Stephen B. Kritchevsky

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).

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.

To define clinically relevant cutpoints for usual gait speed and to investigate their predictive value for health-related events in older persons.Prospective cohort study.Health, Aging and Body Composition Study.Three thousand forty-seven well-functioning older persons (mean age 74.2).Usual gait speed on a 6-m course was assessed at baseline. Participants were randomly divided into two groups to identify (Sample A; n=2,031) and then validate (Sample B; n=1,016) usual gait-speed cutpoints. Rates of persistent lower extremity limitation events (mean follow-up 4.9 years) were calculated according to gait speed in Sample A. A cutpoint (defining high- (< 1 m/s) and low risk (> or = 1 m/s) groups) was identified based on persistent lower extremity limitation events. The predictive value of the identified cutpoints for major health-related events (persistent severe lower extremity limitation, death, and hospitalization) was evaluated in Sample B using Cox regression analyses.A graded response was seen between risk groups and health-related outcomes. Participants in the high-risk group had a higher risk of persistent lower extremity limitation (rate ratio (RR)=2.20, 95% confidence interval (CI)=1.76-2.74), persistent severe lower extremity limitation (RR=2.29, 95% CI=1.63-3.20), death (RR=1.64, 95% CI=1.14-2.37), and hospitalization (RR=1.48, 95% CI=1.02-2.13) than those in the low-risk group.Usual gait speed of less than 1 m/s identifies persons at high risk of health-related outcomes in well-functioning older people. Provision of a clinically meaningful cutpoint for usual gait speed may facilitate its use in clinical and research settings.

Older obese persons with decreased muscle mass or strength are at special risk for adverse outcomes. We discuss potential pathways to muscle impairment in obese individuals and the consequences that joint obesity and muscle impairment may have on health and disability. Tantamount to this discussion is whether low muscle mass or, rather, muscle weakness should be used for the definition.Excess energy intake, physical inactivity, low-grade inflammation, insulin resistance and changes in hormonal milieu may lead to the development of so-called 'sarcopenic obesity'. It was originally believed that the culprit of age-related muscle weakness was a reduction in muscle mass, but it is now clear that changes in muscle composition and quality are predominant. We propose that the risk of adverse outcomes, such as functional limitation and mortality, is better estimated by considering jointly obesity and muscle strength rather than obesity and muscle mass and the term 'sarcopenic obesity' should be revisited.Recognition of obese patients who have associated muscle problems is an essential goal for clinicians. Further research is needed to identify new target for prevention and cure of this important geriatric syndrome.

Background— Inflammation plays an important role in cardiovascular disease. The aim of this study is to investigate the predictive value of several inflammatory markers on the incidence of cardiovascular events in well-functioning older persons. Methods and Results— The subjects were 2225 participants 70 to 79 years old, without baseline cardiovascular disease, who were enrolled in the Health, Aging, and Body Composition study. Incident coronary heart disease (CHD), stroke, and congestive heart failure (CHF) events were detected during an average follow-up of 3.6 years. Blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) were assessed. After adjustment for potential confounders, IL-6 was significantly associated with all outcomes (CHD events, per IL-6 SD increase: RR, 1.27; 95% CI, 1.10 to 1.48; stroke events, per IL-6 SD increase: RR, 1.45; 95% CI, 1.12 to 1.86; CHF events, per IL-6 SD increase: RR, 1.72; 95% CI, 1.40 to 2.12). TNF-α showed significant associations with CHD (per TNF-α SD increase: RR, 1.22; 95% CI, 1.04 to 1.43) and CHF (per TNF-α SD increase: RR, 1.59; 95% CI, 1.30 to 1.95) events. CRP was significantly associated with CHF events (per CRP SD increase: RR, 1.48; 95% CI, 1.23 to 1.78). A composite summary indicator of inflammation showed a strong association with incident cardiovascular events, with an especially high risk if all 3 inflammatory markers were in the highest tertile. Conclusions— Findings suggest that inflammatory markers are independent predictors of cardiovascular events in older persons.

To compare two sarcopenia definitions and examine the relationship between them and lower extremity function and other health related factors using data from the baseline examination of the Health Aging and Body Composition (Health ABC) Study.Observational cohort study.Two U.S. communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania.Participants were aged 70 to 79 (N=2984, 52% women, 41% black).Participants were assessed using dual energy x-ray absorptiometry and were classified as sarcopenic using two different approaches to adjust lean mass for body size: appendicular lean mass divided by height-squared (aLM/ht2) and appendicular lean mass adjusted for height and body fat mass (residuals).These methods differed substantially in the classification of individuals as being sarcopenic, especially those who were more obese. The former method was highly correlated with body mass index and identified fewer overweight or obese individuals as sarcopenic. In both men and women, none of the obese group would be considered sarcopenic using the aLM/ht2 method, compared with 11.5% of men and 21.0% of women using the residuals method. In men, both classifications of sarcopenia were associated with smoking, poorer health, lower activity, and impaired lower extremity function. Fewer associations with health factors were noted in women, but the classification based on both height and fat mass was more strongly associated with lower extremity functional limitations (odds ratio (OR)=0.9, 95% confidence interval (CI)=0.7-1.2 for low kg/ht2; OR=1.9, 95% CI=1.4-2.5 for lean mass adjusted for height and fat mass).These findings suggest that fat mass should be considered in estimating prevalence of sarcopenia in women and in overweight or obese individuals.

Aerobic fitness, an important predictor of cardiovascular disease and mortality, is difficult to assess by maximal exercise testing in older adults. Extended walking tests have been examined as outcome predictors in medically ill populations but not in community-dwelling older adults.To determine whether an extended walking test predicts poor outcomes in older adults.Observational cohort study enrolling 3075 community-dwelling adults aged 70 to 79 years living in Pittsburgh, Pa, or Memphis, Tenn. Of those participating in the Health, Aging, and Body Composition Study, 1584 (52%) were women and 1281 (42%) were black. Participants enrolled from March 1997 to April 1998. Ability to complete the long-distance corridor walk and total performance time was assessed at the baseline examination.Total mortality, incident cardiovascular disease, incident mobility limitation, and mobility disability were ascertained after a mean (SD) of 4.9 (0.9) years.Among patients eligible to exercise, 351 died, 308 had episodes of incident cardiovascular disease, 1116 had occurrences of mobility limitation, and 509 had occurrences of mobility disability. Inability to complete walking 400 m tended to be associated with a higher risk of mortality and incident cardiovascular disease and, after accounting for potential confounders, was associated with incident mobility limitation (212.6 vs 79.1 events/1000 person-years; adjusted hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.58-2.18; P<.001) and mobility disability (85.2 vs 28.8 events/1000 person-years; adjusted HR, 1.95; 95% CI, 1.56-2.44; P<.001). Of those who completed 400 m, each additional minute of performance time was associated with an adjusted HR of 1.29 (95% CI, 1.12-1.48) for mortality, 1.20 (95% CI, 1.01-1.42) for incident cardiovascular disease, 1.52 (95% CI, 1.41-1.63) for mobility limitation, and 1.52 (95% CI, 1.37-1.70) for disability after adjustment for demographics, health behaviors, clinical and subclinical disease, and cardiovascular disease risk factors. Findings were consistent in both men and women and blacks and whites. Among participants who completed the test and after adjusting for potential confounders, those in the poorest quartile of functional capacity (walk time >362 seconds) had a higher risk of death than those in the best quartile (walk time <290 seconds; adjusted HR, 3.23; 95% CI, 2.11-4.94; P<.001).Older adults in the community who reported no difficulty walking had a wide range of performance on this extended walking test. Ability to do the test and performance were important prognostic factors for total mortality, cardiovascular disease, mobility limitation, and mobility disability in persons in their eighth decade.

Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

The loss of muscle mass with aging, or sarcopenia, is hypothesized to be associated with the deterioration of physical function. Our aim was to determine whether low leg muscle mass and greater fat infiltration in the muscle were associated with poor lower extremity performance (LEP).A cross-sectional study, using baseline data of the Health, Aging and Body Composition study (1997/98).Medicare beneficiaries residing in ZIP codes from the metropolitan areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee.Three thousand seventy-five well-functioning black and white men and women aged 70 to 79.Two timed tests (6-meter walk and repeated chair stands) were used to measure LEP. Muscle cross-sectional area and muscle tissue attenuation (indicative of fat infiltration) were obtained from computed tomography scans at the midthigh. Body fat was assessed using dual-energy x-ray absorptiometry.Blacks had greater muscle mass and poorer LEP than whites. Black women had greater fat infiltration into the muscle than white women. After adjustment for clinic site, age, height, and total body fat, smaller muscle area was associated with poorer LEP in all four race-gender groups. (Regression coefficients, expressed per standard deviation (+/-55 cm2) of muscle area, were 0.658 and 0.519 in white and black men and 0.547 and 0.435 in white and black women, respectively, P <.01.) In addition, reduced muscle attenuation-indicative of greater fat infiltration into the muscle-was associated with poorer LEP, independent of total body fat and muscle area. (Regression coefficients per standard deviation (= 7 Hounsfield Units) of muscle attenuation were 0.292 and 0.224 in white and black men, and 0.193 and 0.159 in white and black women, respectively, P <.05). The most important body composition components related to LEP were muscle area in men and total body fat in women. Results were similar after additional adjustment for lifestyle factors and health status. No interactions between race and muscle area (P>.7) or between race and muscle attenuation (P>.2) were observed.Smaller midthigh muscle area and greater fat infiltration in the muscle are associated with poorer LEP in well-functioning older men and women.

To compare two methods for classifying an individual as sarcopenic for predicting decline in physical function in the Health, Aging and Body Composition Study.Observational cohort study with 5 years of follow-up.Communities in Memphis, Tennessee, and Pittsburgh, Pennsylvania.Men and women aged 70 to 79 (N=2,976, 52% women, 41% black).Appendicular lean mass (aLM) was measured using dual energy x-ray absorptiometry, and participants were classified as sarcopenic first using aLM divided by height squared and then using aLM adjusted for height and body fat mass (residuals). Incidence of persistent lower extremity limitation (PLL) was measured according to self-report, and change in objective lower extremity performance (LEP) measures were observed using the Short Physical Performance Battery.There was a greater risk of incident PLL in women who were sarcopenic using the residuals sarcopenia method than in women who were not sarcopenic (hazard ratio (HR)=1.34, 95% confidence interval (CI)=1.11-1.61) but not in men. Those defined as sarcopenic using the aLM/ht(2) method had lower incident PLL than nonsarcopenic men (HR=0.76, 95% CI=0.60-0.96) and women (HR=0.75, 95% CI=0.60-0.93), but these were no longer significant with adjustment for body fat mass. Using the residuals method, there were significantly poorer LEP scores in sarcopenic men and women at baseline and Year 6 and greater 5-year decline, whereas sarcopenic men defined using the aLM/ht(2) method had lower 5-year decline. Additional adjustment for fat mass attenuated this protective effect.These findings suggest that sarcopenia defined using the residuals method, a method that considers height and fat mass together, is better for predicting disability in an individual than the aLM/ht(2) method, because it considers fat as part of the definition.

Several lines of evidence suggest that inflammatory mechanisms contribute to AD.To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders.The authors studied 3,031 African-American and white men and women (mean age 74 years) enrolled in the Health, Aging, and Body Composition Study. Serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) and plasma levels of tumor necrosis factor-alpha (TNFalpha) were measured at baseline; cognition was assessed with the Modified Mini-Mental State Examination (3MS) at baseline and at follow-up. Cognitive decline was defined as a decline of >5 points.In age-adjusted analyses, participants in the highest tertile of IL-6 or CRP performed nearly 2 points lower (worse) on baseline and follow-up 3MS (p < 0.001 for all) and declined by almost 1 point over the >2 years (p = 0.01 for IL-6 and p = 0.04 for CRP) compared with those in the lowest tertile. After multivariate adjustment, 3MS scores among participants in the highest tertile of IL-6 and CRP were similar at baseline but remained significantly lower at follow-up (p < or = 0.05 for both). Those in the highest inflammatory marker tertile were also more likely to have cognitive decline compared with the lowest tertile for IL-6 (26 vs 20%; age-adjusted odds ratio [OR] = 1.34; 95% CI 1.06 to 1.69) and for CRP (24 vs 19%; OR = 1.41; 95% CI 1.10 to 1.79) but not for TNFalpha (23 vs 21%; OR = 1.12; 95% CI 0.88 to 1.43). There was no significant interaction between race and inflammatory marker or between nonsteroidal anti-inflammatory drug use and inflammatory marker on cognition.Serum markers of inflammation, especially IL-6 and CRP, are prospectively associated with cognitive decline in well-functioning elders. These findings support the hypothesis that inflammation contributes to cognitive decline in the elderly.

