet, there was a significant inverse relationship between vitamin C intake and average artery wall thickness adjusted for age, body mass index, fasting serum glucose, systolic and diastolic blood pressures, HDL and LDL cholesterol, total caloric intake, cigarette use, race, and education (test for linear trend across quintiles of intake, P =.019 for women and P =.035 for men). An inverse relationship was also seen between wall thickness and α-tocopherol intake but was significant only in women (test for linear trend, P =.033 for women and P =.13 for men). There was a significant inverse association between carotene intake and wall thickness in older men (test for linear trend, P =.015), but the association weakened after adjustment for potential confounders. No significant relationships were seen in participants Conclusions These data provide limited support for the hypothesis that dietary vitamin C and α-tocopherol may protect against atherosclerotic disease, especially in individuals >55 years old. more...

Background: Excess fat around the heart and aorta may be novel risk factors for heart failure, independent of total adiposity. However, the mechanisms underlying this association are unknown. Purpose: To measure epicardial fat (EAT, within the pericardium), paracardial fat (PAT, outside the pericardium), and periaortic fat around the ascending and descending aorta in older adults to test the hypothesis that visceral adiposity is positively associated with arterial stiffness. Methods: Fat volumes were measured by MRI in 40 high-risk adults (age: 69±9 yrs, 50% female) with hypertension (96%), diabetes (35%), or coronary artery disease (35%) and 20 age- and gender-matched controls. High-risk adults were further characterized as very stiff or moderately stiff based on pulse wave velocity values above or below the median (850 cm/s). EAT and PAT were measured from the base to the apex of the heart. Periaortic fat was measured at the level of the main pulmonary artery. Results: After adjusting for BMI, both high-risk groups had greater periaortic fat compared to controls (p more...

Resistin, a novel adipocytokine, is associated with inflammation and insulin resistance; both mechanisms are known to increase risk for heart failure (HF). We studied 2904 older persons without HF (age 73.3±2.8 years, 47.9% men, 58.6% whites) enrolled in the Health ABC study who underwent serum resistin measurements at baseline. Participants were divided into groups based on tertiles of resistin concentrations and rates of incident HF (defined as hospitalization for new onset HF) were compared by Cox proportional hazards models. After 7.1 year median follow-up 252 participants (8.7%) developed HF. Increasing resistin concentrations were significantly associated with increasing incident HF rates (Figure 1 ). After adjusting for baseline differences (including body mass index) and predictors of incident HF (age, coronary disease, smoking, blood pressure, heart rate, serum glucose, creatinine, and albumin concentrations, and left ventricular hypertrophy), serum resistin concentrations were independently associated with incident HF [highest vs. lowest tertile hazard ratio (HR) 1.96, 95% confidence interval (CI) 1.35–2.82). Further adjustment for markers of inflammation (Creactive protein, interleukin-6, and tumor necrosis factor α) and of insulin resistance (fasting insulin level and hemoglobin A1c) only moderately attenuated this association which remained significant (HR 1.67, 95% CI 1.13–2.60). These findings were consistent in both sexes and among whites and blacks. High serum resistin concentrations are independently associated with increasedrisk for HF. Further studies are needed to confirm these findings. more...