OBJECTIVE A loss of skeletal muscle mass is frequently observed in older adults. The aim of the study was to investigate the impact of type 2 diabetes on the changes in body composition, with particular interest in the skeletal muscle mass. RESEARCH DESIGN AND METHODS We examined total body composition with dual-energy X-ray absorptiometry annually for 6 years in 2,675 older adults. We also measured mid-thigh muscle cross-sectional area (CSA) with computed tomography in year 1 and year 6. At baseline, 75-g oral glucose challenge tests were performed. Diagnosed diabetes (n = 402, 15.0%) was identified by self-report or use of hypoglycemic agents. Undiagnosed diabetes (n = 226, 8.4%) was defined by fasting plasma glucose (≥7 mmol/l) or 2-h postchallenge plasma glucose (≥11.1 mmol/l). Longitudinal regression models were fit to examine the effect of diabetes on the changes in body composition variables. RESULTS Older adults with either diagnosed or undiagnosed type 2 diabetes showed excessive loss of appendicular lean mass and trunk fat mass compared with nondiabetic subjects. Thigh muscle CSA declined two times faster in older women with diabetes than their nondiabetic counterparts. These findings remained significant after adjusting for age, sex, race, clinic site, baseline BMI, weight change intention, and actual weight changes over time. CONCLUSIONS Type 2 diabetes is associated with excessive loss of skeletal muscle and trunk fat mass in community-dwelling older adults. Older women with type 2 diabetes are at especially high risk for loss of skeletal muscle mass.

OBJECTIVES: To determine how three different physical performance measures (PPMs) combine for added utility in predicting adverse health events in elders. DESIGN: Prospective cohort study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Three thousand twenty‐four well‐functioning older persons (mean age 73.6). MEASUREMENTS: Timed gait, repeated chair stands, and balance (semi‐ and full‐tandem, and single leg stands each held for 30 seconds) tests were administered at baseline. Usual gait speed was categorized to distinguish high‐ and low‐risk participants using the previously established 1‐m/s cutpoint. The same population‐percentile (21.3%) was used to identify cutpoints for the repeated chair stands (17.1 seconds) and balance (53.0 seconds) tests. Cox proportional hazard analyses were performed to evaluate the added value of PPMs in predicting mortality, hospitalization, and (severe) mobility limitation events over 6.9 years of follow‐up. RESULTS: Risk estimates for developing adverse health‐related events were similarly large for each of the three high‐risk groups considered separately. Having more PPM scores at the high‐risk level was associated with a greater risk of developing adverse health‐related events. When all three PPMs were considered, having only one poor performance was sufficient to indicate a highly significantly higher risk of (severe) lower extremity and mortality events. CONCLUSION: Although gait speed is considered to be the most important predictor of adverse health events, these findings demonstrate that poor performance on other tests of lower extremity function are equally prognostic. This suggests that chair stand and standing balance performance may be adequate substitutes when gait speed is unavailable.

Background. The Short Physical Performance Battery (SPPB), which includes walking, balance, and chair stands tests, independently predicts mobility disability and activities of daily living disability. To date, however, there is no definitive evidence from randomized controlled trials that SPPB scores can be improved. Our objective was to assess the effect of a comprehensive physical activity (PA) intervention on the SPPB and other physical performance measures.

Patients with major depression have elevated levels of inflammatory cytokines. We examined the link between inflammatory markers and depressed mood in a community-based sample of older people. Data are from 3024 well-functioning older persons, 70-79 years of age, participating in the Health, Aging and Body Composition study. Depressed mood was defined as a Center for Epidemiologic Studies Depression scale score of 16 or higher. Plasma concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and C-reactive protein (CRP) were measured. Compared with the 2879 nondepressed subjects, the 145 persons with depressed mood had higher median plasma levels of IL-6 (2.04 vs. 1.83 pg/mL, p =.02), TNF-alpha (3.43 vs. 3.16 pg/mL, p =.05), and CRP (1.96 vs. 1.66 mg/L, p =.03). After adjustment for health and demographic variables, depressed mood was especially prevalent among persons who had a high (above median) plasma level for at least two of the inflammatory markers. Compared with those without high levels, for persons with a high level for two or all three markers the risk of depressed mood was 2.45 (95% confidence interval [CI] = 1.34-4.47) and 2.40 (95% CI = 1.27-4.53), respectively. The association between depressed mood and serum level of IL-6 was significantly stronger in men than in women. In old age, depressed mood is associated with high levels of inflammatory markers, suggesting that depressed mood is causing and/or caused by systemic inflammation.

Objectives: To examine the association between physical activity and inflammatory markers, with consideration for body fatness and antioxidant use. Design: Cross‐sectional study, using baseline data from the Health, Aging and Body Composition Study. Setting: Metropolitan areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee. Participants: Black and white, well‐functioning men and women (N=3,075), aged 70 to 79. Measurements: Interviewer‐administered questionnaires of previous‐week household, walking, exercise, and occupational/volunteer physical activities. Analysis of covariance was used to examine the association between activity level and serum C‐reactive protein (CRP), interleukin‐6 (IL‐6), and plasma tumor necrosis factor alpha (TNFα) with covariate adjustment. Antioxidant supplement use (multivitamin, vitamins E or C, beta carotene) was evaluated as an effect modifier of the association. Results: Higher levels of exercise were associated with lower levels of CRP ( P&lt;. 01), IL‐6 ( P&lt;. 001), and TNFα ( P=. 02) (e.g., CRP=1.95 mg/L for no exercise and 1.72 for &gt;180 min/wk). Adjustment for body fatness attenuated the associations somewhat. Use of antioxidant supplements modified the CRP ( P interaction =.01) and IL‐6 ( P interaction =.08) associations such that concentrations were low in those taking supplements (e.g., CRP=1.79–1.84 across exercise levels) and higher in nonsupplement users who did no exercise (2.03) than in those who did the most (1.72). Among nonexercisers, higher levels of other physical activity were related to lower levels of CRP ( P&lt;. 01) and IL‐6 ( P=. 02) but not TNFα ( P=. 36), even after accounting for body fat. Conclusion: Inflammatory markers are lower in older adults with higher levels of exercise and nonexercise activity and in antioxidant supplement users regardless of exercise level.

Pericardial fat (ie, fat around the heart) may have a direct role in the atherosclerotic process in coronary arteries through local release of inflammation-related cytokines. Cross-sectional studies suggest that pericardial fat is positively associated with coronary artery disease independent of total body fat.We investigated whether pericardial fat predicts future coronary heart disease events.We conducted a case-cohort study in 998 individuals, who were randomly selected from 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants and 147 MESA participants (26 from those 998 individuals) who developed incident coronary heart disease from 2000 to 2005. The volume of pericardial fat was determined from cardiac computed tomography at baseline.The age range of the subjects was 45-84 y (42% men, 45% white, 10% Asian American, 22% African American, and 23% Hispanic). Pericardial fat was positively correlated with both body mass index (correlation coefficient = 0.45, P < 0.0001) and waist circumference (correlation coefficient = 0.57, P < 0.0001). In unadjusted analyses, pericardial fat (relative hazard per 1-SD increment: 1.33; 95% CI: 1.15, 1.54), but not body mass index (1.00; 0.84, 1.18), was associated with the risk of coronary heart disease. Waist circumference (1.14; 0.97, 1.34; P = 0.1) was marginally associated with the risk of coronary heart disease. The relation between pericardial fat and coronary heart disease remained significant after further adjustment for body mass index and other cardiovascular disease risk factors (1.26; 1.01, 1.59). The relation did not differ by sex.Pericardial fat predicts incident coronary heart disease independent of conventional risk factors, including body mass index.

Chronic inflammation is associated with processes that contribute to the onset or progression of cancer. This study examined the relationships between circulating levels of the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) and total as well as site-specific cancer incidence.Study subjects (n = 2,438) were older adults (ages 70-79 years) participating in the Health Aging and Body Composition study, who did not report a previous cancer diagnosis (except for nonmelanoma skin cancer) at baseline. Incident cancer events (n = 296) were ascertained during an average follow-up of 5.5 years. Inflammatory markers were measured in stored baseline fasting blood samples.The adjusted hazard ratios (95% confidence intervals) for incident cancer associated with a 1-unit increase on the natural log-scale were 1.13 (0.94-1.37), 1.25 (1.09-1.43), and 1.28 (0.96-1.70) for IL-6, CRP, and TNF-alpha, respectively. Markers were more strongly associated with cancer death: hazard ratios were 1.63 (1.19-2.23) for IL-6, 1.64 (1.20-2.24) for CRP, and 1.82 (1.14-2.92) for TNF-alpha. Although precision was low for site-specific analyses, our results suggest that all three markers were associated with lung cancer, that IL-6 and CRP were associated with colorectal cancer, and that CRP was associated with breast cancer. Prostate cancer was not associated with any of these markers.These findings suggest that (a) the associations between IL-6, CRP, and TNF-alpha and the risk of cancer may be site specific and (b) increased levels of inflammatory markers are more strongly associated with the risk of cancer death than cancer incidence.

Background.Weakness is common and contributes to disability, but no consensus exists regarding a strength cutpoint to identify persons at high risk. This analysis, conducted as part of the Foundation for the National Institutes of Health Sarcopenia Project, sought to identify cutpoints that distinguish weakness associated with mobility impairment, defined as gait speed less than 0.8 m/s.

Objectives: To determine whether older adults who exercise demonstrate higher levels of physical function than those who do not exercise but are physically active throughout the day. Design: Cross‐sectional examination of baseline data from the Health, Aging and Body Composition (Health ABC) study. Setting: Health ABC field centers in Pittsburgh, Pennsylvania, and Memphis, Tennessee. Participants: Three thousand seventy‐five well‐functioning black and white men and women aged 70 to 79. Measurements: Physical activity and exercise were assessed using a modified leisure‐time physical activity questionnaire. Participants were classified as inactive (reporting &lt;1,000 kcal/wk of exercise activity and ≤2,719 kcal/wk of total physical activity), lifestyle active (reporting &lt;1,000 kcal/wk of exercise activity and &gt;2,719 kcal/wk of total physical activity), or exerciser (reporting≥1,000 kcal/wk of exercise activity). Physical function measures included the Established Populations for the Epidemiologic Studies of the Elderly (EPESE) battery, the Health ABC battery, a 400‐m walk test, and isokinetic strength testing of the knee extensors. Results: The lifestyle active and exerciser groups had similar total activity levels (men: 6,135 kcal/wk and 6,734 kcal/wk, respectively; P= .108; women: 5,695 kcal/wk and 5,854 kcal/wk, respectively; P= .335). When examining lower extremity performance in relation to physical activity, a progressive trend was evident, with the inactive individuals most likely to have impaired performance on the EPESE battery (men: 33.7%, 24.3%, and 19.1%, P &lt;.001; women: 49.9%, 37.3%, and 28.4%, P &lt;.001; inactive, lifestyle active, and exerciser, respectively). Progressive trends of similar magnitude were present for the Health ABC battery, time to walk 400 m, and knee extensor strength. In multivariate linear regression, those in the inactive and lifestyle active groups had poorer scores on the Health ABC performance battery than individuals in the exercise group after controlling for demographic factors and prevalent disease (men: inactive β=−0.27, P &lt;.001, lifestyle active β=−0.07, P= .032; women: inactive β=−0.23, P &lt;.001, lifestyle active β=−0.07, P &lt;.059). After controlling for demographic factors and prevalent disease, the lifestyle active and exercisers had similar proportions of functionally limited older persons (scoring &lt;10 on the EPESE battery). Conclusion: Older adults who participate in 20 to 30 minutes of moderate‐intensity exercise on most days of the week have better physical function than older persons who are active throughout the day or who are inactive. Any type of physical activity is better than no activity for protection against functional limitations, but exercise confers greater benefit for physical capacity.

The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults.Inflammation is associated with HF risk factors and also directly affects myocardial function.The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white).During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001).Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

Considerable evidence suggests that the loss of strength and muscle mass appear to be inevitable consequences of aging. Moreover, aging is associated with an increase in body fat. This study examined whether increased physical activity could prevent or reverse the losses of strength and skeletal muscle mass as well as the gain in fat in older adults. Eleven men and 31 women completed a randomized trial consisting of either a physical activity (PA; n = 22) or successful aging health educational control (SA; n = 20) group. Isokinetic knee extensor strength and computed tomography-derived midthigh skeletal muscle and adipose tissue cross-sectional areas (CSA) were assessed at baseline and at 12 mo following randomization. Total body weight and muscle CSA decreased in both groups, but these losses were not different between groups. Strength adjusted for muscle mass decreased (−20.1 ± 9.3%, P &lt; 0.05) in SA. The loss of strength was completely prevented in PA (+2.5 ± 8.3%). In addition, there was a significant increase (18.4 ± 6.0%) in muscle fat infiltration in SA, but this gain was nearly completely prevented in PA (2.3 ± 5.7%). In conclusion, regular physical activity prevents both the age-associated loss of muscle strength and increase in muscle fat infiltration in older adults with moderate functional limitations.

Key Points Geriatric assessment, with a focus on cognitive and physical function, improves prediction of survival among older adults treated for AML. Use of geriatric assessment may inform trial design and interventions to improve outcomes for older adults with AML.

Background.Emerging evidence indicates an association between cognitive function and physical performance in late life.This study examines the relationship between cognitive function and subsequent gait speed decline among high-functioning older adults. Methods. Measures of global cognitive function (Modified Mini Mental State Examination [3MS]) and executive control function (ECF) (a clock drawing task [CLOX 1] and the 15-item Executive Interview [EXIT 15]) were obtained in the Health, Aging, and Body Composition Study in 1999-2000.Gait-speed (meters/second) was assessed over 20 meters at usual pace.Using a mixed model, we assessed the relationship between baseline cognitive function and gait-speed change over 3 years.Results.Two thousand, three hundred forty-nine older adults (mean age 75.6 6 2.9 years) completed the assessments.After adjustment for baseline gait speed, a 1-standard-deviation (SD) lower performance on each cognitive test was associated with greater gait-speed decline over 3 years: 0.016 m/s for the 3MS (SD ¼ 8.1), 0.009 m/s for CLOX 1 (SD ¼ 2.4), and 0.012 m/s for EXIT 15 (SD ¼ 4.1) ( p , .0005 for all).After adjustment for comorbidities, the effect size was attenuated for 3MS and CLOX 1, and the association for EXIT 15 was no longer significant.Depression score was most strongly associated with the EXIT 15 effect reduction. Conclusion.Global and executive cognitive functions predict declines in gait speed.The association of ECF with gait speed decline is attenuated by comorbid conditions, particularly depression.Elucidation of the mechanisms underlying these associations may point to new pathways for the treatment of physical decline associated with diminished cognitive function.

Vitamin D status has been hypothesized to play a role in musculoskeletal function. Using data from the InCHIANTI study, we examined the association between vitamin D status and physical performance.A representative sample of 976 persons aged 65 years or older at study baseline were included. Physical performance was assessed using a short physical performance battery (SPPB) and handgrip strength. Multiple linear regression was used to examine the association between vitamin D (serum 25OHD), parathyroid hormone (PTH), and physical performance adjusting for sociodemographic variables, behavioral characteristics, body mass index, season, cognition, health conditions, creatinine, hemoglobin, and albumin.Approximately 28.8% of women and 13.6% of men had vitamin D levels indicative of deficiency (serum 25OHD < 25.0 nmol/L) and 74.9% of women and 51.0% of men had vitamin D levels indicative of vitamin D insufficiency (serum 25OHD < 50.0 nmol/L). Vitamin D levels were significantly associated with SPPB score in men (beta coefficient [standard error (SE)]: 0.38 [0.18], p =.04) and handgrip strength in men (2.44 [0.84], p =.004) and women (1.33 [0.53], p =.01). Men and women with serum 25OHD < 25.0 nmol/L had significantly lower SPPB scores whereas those with serum 25OHD < 50 nmol/L had significantly lower handgrip strength than those with serum 25OHD > or =25 and > or =50 nmol/L, respectively (p <.05). PTH was significantly associated with handgrip strength only (p =.01).Vitamin D status was inversely associated with poor physical performance. Given the high prevalence of vitamin D deficiency in older populations, additional studies examining the association between vitamin D status and physical function are needed.

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.

It is unclear if physical activity (PA) can prevent or reverse frailty. We examined different doses and types of PA and their association with the onset and severity of frailty.Health, Aging and Body Composition (Health ABC) study participants (N = 2,964) were followed for 5 years, with frailty defined as a gait speed of less than 0.60 m/s and/or inability to rise from a chair without using one's arms. Individuals with one impairment were considered moderately frail and those with both severely frail. We examined PA doses of volume and intensity, activity types (eg, lifestyle vs exercise activities), and their associations with incident frailty and transition to severe frailty in those who became frail.Adjusted models indicated that sedentary individuals had significantly increased odds of developing frailty compared with the exercise active group (adjusted odds ratio [OR] = 1.45; 95% confidence interval [CI]: 1.04-2.01), whereas the lifestyle active did not. Number of diagnoses was the strongest predictor of incident frailty. In those who became frail during follow-up (n = 410), there was evidence that the sedentary (adjusted OR = 2.80; 95% CI: 0.98-8.02) and lifestyle active (adjusted OR = 2.81; 95% CI: 1.22-6.43) groups were more likely to have worsening frailty over time.Despite the strong relationship seen between comorbid conditions and onset of frailty, this observational study suggests that participation in self-selected exercise activities is independently associated with delaying the onset and the progression of frailty. Regular exercise should be further examined as a potential factor in frailty prevention for older adults.

Background.Low lean mass is potentially clinically important in older persons, but criteria have not been empirically validated. As part of the FNIH (Foundation for the National Institutes of Health) Sarcopenia Project, this analysis sought to identify cutpoints in lean mass by dual-energy x-ray absorptiometry that discriminate the presence or absence of weakness (defined in a previous report in the series as grip strength <26kg in men and <16kg in women).

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

OBJECTIVES: To determine the effects of a long‐term exercise intervention on two prominent biomarkers of inflammation (C‐reactive protein (CRP) and interleukin‐6 (IL‐6)) in elderly men and women. DESIGN: Single‐blind, randomized, controlled trial: The Lifestyle Interventions and Independence for Elders (LIFE) Trial. SETTING: The Cooper Institute, Dallas, Texas; Stanford University, Stanford, California; University of Pittsburgh, Pittsburgh, Pennsylvania; and Wake Forest University, Winston‐Salem, North Carolina. PARTICIPANTS: Four hundred twenty‐four elderly (aged 70–89), nondisabled, community‐dwelling men and women at risk for physical disability. INTERVENTION: A 12‐month moderate‐intensity physical activity (PA) intervention and a successful aging (SA) health education intervention. MEASUREMENTS: CRP and IL‐6. RESULTS: After adjustment for baseline IL‐6, sex, clinic site, diabetes mellitus, treatment group, visit, and group‐by‐visit interaction, the PA intervention resulted in a lower ( P =.02) IL‐6 concentration than the SA intervention. Adjusted mean IL‐6 at month 12 was 8.5% (0.21 pg/mL) higher in the SA than the PA group. There were no significant differences in CRP between the groups at 12 months ( P =.09). Marginally significant interaction effects of the PA intervention according to baseline functional status ( P =.05) and IL‐6 (above vs below the median; P =.06) were observed. There was a greater effect of the PA intervention on participants with lower functional status and those with a higher baseline IL‐6. CONCLUSION: Greater PA results in lower systemic concentrations of IL‐6 in elderly individuals, and this benefit is most pronounced in individuals at the greatest risk for disability and subsequent loss of independence.

Chronic subclinical inflammation may contribute to impaired physical function in older adults; however, more data are needed to determine whether inflammation is a common mechanism for functional decline, independent of disease or health status.We examined associations between physical function and inflammatory biomarkers in 542 older men and women enrolled in four clinical studies at Wake Forest University between 2001 and 2006. All participants were at least 55 years and had chronic obstructive pulmonary disease, congestive heart failure, high cardiovascular risk, or self-reported physical disability. Uniform clinical assessments were used across studies, including grip strength; a Short Physical Performance Battery (SPPB; includes balance, 4-m walk, and repeated chair stands); inflammatory biomarker assays for interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and C-reactive protein (CRP); and anthropometric measures.Higher levels of CRP and IL-6, but not TNF-alpha, were associated with lower grip strength and SPPB scores and longer times to complete the 4-m walk and repeated chair stands tests, independent of age, gender, and race. More importantly, these relationships were generally independent of disease status. Further adjustment for fat mass, lean mass, or percent body fat altered some of these relationships but did not significantly change the overall results.Elevated CRP and IL-6 levels are associated with poorer physical function in older adults with various comorbidities, as assessed by a common battery of clinical assessments. Chronic subclinical inflammation may be a marker of functional limitations in older persons across several diseases/health conditions.

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1×10E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9×10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6×10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants.Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)

Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.The objective of the study was to identify common genetic variants that are associated with macronutrient intake.We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

In older adults, every 0.1-m/s slower gait speed is associated with a 12% higher mortality. However, little research has identified risk factors for gait-speed decline.We assessed the association between several measures of body composition and age-related decline in gait speed.Data were from 2306 older adults who were participating in the Health, Aging, and Body Composition cohort and were followed for 4 y (50% women; 38% black). Usual walking speed (m/s) over 20 m was measured in years 2 through 6, and the baseline and changes in several measures of body composition were included in mixed-effects models.Gait speed declined by 0.06 ± 0.00 m/s over the 4-y period. Baseline thigh intermuscular fat predicted the annual gait-speed decline (±SE) in both men and women (-0.01 ± 0.00 and -0.02 ± 0.00 m/s per 0.57 cm(2), respectively; P < 0.01). In men, but not in women, this relation was independent of total body adiposity. In longitudinal analyses, changes in thigh intermuscular fat and total thigh muscle were the only body-composition measures that predicted gait-speed decline in men and women combined. When modeled together, every 5.75-cm(2) increase in thigh intermuscular fat was associated with a 0.01 ± 0.00-m/s decrease in gait speed, whereas every 16.92-cm(2) decrease in thigh muscle was associated with a 0.01 ± 0.00-m/s decrease in gait speed.High and increasing thigh intermuscular fat are important predictors of gait-speed decline, implying that fat infiltration into muscle contributes to a loss of mobility with age. Conversely, a decreasing thigh muscle area is also predictive of a decline in gait speed.

Summary Background and objectives Kidney Disease Improving Global Outcomes guidelines recommend against bone mineral density (BMD) screening in CKD patients with mineral bone disease, due to a lack of association of BMD with fractures in cross-sectional studies in CKD. We assessed whether BMD is associated with fractures in participants with and without CKD in the Health, Aging, and Body Composition study, a prospective study of well functioning older individuals. Design, setting, participants, &amp; measurements Hip BMD was measured by dual-energy x-ray absorptiometry. Osteoporosis was defined as a femoral neck BMD (FNBMD) T score below −2.5 and CKD as an estimated GFR &lt;60 ml/min per 1.73 m 2 . The association of BMD with incident nonspine, fragility fractures to study year 11 was analyzed using Cox proportional hazards analyses, adjusting for age, race, sex, body mass index, hyperparathyroidism, low vitamin D level, and CKD. Interaction terms were used to assess whether the association of BMD with fracture differed in those with and without CKD. Results There were 384 incident fractures in 2754 individuals (mean age 73.6 years). Lower FNBMD was associated with greater fracture, regardless of CKD status. After adjustment, the hazard ratios (95% confidence intervals) were 2.74 (1.99, 3.77) and 2.15 (1.80, 2.57) per lower SD FNBMD for those with and without CKD, respectively (interaction P =0.68), and 2.10 (1.23, 3.59) and 1.63 (1.18, 2.23) among those with osteoporosis in patients with and without CKD, respectively (interaction P =0.75). Conclusions BMD provides information on risk for fracture in older individuals with or without moderate CKD.

<h3>Background and Objectives</h3> DNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer9s Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults. <h3>Methods</h3> We tested 3 “generations” of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer9s Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia. <h3>Results</h3> In ADNI (<i>N</i> = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08–0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = −0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = −0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort (<i>N</i> = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07–1.49]). <h3>Discussion</h3> Third-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.

Abstract Background The Study of Muscle, Mobility and Aging (SOMMA) aims to understand the biological basis of many facets of human aging, with a focus on mobility decline, by creating a unique platform of data, tissues, and images. Methods The multidisciplinary SOMMA team includes 2 clinical centers (University of Pittsburgh and Wake Forest University), a biorepository (Translational Research Institute at Advent Health), and the San Francisco Coordinating Center (California Pacific Medical Center Research Institute). Enrollees were age ≥70 years, able to walk ≥0.6 m/s (4 m); able to complete 400 m walk, free of life-threatening disease, and had no contraindications to magnetic resonance or tissue collection. Participants are followed with 6-month phone contacts and annual in-person exams. At baseline, SOMMA collected biospecimens (muscle and adipose tissue, blood, urine, fecal samples); a variety of questionnaires; physical and cognitive assessments; whole-body imaging (magnetic resonance and computed tomography); accelerometry; and cardiopulmonary exercise testing. Primary outcomes include change in walking speed, change in fitness, and objective mobility disability (able to walk 400 m in 15 minutes and change in 400 m speed). Incident events, including hospitalizations, cancer diagnoses, fractures, and mortality are collected and centrally adjudicated by study physicians. Results SOMMA exceeded its goals by enrolling 879 participants, despite being slowed by the COVID-19 pandemic: 59.2% women; mean age 76.3 ± 5.0 years (range 70–94); mean walking speed 1.04 ± 0.20 m/s; 15.8% identify as other than Non-Hispanic White. Over 97% had data for key measurements. Conclusions SOMMA will provide the foundation for discoveries in the biology of human aging and mobility.

To examine the relationship between indicators of inflammation and the incidence of mobility limitation in older persons.Prospective cohort study: the Health, Aging and Body Composition Study.Pittsburgh, Pennsylvania, and Memphis, Tennessee.A total of 2,979 men and women, aged 70 to 79, without mobility limitation at baseline.Serum levels of interleukin (IL)-6, tumor necrosis factor alpha (TNFalpha), and C-reactive protein (CRP) and soluble cytokine receptors (IL-2sR, IL-6sR, TNFsR1, TNFsR2) were measured. Mobility limitation was assessed and defined as reporting difficulty or inability to walk one-quarter of a mile or to climb 10 steps during two consecutive semiannual assessments over 30 months.Of the 2,979 participants, 30.1% developed incident mobility limitation. After adjustment for confounders (demographics, prevalent conditions at baseline, body composition), the relative risk (RR) of incident mobility limitation per standard deviation (SD) increase was 1.19 (95% confidence interval (CI)=1.10-1.28) for IL-6, 1.20 (95% CI=1.12-1.29) for TNFalpha, and 1.40 (95% CI=1.18-1.68) for CRP. The association between inflammation and incident mobility limitation was especially strong for the onset of more severe mobility limitation and when the levels of multiple inflammatory markers were high. When persons with baseline or incident cardiovascular disease events or persons who were hospitalized during study follow-up were excluded, findings remained similar. In a subset (n=499), high levels of the soluble receptors IL2sR and TNFsR1 (per SD increase: RR=1.23 (95% CI=1.04-1.46) and RR=1.28 (95% CI=1.04-1.57), respectively) were also associated with incident mobility limitation.Findings suggest that inflammation is prognostic for incident mobility limitation over 30 months, independent of cardiovascular disease events and incident severe illness.

This study investigates the association of several inflammatory markers with subclinical and clinical cardiovascular disease in older men and women. Data are from the baseline assessment of 3,045 well-functioning persons aged 70 to 79 years, participating in the Health, Aging and Body Composition study. The study sample was divided into 3 groups: "cardiovascular disease" (diagnosis of congestive heart failure, coronary artery disease, peripheral artery disease, or stroke), "subclinical cardiovascular disease" (positive findings on the Rose questionnaire for angina or claudication, ankle-brachial index <0.9, or electrocardiographic abnormalities), and "no cardiovascular disease." Serum levels of interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, and the soluble receptors IL-6 soluble receptor, IL-2 soluble receptor, TNF soluble receptor I, and TNF soluble receptor II were assessed. Of those with IL-6 levels in the highest compared with the lowest tertile, the odds ratio (OR) for subclinical cardiovascular disease was 1.58 (95% confidence interval [CI] 1.26 to 1.97) and for clinical cardiovascular disease was 2.35 (95% CI 1.79 to 3.09). A similar association was found for TNF-alpha (OR 1.48, 95% CI 1.16 to 1.88 and OR 2.05, 95% CI 1.55 to 2.72, respectively). In adjusted analyses, CRP was not significantly associated with overall subclinical or clinical cardiovascular disease, although additional analyses did find a strong specific association between CRP and congestive heart failure (OR 1.64, 95% CI 1.11 to 2.41). Of the soluble cytokine receptors, only TNF soluble receptor I showed a significant association with clinical cardiovascular disease. Thus, our findings suggest an important role for IL-6 and TNF-alpha in clinical as well as subclinical cardiovascular disease. In this study, CRP had a weaker association with cardiovascular disease than the cytokines.

Despite the rising heart failure (HF) incidence and aging United States population, there are no validated prediction models for incident HF in the elderly. We sought to develop a new prediction model for 5-year risk of incident HF among older persons.Proportional hazards models were used to assess independent predictors of incident HF, defined as hospitalization for new-onset HF, in 2935 elderly participants without baseline HF enrolled in the Health ABC study (age, 73.6 +/- 2.9 years, 47.9% males, 58.6% whites). A prediction equation was developed and internally validated by bootstrapping, allowing the development of a 5-year risk score. Incident HF developed in 258 (8.8%) participants during 6.5 +/- 1.8 years of follow-up. Independent predictors of incident HF included age, history of coronary disease and smoking, baseline systolic blood pressure and heart rate, serum glucose, creatinine, and albumin levels, and left ventricular hypertrophy. The Health ABC HF model had a c-statistic of 0.73 in the derivation dataset, 0.72 by internal validation (optimism-corrected), and good calibration (goodness-of-fit 2 6.24, P=0.621). A simple point score was created to predict incident HF risk into 4 risk groups corresponding to <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk. The actual 5-year incident HF rates in these groups were 2.9%, 5.7%, 13.3%, and 36.8%, respectively.The Health ABC HF prediction model uses common clinical variables to predict incident HF risk in the elderly, an approach that may be used to target and treat high-risk individuals.

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-α), 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.

Background: Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control.Methods: Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n=1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs).Results: Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia.Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95%

OBJECTIVES: To identify levels of knee extensor strength that are associated with high and low risk of incident severe mobility limitation (SML) in initially well‐functioning older adults. DESIGN: Prospective cohort study. SETTING: University clinic center. PARTICIPANTS: One thousand three hundred fifty‐five men and 1,429 women (aged 73.6±2.85) who reported no mobility limitation. MEASUREMENTS: Unilateral knee extensor isokinetic strength of participants was obtained. Participants were followed over a median of 5.90 years for the onset of SML, defined as two consecutive reports of a lot of difficulty or inability to walk one‐quarter of a mile or climb 10 steps. Deciles of knee extension strength relative to body weight were evaluated to identify cutpoints most predictive of incident SML. Cutpoints were then compared with prevalence of having slow gait speed (&lt;1.22 m/s) and mortality. RESULTS: Two sex‐specific knee extension strength cutpoints were found. High and low risk of SML corresponded to less than 1.13 newton‐meters (Nm)/kg (1st decile) and more than 1.71 Nm/kg (6th decile) in men and less than 1.01 Nm/kg (3rd decile) and more than 1.34 Nm/kg (7th decile) in women, respectively. Moderate risk was defined as being between the low‐ and high‐risk cutpoints. Individuals with knee extension strength in the high‐ and moderate‐risk categories were more likely to have a gait speed less than 1.22 m/s (hazard ratio (HR)=7.00, 95% confidence interval (CI)=5.47–8.96 and HR=2.14 7.00, 95% CI=1.73–2.64, respectively) and had a higher risk of death (HR=1.77, 95% CI=1.41–2.23 and HR=1.51, 95% CI=1.24–1.84, respectively) than individuals in the low‐risk category. Adjustment for demographic factors, health behaviors, and medical conditions did not alter these associations. CONCLUSION: Knee extensor strength cutpoints provide objective markers to identify initially well‐functioning older adults at high and low risk of future mobility limitation.

Abstract Objective To examine the cross‐sectional association between use of medications that have a bone antiresorptive effect (estrogen, raloxifene, and alendronate) and both the structural features of knee osteoarthritis (OA), assessed by magnetic resonance imaging (MRI) and radiography, and the symptoms of knee OA in elderly women. Methods Women in the Health, Aging and Body Composition Study underwent MRI and radiography of the knee if they reported symptoms of knee OA, and women without significant knee symptoms were selected as controls. MR images of the knee were assessed for multiple features of OA using the Whole‐Organ MRI scoring method, and radiographs were read for Kellgren and Lawrence grade and individual features of OA. Concurrent medication use and knee symptoms were assessed by interview, and knee pain severity was evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results There were 818 postmenopausal women from whom we obtained MR images of the knee and data on medication use. Among these women, 214 (26.2%) were receiving antiresorptive drugs. We found no significant association between overall use of antiresorptive drugs and the presence of knee pain and radiographic changes of OA of the knee. Use of alendronate, but not estrogen, was associated with less severity of knee pain as assessed by WOMAC scores. Both alendronate use and estrogen use were associated with significantly less subchondral bone attrition and bone marrow edema–like abnormalities in the knee as assessed by MRI, as compared with women who had not received these medications. Conclusion Elderly women being treated with alendronate and estrogen had a significantly decreased prevalence of knee OA–related subchondral bone lesions compared with those reporting no use of these medications. Alendronate use was also associated with a reduction in knee pain according to the WOMAC scores.

Background.Recently, subclinical aspiration has been identified in approximately 30% of community-dwelling older adults. Given that the tongue is a key component of the safe swallow, we hypothesized healthy older adults who aspirate will generate less tongue strength than adults who do not aspirate. Furthermore, as muscle weakness may reflect a global effect of aging, we further investigated whether tongue strength is correlated with handgrip strength.

To determine the relationships between low back pain (LBP) frequency and intensity and self-reported and performance-based physical function in a large cohort of well-functioning older adults.Cross-sectional survey and examination.Community-based cohort of the Health, Aging, and Body Composition (Health ABC) study.Participants were 2,766 community-dwelling adults, aged 70-79; 42% were African American, 52% were men.1) Back pain-location, frequency, intensity; 2) Hip and/or knee pain; 3) Body mass index (BMI); 4) Self-reported difficulty doing functional tasks; 5) Lower extremity function, using the battery from the Established Populations for Epidemiologic Studies in the Elderly (EPESE); 6) Self-rated health; 7) Comorbidity; 8) Depressive symptoms, using the Center for Epidemiological Studies-Depression (CES-D) scale.LBP was common (36%), and its frequency/intensity was significantly associated with other pain and comorbidities. In gender-specific models, LBP frequency/intensity was not significantly associated with EPESE performance score after adjusting for age, race, BMI, CES-D score, knee pain, hip pain, and other comorbidities. LBP frequency/intensity, however, was significantly associated with self-reported difficulty with most functional tasks after adjusting for important confounders.Among well-functioning community-dwelling older adults, LBP frequency/intensity was associated with perceived difficulty in performing important functional tasks, but not with observed physical performance. The demonstrated dose-response relationship between pain frequency/intensity and self-reported task performance difficulty underscores the importance of clinical efforts to treat pain without necessarily eradicating it. Additional work is needed to determine whether back pain is associated with a risk for progressive functional decline and loss of independence in older adults and whether therapeutic interventions can ameliorate decline and, therefore, preserve independence.

The purpose of this study was to assess whether metabolic syndrome (MetSyn) predicts a higher risk for cardiovascular events in older adults. The importance of MetSyn as a risk factor has not previously focused on older adults and deserves further study. We studied the impact of MetSyn (38% prevalence) on outcomes in 3,035 participants in the Health, Aging, and Body Composition (Health ABC) study (51% women, 42% black, ages 70 to 79 years). During a 6-year follow-up, there were 434 deaths overall, 472 coronary events (CE), 213 myocardial infarctions (MI), and 231 heart failure (HF) hospital stays; 59% of the subjects had at least one hospital stay. Coronary events, MI, HF, and overall hospital stays occurred significantly more in subjects with MetSyn (19.9% vs. 12.9% for CE, 9.1% vs. 5.7% for MI, 10.0% vs. 6.1% for HF, and 63.1% vs. 56.1% for overall hospital stay; all p < 0.001). No significant differences in overall mortality was seen; however, there was a trend toward higher cardiovascular mortality (5.1% vs. 3.8%, p = 0.067) and coronary mortality (4.5% vs. 3.2%, p = 0.051) in patients with MetSyn. After adjusting for baseline characteristics, patients with MetSyn were at a significantly higher risk for CE (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.28 to 1.91), MI (HR 1.51, 95% CI 1.12 to 2.05), and HF hospital stay (HR 1.49, 95% CI 1.10 to 2.00). Women and whites with MetSyn had a higher coronary mortality rate. The CE rate was higher among subjects with diabetes and with MetSyn; those with both had the highest risk. Overall, subjects over 70 years are at high risk for cardiovascular events; MetSyn in this group is associated with a significantly greater risk.

OBJECTIVES: To examine whether total and abdominal adiposity are risk factors for the development of chronic heart failure (CHF) in older men and women. DESIGN: Prospective, longitudinal cohort: The Health, Aging and Body Composition study. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania, metropolitan areas. PARTICIPANTS: Three thousand seventy‐five well‐functioning community‐dwelling older adults aged 70 to 79. MEASUREMENTS: Body composition using dual energy X‐ray absorptiometry, visceral adipose tissue area using computed tomography, adjudicated CHF. RESULTS: Of the remaining (640 participants excluded from original group of 3,075) 2,435 participants (1,081 men, 1,354 women) without coronary heart disease or CHF at baseline, there were 166 confirmed diagnoses of CHF during the median±standard deviation (SD) follow‐up of 6.1±1.4 years. After adjustment for age, race, sex, site, education, smoking, and chronic obstructive pulmonary disorder, all adiposity variables (body mass index (BMI), adipose tissue mass, percentage body fat, waist‐to‐thigh ratio, waist circumference, and visceral and subcutaneous abdominal adipose tissue) were significant predictors of the development of CHF. In a model that included waist circumference and BMI, waist circumference was associated with incident CHF (hazard ratio (HR)=1.27, 95% confidence interval (CI)=1.04–1.54 per SD increase, P= .02), but BMI was not (HR=1.08, 95% CI=0.86–1.35). When waist circumference and percentage fat were included together, both variables were significant predictors of CHF (waist: HR=1.17, 95% CI=1.00–1.36 per SD increase, P= .05; percentage fat: HR=1.47, 95% CI=1.16–1.87 per SD increase, P= .002). Stepwise adjustment for inflammation, hypertension, insulin resistance, and diabetes mellitus did not decrease the relative risk of a greater waist circumference for the development of CHF (all HR=1.27–1.32, 95% CI=1.02–1.61 per SD increase). CONCLUSION: Abdominal body fat distribution may be a stronger risk factor for CHF than overall obesity.

The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described.We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF.During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P < .001).Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts.

The objective of this study was to assess the association of inflammation with hyperglycemia (impaired fasting glucose [IFG]/impaired glucose tolerance [IGT]) and diabetes in older individuals.Baseline data from the Health, Aging and Body Composition study included 3,075 well-functioning black and white participants, aged 70-79 years.Of the participants, 24% had diabetes and 29% had IFG/IGT at baseline. C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels (P < 0.001) were significantly higher among diabetic participants and those with IFG/IGT. Odds of elevated IL-6 and TNF-alpha (>75th percentile) were, respectively, 1.95 (95% CI 1.56-2.44) and 1.88 (1.51-2.35) for diabetic participants and 1.51 (1.21-1.87) and 1.14 (0.92-1.42) for those with IFG/IGT after adjustment for age, sex, race, smoking, alcohol intake, education, and study site. Odds ratios for elevated CRP were 2.90 (2.13-3.95) and 1.45 (1.03-2.04) for diabetic women and men and 1.33 (1.07-1.69) for those with IFG/IGT regardless of sex. After adjustment for obesity, fat distribution, and inflammation-related conditions, IL-6 remained significantly related to both diabetes and IFG/IGT. CRP in women and TNF-alpha in both sexes were significantly related to diabetes, respectively, whereas risk estimates for IFG/IGT were decreased by adjustment for adiposity. Among diabetic participants, higher levels of HbA(1c) were associated with higher levels of all three markers of inflammation, but only CRP remained significant after full adjustment.Our findings show that dysglycemia is associated with inflammation, and this relationship, although consistent in diabetic individuals, also extends to those with IFG/IGT.

<h3>Context</h3> Depression has been hypothesized to result in abdominal obesity through the accumulation of visceral fat. No large study has tested this hypothesis longitudinally. <h3>Objective</h3> To examine whether depressive symptoms predict an increase in abdominal obesity in a large population-based sample of well-functioning older persons. <h3>Design</h3> The Health, Aging, and Body Composition Study, an ongoing prospective cohort study with 5 years of follow-up. <h3>Setting</h3> Community-dwelling older persons residing in the areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee. <h3>Participants</h3> A total of 2088 well-functioning white and black persons aged 70 to 79 years. <h3>Main Outcome Measures</h3> Baseline depression was defined as a Center for Epidemiological Studies Depression score of 16 or higher. At baseline and after 5 years, overall obesity measures included body mass index (calculated as weight in kilograms divided by height in meters squared) and percentage of body fat (measured by dual-energy x-ray absorptiometry). Abdominal obesity measures included waist circumference, sagittal diameter, and visceral fat (measured by computed tomography). <h3>Results</h3> After adjustment for sociodemographics, lifestyle, diseases, and overall obesity, baseline depression was associated with a 5-year increase in sagittal diameter (β = .054;<i>P</i> = .01) and visceral fat (β = .080;<i>P</i> = .001). <h3>Conclusions</h3> This study shows that depressive symptoms result in an increase in abdominal obesity independent of overall obesity, suggesting that there may be specific pathophysiological mechanisms that link depression with visceral fat accumulation. These results might also help explain why depression increases the risk of diabetes and cardiovascular disease.

<h3>Context</h3>Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.<h3>Objective</h3>To investigate whether common variation within genes encoding the vitamin D–binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.<h3>Design, Setting, and Participants</h3>Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.<h3>Main Outcome Measure</h3>Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.<h3>Results</h3>Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.<h3>Conclusion</h3>Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

Skeletal muscle relies upon regeneration to maintain homeostasis and repair injury. This process involves the recruitment of the tissue's resident stem cell, the muscle progenitor cell, and a subsequent proliferative response by newly generated myoblasts, which must then align and fuse to generate new muscle fibers. During regeneration, cells rely on environmental input for direction. Extracellular matrix (ECM) represents a crucial component of a cell's microenvironment that aids in guiding muscle regeneration. We hypothesized that ECM extracted from skeletal muscle would provide muscle progenitor cells and myoblasts with an ideal substrate for growth and differentiation ex vivo. To test this hypothesis, we developed a method to extract ECM from the large thigh muscles of adult rats and present it to cells as a surface coating. Myogenic cells cultured on ECM extract experienced enhanced proliferation and differentiation relative to standard growth surfaces. As the methodology can be applied to any size muscle, these results demonstrate that bioactive ECM can be readily obtained from skeletal muscle and used to develop biomaterials that enhance muscle regeneration. Furthermore, the model system demonstrated here can be applied to the study of interactions between the ECM of a particular tissue and a cell population of interest.

To study the levels of systemic markers for inflammation with parameters of periodontal diseases in older people.A cross-sectional study was conducted in a cohort that is being followed prospectively on the effects of aging and body composition on morbidity.University of Pittsburgh, Pittsburgh, and University of Tennessee, Memphis.One thousand one hundred thirty-one participants (mean age+/-standard deviation 72.7+/-2.8); 66% white and 50% male.Periodontal examination, including probing depth and attachment loss, was performed. Periodontal disease extent was divided into 0% of sites with probing depth of 6 mm or more, 1% to 10% of sites with probing depth of 6 mm or more and more than 10% of sites with probing depth of 6 mm or more. Subgingival plaque samples were collected from four molar teeth, and the levels of periodontal pathogens were determined using the benzoyl-DL-arginine-naphthylamide (BANA) test. Plasma interleukin-6 (IL-6), C-reactive protein (CRP), plasminogen activator inhibitor type-1 (PAI-1), and tumor necrosis factor alpha (TNF-alpha) levels were measured in all participants. Assessments of risk factors associated with elevated levels of markers of systemic inflammation were also determined. Multiple regression analysis was employed to analyze the data.IL-6 levels were significantly higher in participants with more-extensive periodontal disease than in other participants. Periodontal disease extent was significantly associated with higher TNF-alpha plasma levels, controlling for established risk factors for elevated TNF-alpha levels. Participants with BANA-positive species had significantly higher CRP plasma levels when controlling for risk factors for elevated CRP levels.Periodontal disease and infection may be modifiable risk indicators for elevated levels of systemic inflammatory markers in older people.

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-alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1).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 <0.001) and CRP (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-alpha and PAI-1 (P=0.137 and 0.08, respectively).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.

Objectives: To determine the incidence and correlates of combined declines in cognitive and physical performance. Design: Cohort study of community‐dwelling older women with moderate to severe disability. Setting: The community surrounding Baltimore, Maryland. Participants: Participants in the Women's Health and Aging Study I with Mini‐Mental State Examination (MMSE) score or 24 or greater and walking speed greater than 0.4 m/s at baseline. Measurements: Cognitive decline was defined as an MMSE score less than 24 and physical decline as a walking speed of 0.4 m/s or less in at least one of the three annual follow‐up visits. Participants were stratified into groups based on cognitive or physical decline or both. Group characteristics were compared, and results were adjusted for age, race, education, and significant covariates. Results: Of 558 women that met the baseline MMSE and walking speed inclusion criteria, 21% developed physical decline, 12% developed cognitive decline, and 11% experienced combined cognitive and physical decline. After adjustment, physical decline was associated with age, nonwhite race, former smoking, baseline walking speed, and instrumental activities of daily living (IADL) impairment. Cognitive decline was associated with age and baseline MMSE score. Combined decline was associated with age, baseline walking speed, MMSE score, IADL impairment, as well as current smoking (odds ratio (OR)=5.66, 95% confidence interval (CI)=1.49–21.54) and hemoglobin level (OR=0.68, 95% CI=0.47–0.98). Conclusion: Potential predictors of cognitive and physical performance decline were identified. The association between smoking and lower hemoglobin levels and combined cognitive and physical decline may represent potentially modifiable risk factors and should be confirmed in future studies.

BackgroundCognitive impairment is an important contributor to disability. Limited clinical trial evidence exists regarding the impact of physical exercise on cognitive function (CF). We report results of a pilot study to provide estimates of the relative impact of physical activity (PA) on 1-year changes in cognitive outcomes and to characterize relationships between changes in mobility disability and changes in cognition in older adults at increased risk for disability.

OBJECTIVES: To examine dog walking among dog owners and the relationship between walking behavior of dog owners and non‐dog owners and maintained gait speed over 3 years. DESIGN: Cross‐sectional and longitudinal analyses of a prospective cohort study. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Two thousand five hundred thirty‐three community‐dwelling adults aged 71 to 82 at 36 months of the Health, Aging and Body Composition Study. MEASUREMENTS: Dog ownership, reported walking behavior, change in walking behavior, and usual and rapid gait speed over 3 years. RESULTS: Of 394 dog owners, only 36% walked their dogs at least three times per week. Cross‐sectionally, dog walkers were more likely to achieve 150 minutes of walking per week and had faster usual and rapid walking speeds (1.20 vs 1.14 m/s and 1.62 vs 1.52 m/s, respectively; P &lt;.01 for both) than non‐dog owners who did not walk at least three times per week and similar speeds as non‐dog owners who walked at least 150 minutes per week ( P &gt;.50). Three years later, subjects who had been dog walkers at baseline were approximately twice as likely as any other group to achieve recommended walking levels, independent of covariates. Dog walkers experienced similar declines in usual and rapid walking speed as non‐dog owners who walked at least three times per week but maintained their initial mobility advantage. CONCLUSION: Although dog ownership appears to facilitate walking behavior, only a minority of older dog owners walk their dogs. The mobility advantage of dog ownership was seen only in dog walkers and was similar to that associated with any walking. Given suboptimal walking activity in older adults, examining the degree to which dog ownership promotes walking activity in persons who do little walking on their own appears worth pursuing.

<h3>Background</h3> Cross-sectional studies find an elevated prevalence of depression among subjects with diabetes mellitus (DM). The causal mechanisms and temporal sequence of this association have not been clearly delineated. This study investigated the prospective relationship between DM and depressive symptoms. <h3>Methods</h3> The Health, Aging, and Body Composition Study was a cohort study conducted in the metropolitan areas of Memphis, Tenn, and Pittsburgh, Pa. The analysis included 2522 community-dwelling subjects, aged 70 to 79 years, without baseline depressive symptoms. Incident depressed mood was defined as use of antidepressants at follow-up visits or presence of depressive symptoms (score ≥10 on the 10-item Center for Epidemiological Studies Depression scale). Presence of incident depressed mood at 2 consecutive annual clinic visits defined the incidence of recurrent depressed mood. Diabetes mellitus status, glycosylated hemoglobin (HbA1c) level, and DM-related comorbidities were assessed at baseline. Diabetes mellitus status was further characterized as absent, controlled (HbA1c level &lt;7%), or uncontrolled (HbA1c level ≥7%). Discrete time survival analysis was used to estimate depressive events risk. <h3>Results</h3> During a mean follow-up of 5.9 years, participants with DM had a higher age-, sex-, race-, and site-adjusted incidence of depressed mood (23.5% vs 19.0%) (<i>P</i> = .02) and recurrent depressed mood (8.8% vs 4.3%) (<i>P</i>&lt;.001) than those without DM. Diabetes mellitus was associated with a 30% increased risk of incident depressed mood (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.07-1.61), which was attenuated after adjustment for DM-related comorbidities (OR, 1.20; CI, 0.97-1.48). A stronger relationship was observed between DM and recurrent depressed mood (OR, 1.91; CI, 1.32-2.76), particularly among participants with poor glycemic control. <h3>Conclusion</h3> Among well-functioning older adults, DM is associated with increased risk of depressive symptoms.

Background.The concept of sarcopenia has expanded recently to include muscle strength or physical performance. We investigated whether the Europe Working Group on Sarcopenia in Older People (EWGSOP) definition of sarcopenia predicts the risk of all-cause mortality in community-dwelling older adults.

Pericardial fat has a higher secretion of inflammatory cytokines than subcutaneous fat. Cytokines released from pericardial fat around coronary arteries may act locally on the adjacent cells.We examined the relationship between pericardial fat and calcified coronary plaque.Participants in the community-based Multi-Ethnic Study of Atherosclerosis (MESA) underwent a computed tomography (CT) scan for the assessment of calcified coronary plaque in 2000/2002. We measured the volume of pericardial fat using these scans in 159 whites and blacks without symptomatic coronary heart disease from Forsyth County, NC, aged 55-74 years.Calcified coronary plaque was observed in 91 participants (57%). After adjusting for height, a 1 s.d. increment in pericardial fat was associated with an increased odds of calcified coronary plaque (odds ratio (95% confidence interval): 1.92 (1.27, 2.90)). With further adjustment of other cardiovascular factors, pericardial fat was still significantly associated with calcified coronary plaque. This relationship did not differ by gender and ethnicity. On the other hand, BMI and height-adjusted waist circumference were not associated with calcified coronary plaque.Pericardial fat is independently associated with calcified coronary plaque.

Objective: We aimed to determine whether hearing impairment (HI) in older adults is associated with the development of frailty and falls. Method: Longitudinal analysis of observational data from the Health, Aging and Body Composition study of 2,000 participants aged 70 to 79 was conducted. Hearing was defined by the pure-tone-average of hearing thresholds at 0.5, 1, 2, and 4 kHz in the better hearing ear. Frailty was defined as a gait speed of &lt;0.60 m/s and/or inability to rise from a chair without using arms. Falls were assessed annually by self-report. Results: Older adults with moderate-or-greater HI had a 63% increased risk of developing frailty (adjusted hazard ratio [HR] = 1.63, 95% confidence interval [CI] = [1.26, 2.12]) compared with normal-hearing individuals. Moderate-or-greater HI was significantly associated with a greater annual percent increase in odds of falling over time (9.7%, 95% CI = [7.0, 12.4] compared with normal hearing, 4.4%, 95% CI = [2.6, 6.2]). Discussion: HI is independently associated with the risk of frailty in older adults and with greater odds of falling over time.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Although several cross-sectional studies have linked obesity and depression, less is known about their longitudinal association and about the relative influence of obesity subtypes. We prospectively examined whether obesity (specifically, abdominal) increased the risk of onset of depression in a population-based sample of older persons.Participants were 2,547 nondepressed, well-functioning white and black persons, aged 70-79 years, enrolled in the Health, Aging, and Body Composition Study, an ongoing prospective community-based cohort study. Baseline measurements were conducted between April 1997 and June 1998. Overall obesity was assessed by body mass index (BMI) and percent body fat (measured by dual energy x-ray absorptiometry), whereas abdominal obesity measures included waist circumference, sagittal diameter, and visceral fat (measured by computer tomography). Onset of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression 10-item score > or = 10 at any annual follow-up over 5 years and/or new antidepressant medication use. Persistent depression was defined as depression at 2 consecutive follow-up visits.Over 5 years, significant depressive symptoms emerged in 23.7% of initially nondepressed persons. In men, both overall (BMI: hazard ratio [HR] per SD increase = 1.20; 95% CI, 1.03-1.40) and abdominal obesity (visceral fat: HR per SD increase = 1.19; 95% CI, 1.07-1.33) predicted onset of depressive symptoms after adjustment for sociodemographics. When BMI and visceral fat were adjusted for each other, only visceral fat was significantly associated with depression onset (HR = 1.18; 95% CI, 1.04-1.34). Stronger associations were found for persistent depressive symptoms. No associations were found in women.This study shows that obesity, in particular visceral fat, increases the risk of onset of significant depressive symptoms in men. These results suggest that specific mechanisms might relate visceral fat to the onset of depression.

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

Mobility limitations are prevalent, potentially reversible precursors to mobility loss that may go undetected in older adults. This study evaluates standardized administration of an endurance walk test for identifying unrecognized and impending mobility limitation in community elders.Men and women (1480 and 1576, respectively) aged 70-79 years with no reported mobility limitation participating in the Health, Aging and Body Composition study were administered the Long Distance Corridor Walk. Walk performance was examined to determine unrecognized mobility deficits at baseline and predict new self-recognition of mobility limitation within 2 years.On testing, 23% and 36% of men and women evidenced mobility deficits defined as a contraindication to exertion, meeting stopping criteria or exceeding 7 minutes to walk 400 m. Unrecognized deficits increased with age and were more prevalent in blacks, smokers, obese individuals, and infrequent walkers. Within 2 years, 21% and 34% of men and women developed newly recognized mobility limitation; those with baseline unrecognized deficits had higher rates, 40% and 54% (p <.001), respectively. For each additional 30 seconds over 5 minutes needed to walk 400 m, likelihood of newly recognized mobility limitation increased by 65% and 37% in men and women independent of age, race, obesity, smoking status, habitual walking, reported walking ease, and usual gait speed.A sizable proportion of elders who report no walking difficulty have observable deficits in walking performance that precede and predict their recognition of mobility limitation. Endurance walk testing can help identify these deficits and provide the basis for treatment to delay progression of mobility loss.

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

Objectives To test the feasibility and utility of a bedside geriatric assessment ( GA ) to detect impairment in multiple geriatric domains in older adults initiating chemotherapy for acute myelogenous leukemia ( AML ). Design Prospective observational cohort study. Setting Single academic institution. Participants Individuals aged 60 and older with newly diagnosed AML and planned chemotherapy. Measurements Bedside GA was performed during inpatient exmination for AML . GA measures included the modified Mini‐Mental State Examination; Center for Epidemiologic Studies Depression Scale; Distress Thermometer, Pepper Assessment Tool for Disability (includes self‐ reported activities of daily living ( ADL s), instrumental ADL s, and mobility questions); Short Physical Performance Battery (includes timed 4‐m walk, chair stands, standing balance); grip strength, and Hematopoietic Cell Transplantation Comorbidity Index. Results Of 54 participants (mean age 70.8 ± 6.4) eligible for this analysis, 92.6% completed the entire GA battery (mean time 44.0 ± 14 minutes). The following impairments were detected: cognitive impairment, 31.5%; depression, 38.9%; distress, 53.7%; impairment in ADLs , 48.2%; impaired physical performance, 53.7%; and comorbidity, 46.3%. Most were impaired in one (92.6%) or more (63%) functional domains. For the 38 participants rated as having good performance status according to standard oncologic assessment (Eastern Cooperative Oncology Performance Scale score ≤1), impairments in individual GA measures ranged from 23.7% to 50%. Significant variability in cognitive, emotional, and physical status was detected even after stratification according to tumor biology (cytogenetic risk group classification). Conclusion Inpatient GA was feasible and added new information to standard oncology assessment, which may be important for stratifying therapeutic risk in older adults with AML .

As researchers, journal editors, and representatives of non-governmental organisations, we are writing to express our concern about the way in which the health implications of population ageing are misrepresented in the media, in policy debates, and sometimes in academic research. Ageing is most often framed in negative terms, questioning whether health services, welfare provision, and economic growth are sustainable. We argue that, instead of being portrayed as a problem, increased human longevity should be a cause for celebration. Moreover, population ageing provides opportunities to rethink health policy for the benefit of all—old and young. Depictions of older people remain stereotyped and generalised, distorting public opinion and skewing policy debates. For example, the use of economic dependency ratios, one of the commonest measures of ageing, assumes that anyone aged 65 years or older is unproductive. Similarly, the use of disability-adjusted life years to capture the health of a population explicitly views older people as a social and economic burden. Yet many older people continue to make substantial social, economic, and cultural contributions, which can be enhanced by measures that improve their health and functional status. Obviously we recognise that the ideals of active ageing might not be achievable for every older person, particularly if they have complex comorbidity or severe cognitive impairments. The economic and non-economic costs of care provision for these people are undeniable and will rise as the numbers surviving to very old ages increase. Yet their experiences cannot be extrapolated to older people in general; the effects of population ageing on health spending are not as inelastic as is often claimed. This is particularly true in low-income and middle-income countries, where the relation between health needs and spending is, at best, tenuous. In all countries, demographic effects are strongly mediated by a wide range of unrelated effects, many of which depend on political decisions. Health spending and health-service use are more closely associated with how close one is to death than with chronological age. Indeed, it is often the case that less is spent on older people than on younger people with similar conditions. The key issue in determining the relation between population ageing and health spending is the health and functional status of older people. The association between chronological age and health status is much more variable than is often realised, particularly for those at relatively younger ages (60s and 70s). Newly available data from WHO1WHOWHO Study on global AGEing and adult health (SAGE).http://www.who.int/healthinfo/systems/sage/en/index.htmlGoogle Scholar show substantial differences in the health and functional status of older populations in different developing countries. There are also substantial differences in health status within the UK and other developed countries. We still do not understand fully these complex variations in health and functional status. Nevertheless, there is clear evidence that they can be affected substantially by relatively cheap and simple interventions such as the effective management of hypertension, diabetes, and hypercholesterolaemia, and the promotion of healthy lifestyles, in particular regular physical activity.2Lim S Gaziano T Gakidou E et al.Prevention of cardiovascular disease in high-risk individuals in low and middle income countries: health effects and costs.Lancet. 2007; 370: 2054-2062Summary Full Text Full Text PDF PubMed Scopus (271) Google Scholar Yet in most countries these interventions are not available to large sections of adult populations. The failure of national governments and international agencies to prioritise these cheap and effective treatments represents a missed opportunity to reduce mortality, illness, and disability on an unprecedented scale. Although the non-communicable disease (NCD) agenda has gathered some momentum in recent years, international health spending in low-income and middle-income countries remains heavily focused on infectious diseases and mother and child health. Yet now that NCDs are on the policy agenda, there are worrying signs of discrimination against older people. Background documents from the UN High-Level Meeting in September, 2010, describe the deaths of people younger than 60 or 70 years as “premature mortality”,3WHOAccelerating the MDGs by addressing NCDs: MDG side-event on non-communicable diseases (New York, 20 September 2010).http://www.who.int/nmh/events/2010/discussion_paper_20100920.pdfGoogle Scholar implying that deaths of people at older ages should receive a lower priority. If we do not challenge existing policy paradigms and the social attitudes that underpin them, population ageing might indeed lead to a crisis in the provision of health and welfare services. Instead, we should see it as a welcome opportunity to challenge outdated public perceptions, political priorities, and policy models. This challenge will include reorientating health and welfare models to deliver more efficient, equitable, and sustainable interventions. It might also include the diversion of resources from consumer spending, which in many countries has risen spectacularly over the past 30 years, towards meeting the needs of vulnerable people, whatever their age. This is an overtly political challenge; responding positively to it will benefit people of all ages in all societies. Participation by LF does not necessarily represent the views of the National Institute on Aging, the National Institutes of Health, or the US Department of Health & Human Services. We declare that we have no conflicts of interest. Ageing well: a global priorityApril 7 is World Health Day , the theme of which is ageing. Globally, we are getting older. 5 years from now, for the first time in history, the number of people aged 65 years and older will outnumber children younger than 5 years. Advances in medicine, socioeconomic development, and declining fertility have all contributed to this demographic shift, and countries need to adapt to this change in a positive and inclusive way. Full-Text PDF

the xanthophylls lutein (L) and zeaxanthin (Z) exist in relatively high concentration in multiple central nervous tissues (e.g. cortex and neural retina). L + Z in macula (i.e. macular pigment, MP) are thought to serve multiple functions, including protection and improvement of visual performance. Also, L + Z in the macula are related to L + Z in the cortex.to determine whether macular pigment optical density (MPOD, L + Z in the macula) is related to cognitive function in older adults.participants were older adults (n = 108, 77.6 ± 2.7 years) sampled from the age-related maculopathy ancillary study of the Health Aging and Body Composition Study (Memphis, TN, USA). Serum carotenoids were measured using high performance liquid chromatography. MPOD was assessed using heterochromatic flicker photometry. Eight cognitive tests designed to evaluate several cognitive domains including memory and processing speed were administered. Partial correlation coefficients were computed to determine whether cognitive measures were related to serum L + Z and MPOD.MPOD levels were significantly associated with better global cognition, verbal learning and fluency, recall, processing speed and perceptual speed, whereas serum L + Z was significantly related to only verbal fluency.MPOD is related to cognitive function in older people. Its role as a potential biomarker of cognitive function deserves further study.

C HRONIC infl ammation is a key component of aging- related pathologies ( 1 ).For example, higher levels of the infl ammatory biomarker C-reactive protein (CRP) are associated with increased risk of cardiovascular and noncardiovascular morbidity and mortality ( 2 , 3 ) as well as dementia, sarcopenia , and osteoporosis ( 4 ).Many studies have likewise shown associations of interleukin-6 (IL-6) with aging-related declines in physical and cognitive function, frailty , and increased risk of death in older adults ( 5 -10 ).Other infl ammatory markers have also been associated with the components of the frail phenotype ( 11 ) as well as frailty itself ( 12 ) .Little is known about how infl ammation evolves over time.Aging is a dynamic and complex process.There is remarkable heterogeneity in rates of declines in physical and cognitive functioning ( 13 ).Infl ammation status likely also changes over time.We hypothesized that change in infl ammation status over time would be more strongly associated

To determine whether preservation of physical function with aging may be partially met through modification in dietary protein intake.Prospective cohort study.Women's Health Initiative (WHI) Clinical Trials (CT) and Observational Study (OS) conducted at 40 clinical centers.Women aged 50 to 79 (N = 134,961) with dietary data and one or more physical function measures.Physical function was assessed using the short-form RAND-36 at baseline and annually beginning in 2005 for all WHI participants and at closeout for CT participants (average ~7 years after baseline). In a subset of 5,346 participants, physical performance measures (grip strength, number of chair stands in 15 seconds, and timed 6-m walk) were assessed at baseline and Years 1, 3, and 6. Calibrated energy and protein intake were derived from regression equations using baseline food frequency questionnaire data collected on the entire cohort and doubly labeled water and 24-hour urinary nitrogen collected from a representative sample as reference measures. Associations between calibrated protein intake and each of the physical function measures were assessed using generalized estimating equations.Calibrated protein intake ranged from 6.6% to 22.3% energy. Higher calibrated protein intake at baseline was associated with higher self-reported physical function (quintile (Q)5, 85.6, 95% confidence interval (CI) = 81.9-87.5; Q1, 75.4, 95% CI = 73.2-78.5, P trend = .002) and a slower rate of functional decline (annualized change: Q5, -0.47, 95% CI = -0.63 to -0.39; Q1, -0.98, 95% CI = -1.18 to -0.75, P trend = .02). Women with higher calibrated protein intake also had greater grip strength at baseline (Q5, 24.7 kg, 95% CI = 24.3-25.2 kg; Q1, 24.1 kg, 95% CI = 23.6-24.5 kg, P trend = .04) and slower declines in grip strength (annualized change: Q5, -0.45 kg, 95% CI = -0.39 to -0.63 kg; Q1, -0.59 kg, 95% CI = -0.50 to -0.66 kg, P trend = .03). Women with higher calibrated protein intake also completed more chair stands at baseline (Q5, 7.11, 95% CI = 6.91-7.26; Q1, 6.61, 95% CI = 6.46-6.76, P trend = .002).Higher calibrated protein intake is associated with better physical function and performance and slower rates of decline in postmenopausal women.

Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

Although there is evidence linking smoking and heart failure (HF), the association between lifetime smoking exposure and HF in older adults and the strength of this association among current and past smokers is not well known.We examined the association between smoking status, pack-years of exposure, and incident HF risk in 2,125 participants of the Health, Aging, and Body Composition Study (age 73.6 ± 2.9 years, 69.7% women, 54.2% whites) using proportional hazard models.At inception, 54.8% of participants were nonsmokers, 34.8% were past smokers, and 10.4% were current smokers. During follow-up (median 9.4 years), HF incidence was 11.4 per 1,000 person-years in nonsmokers, 15.2 in past smokers (hazard ratio [HR] vs nonsmokers 1.33, 95% CI 1.01-1.76, P = .045), and 21.9 in current smokers (HR 1.93, 95% CI 1.30-2.84, P = .001). After adjusting for HF risk factors, incident coronary events, and competing risk for death, a dose-effect association between pack-years of exposure and HF risk was observed (HR 1.09, 95% CI 1.05-1.14, P < .001 per 10 pack-years). Heart failure risk was not modulated by pack-years of exposure in current smokers. In past smokers, HR for HF was 1.05 (95% CI 0.64-1.72) for 1 to 11 pack-years, 1.23 (95% CI 0.82-1.83) for 12 to 35 pack-years, and 1.64 (95% CI 1.11-2.42) for >35 pack-years of exposure in fully adjusted models (P < .001 for trend) compared with nonsmokers.In older adults, both current and past cigarette smoking increase HF risk. In current smokers, this risk is high irrespective of pack-years of exposure, whereas in past smokers, there was a dose-effect association.

Aging-related illnesses are increasing and effective strategies to prevent and/or treat them are lacking. This is because of a poor understanding of therapeutic targets. Low-grade inflammation is often higher in older adults and remains a key risk factor of aging-related morbidities and mortalities. Emerging evidence indicates that abnormal (dysbiotic) gut microbiome and dysfunctional gut permeability (leaky gut) are linked with increased inflammation in older adults. However, currently available drugs do not treat aging-related microbiome dysbiosis and leaky gut, and little is known about the cellular and molecular processes that can be targeted to reduce leaky gut in older adults. Here, we demonstrated that metformin, a safe Food and Drug Administration-approved antidiabetic drug, decreased leaky gut and inflammation in high-fat diet-fed older obese mice, by beneficially modulating the gut microbiota. In addition, metformin increased goblet cell mass and mucin production in the obese older gut, thereby decreasing leaky gut and inflammation. Mechanistically, metformin increased the goblet cell differentiation markers by suppressing Wnt signaling. Our results suggest that metformin can be used as a regimen to prevent and treat aging-related leaky gut and inflammation, especially in obese individuals and people with western-style high-fat dietary lifestyle, by beneficially modulating gut microbiome/goblet cell/mucin biology.

Cellular metabolism and environmental interactions generate molecular damage affecting all levels of biological organization. Accumulation of this damage over time is thought to have a central role in the aging process. Insufficient attention has been paid to the role of molecular damage in aging-related phenotypes, particularly in humans, in part because of the difficulty in measuring its various forms. Recently, omics approaches have been developed that begin to address this challenge, because they can assess a sizable proportion of age-related damage at the level of small molecules, proteins, RNA, DNA, organelles and cells. This Review describes the concept of molecular damage in aging and discusses its diverse aspects from theoretical models to experimental approaches. Measurement of multiple types of damage enables studies of the role of damage in aging and lays a foundation for testing interventions that reduce the burden of molecular damage, thereby targeting aging. In this Review, the authors discuss the concept of molecular damage in aging, from theoretical models to experimental approaches and how to test interventions targeting aging that reduce its burden.

Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness, is largely understudied.In the Study of Muscle, Mobility, and Aging, we collected vastus lateralis biopsies from older adults (n = 879, 70-94 years, 59.2% women). Maximal State 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2 peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta coefficients expressed per 1-SD increment in the independent variable.Max OXPHOS was associated with leg power for both women (β = 0.12 Watts/kg, p < .001) and men (β = 0.11 Watts/kg, p < .050). ATPmax was associated with leg power for men (β = 0.09 Watts/kg, p < .05) but was not significant for women (β = 0.03 Watts/kg, p = .11). Max OXPHOS and ATPmax were associated with VO2 peak in women and men (Max OXPHOS, β women = 1.03 mL/kg/min, β men = 1.32 mL/kg/min; ATPmax β women = 0.87 mL/kg/min, β men = 1.50 mL/kg/min; all p < .001).Higher muscle mitochondrial energetics measures were associated with both better cardiorespiratory fitness and greater leg power in older adults. Muscle mitochondrial energetics explained a greater degree of variance in VO2 peak compared to leg power.

Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE) (control) in 5,145 individuals with overweight/obesity and type 2 diabetes, found no significant differences in all-cause or cardiovascular mortality or morbidity during 9.6 (median) years of intervention. Participants in ILI who lost ≥10% at 1 year had lower risk of composite cardiovascular outcomes relative to DSE. Since effects of ILI may take many years to emerge, we conducted intent-to-treat analyses comparing mortality in ILI over 16.7 years (9.6 years of intervention and then observation) to DSE. In a secondary exploratory analysis, we compared mortality by magnitude of weight loss in ILI relative to DSE.Primary outcome was all-cause mortality from randomization to 16.7 years. Other outcomes included cause-specific mortality, interactions by subgroups (age, sex, race/ethnicity, and cardiovascular disease history), and an exploratory analysis by magnitude of weight loss in ILI versus DSE as reference. Analyses used proportional hazards regression and likelihood ratio.The incidence of all-cause mortality did not differ significantly in ILI and DSE (549 and 589 participants, respectively) (hazard ratio [HR] 0.91 [95% CI 0.81, 1.02]; P = 0.11). There were no significant differences between treatments in cause-specific mortality or within prespecified subgroups. ILI participants who lost ≥10% at 1 year had a 21% reduced risk of mortality (HR 0.79 [95% CI 0.67, 0.94]; P = 0.007) relative to DSE.ILI focused on weight loss did not significantly affect mortality risk. However, ILI participants who lost ≥10% had reduced mortality relative to DSE.

Abstract Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community‐based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO 2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO 2 peak, while greater oxidation of myomesin‐1, myomesin‐2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin‐2, alpha‐actinin‐2, and skeletal muscle alpha‐actin were associated with lower leg power and strength. We also observed an unexpected correlation ( R = 0.48) between a higher oxidation level of eight Cys sites in alpha‐actinin‐3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

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.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<0.001). The odds ratio for high CHD risk in the highest quintile of oxLDL, compared with the lowest quintile and after adjusting for age, sex, race, LDL cholesterol, smoking status, and C-reactive protein, was 2.79 (P<0.001).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.

ContextTraumatic or bloody lumbar puncture (LP) reduces the diagnostic value of the procedure and may worsen the outcome of patients with acute lymphoblastic leukemia (ALL). Little is known about the risk factors for traumatic and bloody LP.ObjectivesTo determine the risk factors for traumatic and bloody LP.Design, Setting, and PatientsRetrospective cohort study of 956 consecutive patients with newly diagnosed childhood ALL who were treated at a pediatric cancer center between February 1984 and July 1998.InterventionsAll patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy.Main Outcome MeasureTraumatic LP was defined as an LP in which cerebrospinal fluid contained at least 10 red blood cells (RBCs) per microliter and bloody LP as one in which the cerebrospinal fluid contained at least 500 RBCs per microliter.ResultsOf the 5609 LPs evaluated, 1643 (29%) were traumatic and 581 (10%) were bloody. The estimated odds ratios (ORs) and 95% confidence intervals (CIs) for traumatic LP were 1.5 (95% CI, 1.2-1.8) for black vs white race, 2.3 (95% CI, 1.7-3.0) for age younger than 1 year vs 1 year or older, 1.4 (95% CI, 1.2-1.7) for early vs recent (dedicated procedure area and general anesthesia) treatment era, 1.5 (95% CI, 1.2-1.8) for platelet count of 100 × 103/µL or more vs less than 100 × 103/µL, 10.8 (95% CI, 7.7-15.2) for short (1 day) vs longer (&gt;15 days) interval since the previous LP, and 1.4 (95% CI, 1.1-1.8) for the least vs the most experienced practitioners. Analyses for bloody LP yielded similar results.ConclusionsThe unmodifiable risk factors for traumatic and bloody LP include black race, age younger than 1 year, a traumatic or bloody previous LP performed within the past 2 weeks, and a previous LP performed when the platelet count was 50 × 103/µL or less. Modifiable risk factors include procedural factors reflected in treatment era, platelet count of 100 × 103/µL or less, an interval of 15 days or less between LPs, and a less experienced practitioner.

Rationale: Elevated proinflammatory cytokines are associated with severity of pneumonia, but the role of preinfection cytokine levels in the predisposition to pneumonia in humans is less clear.Objective: To ascertain role of preinfection inflammatory markers on susceptibility to community-acquired pneumonia (CAP).Methods: Longitudinal analysis over 6.5 yr of a cohort that consisted of 70- to 79-yr-old well-functioning elderly individuals.Measurements: Association between preinfection tumor necrosis factor (TNF), interleukin 6 (IL-6), and C-reactive protein (CRP) levels and CAP requiring hospitalization.Results: Of the 3,075 participants, 161 (5.2%) developed at least one episode of CAP requiring hospitalization over a median duration of 3.3 yr. The highest tertiles of TNF (> 3.7 pg/ml) and IL-6 (> 2.4 pg/ml) were associated with increased risk of CAP, and the adjusted odds ratios were 1.6 (95% confidence interval [CI], 1.02–2.7) and 1.7 (95% CI, 1.1–2.8), respectively. The adjusted risk of CAP with at least one of these markers in the highest tertile was 1.6 (95% CI, 1.1–2.3). TNF and IL-6 levels in the highest tertile had a synergistic effect (p = 0.01 for interaction), and risk of CAP for both markers in the highest tertile was 2.8 (95% CI, 1.8–4.3). An FEV1 of 50% or less of predicted was associated with the highest risk of CAP (adjusted odds ratio, 3.6; 95% CI, 2.3–5.6). Furthermore, TNF and IL-6 levels modified risk of CAP in participants with coexisting medical conditions and history of smoking.Conclusion: In the well-functioning elderly subjects, preinfection systemic levels of TNF and IL-6 were associated with higher risk of CAP requiring hospitalization in smokers and those with coexisting medical conditions.

The effect of the recent obesity epidemic on body composition remains unknown. Furthermore, age-related changes in body composition are still unclear.The objective was to simultaneously examine the effects of birth cohort and age on body composition.A total of 1786 well-functioning, community-based whites and blacks (52% women and 35% blacks) aged 70-79 y from the Health, Aging, and Body Composition Study underwent dual-energy X-ray absorptiometry annually from 1997 to 2003.At baseline, mean +/- SD percentage body fat, fat mass, and lean mass (bone-free) were 28 +/- 5%, 24 +/- 7 kg, and 56 +/- 7 kg, respectively, for men and 39 +/- 6%, 28 +/- 9 kg, and 40 +/- 6 kg for women. Mixed models were used to assess the effects of cohort and age-related changes on body composition. Later cohorts in men had a greater percentage body fat (0.32% per birth year, P < 0.0001) than did earlier cohorts. This cohort effect was due to a greater increase in fat mass than in lean mass (0.45 kg and 0.17 kg/birth year, respectively). With increasing age, percentage body fat in men initially increased and then leveled off. This age-related change was due to an accelerated decrease in lean mass and an initial increase and a later decrease in fat mass. Similar but less extreme effects of cohort and age were observed in women.The combination of effects of both birth cohort and age leads to bigger body size and less lean mass in the elderly.

BMD was examined in users of NSAIDs (by COX selectivity) and aspirin in the Health ABC cohort (n = 2853). Significantly higher BMD was found in users of relative COX-2 selective NSAIDs with aspirin (COX-2/ASA) compared with nonusers. This suggests a role for COX-2/ASA in osteoporosis.The purpose of this study was to determine the relationship of nonsteroidal anti-inflammatory drug (NSAID) use, by cyclo-oxygenase selectivity (COX), and aspirin use on bone mineral density (BMD) in participants from the Health, Aging, and Body Composition (Health ABC) population-based cohort. It is known that NSAIDs inhibit the COX enzyme and decrease production of prostaglandins, which are involved in regulation of bone turnover. COX has two isoforms, COX-1 and COX-2. Production of prostaglandins associated with bone loss is primarily mediated through the COX-2 pathway. In addition, aspirin may have effects on bone independent of the prostaglandin pathway.NSAID (by COX selectivity) and aspirin use and BMD were assessed in 2853 adults (49.5% women, 50.5% men: 43.1% black, 56.9% white; mean age: 73.6 years) from the Health ABC cohort. For the purposes of this analysis, relative COX-1 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of > 1 in whole blood, and relative COX-2 selective NSAIDs were defined as having a ratio of COX-1 IC50 to COX-2 IC50 of < 1 in whole blood. Analysis of covariance was used to compare BMD across each NSAID use and aspirin use category adjusting for age, race, gender, weight, height, study site, calcium and vitamin D supplementation, Womac score, history of rheumatoid arthritis, history of arthritis other than rheumatoid, and smoking status.After adjustment for possible confounders, current use of relative COX-2 selective NSAIDs with aspirin was associated with higher BMD at the whole body (4.2%, 1.2-7.3 CI) and total hip (4.6%, 0.5-8.8 CI) by DXA and at both trabecular (34.1%, 15.4-52.7 CI) and cortical spine (12.8%, 2.3-23.3 CI) by quantitative computed tomography.Our data suggest that the combination of relative COX-2 selective NSAIDs and aspirin is associated with higher BMD at multiple skeletal sites in men and women.

Objectives: To evaluate whether older persons using angiotensin‐converting enzyme (ACE) inhibitors have a larger lower extremity muscle mass (LEMM) than users of other antihypertensive drugs. Design: Cross‐sectional analysis of data from the Health, Aging and Body Composition (Health ABC) Study. Setting: University of Tennessee, Memphis, and University of Pittsburgh clinics. Participants: A community‐based sample of 2,431 well functioning participants of the Health ABC, aged 70 to 79, who were free of heart failure, were selected according to use of antihypertensive medications: ACE inhibitors (n=197), β‐blockers (n=169), thiazides (n=216), calcium‐channel blockers (n=340), or none (n=1,509). Measurements: LEMM, assessed using dual‐energy x‐ray absorptiometry, compared by index drug in analysis of variance models unadjusted and adjusted for demographics, study site, height, body fat, physical activity, blood pressure, coronary artery disease, diabetes mellitus, and chronic pulmonary disease. Results: LEMM significantly differed across the study groups, being larger in users of ACE inhibitors than in users of other drugs (unadjusted and adjusted models). LEMM was comparable in users of ACE inhibitors and no drug users. A trend toward larger LEMM was also observed in sex‐ and ethnicity‐stratified analyses and in the subgroup of noncoronary hypertensive participants. Conclusion: In older persons, use of ACE inhibitors is associated cross‐sectionally with larger LEMM. This finding suggests a possible explanation of the benefits of ACE inhibitors in wasting syndromes. If confirmed in longitudinal studies, this pharmacological action might have important implications for the prevention of physical disability in older patients with hypertension.

To test the hypothesis that increased long-term mortality after hospitalization for community-acquired pneumonia (CAP) is independent of comorbid conditions.Prospective observational cohort study in metropolitan areas.Memphis, Tennessee, and Pittsburgh, Pennsylvania.Three thousand seventy-five subjects aged 70 to 79 over 5.2 years.Unadjusted and adjusted mortality from an initial hospitalization for CAP were compared with mortality from different causes of hospitalization, including cancer, fracture, congestive heart failure (CHF), cerebrovascular accident (CVA), and other causes. Demographics, smoking, nutritional markers, functional status, inflammatory markers, and chronic health conditions were adjusted for.Of the 106 subjects hospitalized for CAP, 22 (20.8%) and 38 (35.8%) died at 1 and 5 years. Subjects hospitalized with CAP had higher mortality than nonhospitalized subjects (adjusted odds ratio (OR)=7.8, 95% confidence interval (CI)=4.2-14.4). One- and 5-year mortality after CAP hospitalization were higher than mortality from other causes requiring hospitalization and remained unchanged in multivariable analysis (adjusted OR=3.5, 95% CI=1.5-8.1; adjusted OR=5.6, 95% CI=2.8-11.2, respectively). One- and 5-year mortality after hospitalization for CAP were similar to or higher than mortality after an initial hospitalization for CHF, CVA, or fracture. Rehospitalization was common in subjects hospitalized for CAP and may explain greater long-term mortality.In this high-functioning cohort of older persons, an initial hospitalization for CAP was associated with greater long-term mortality, independent of prehospitalization comorbid conditions. Hospitalization for CAP has as serious a prognosis as hospitalization for CHF, stroke, or major fracture.

The LIFE study is a multicenter pilot for a proposed full scale, two-arm randomized controlled trial that will contrast the effect of a physical activity intervention with a successful aging education program on the occurrence of incident major mobility disability (the inability to complete a 400 m walk) or death in at-risk sedentary older adults. Four hundred older adults from 4 clinical sites will be recruited for this purpose. All participants will be followed for at least 1-year; however, we will continue to follow all participants until the final randomized individual has reached the 1-year mark. This will enable us to acquire additional information about maintenance. Additional outcomes will include lower extremity physical performance as well as gait speed over 4 m and 400 m. These latter measures will provide data on the efficacy of the intervention on intermediate endpoints linked to the primary outcome of interest. The goals of the pilot study are to (a) estimate the sample size needed for a full scale trial, (b) examine the consistency of the effects of the physical activity intervention on several continuous measures of physical function, (c) assess the feasibility of recruitment, (d) evaluate study adherence and retention, (d) evaluate the efficacy of a stepped care approach for managing intercurrent illness in this at-risk population, and (e) develop a comprehensive system for monitoring and ensuring participant safety. Other goals of this pilot phase include assessments of health-related quality of life and cost-effectiveness.

Sex steroid hormone levels decline with age and in some studies this decline has been linked with depressive symptoms. This study investigates the association between total testosterone, free testosterone, and DHEAS levels with depressive symptoms in a well-functioning elderly population.Data are from 2855 well-functioning elderly men and women, 70-79 years of age, participating in the Health, Aging, and Body Composition study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression scale. Total testosterone, free testosterone, and DHEAS levels were assessed after an overnight fast.In men and women, DHEAS levels and depressive symptoms were inversely associated after adjustment for covariates (men: beta=-0.059, p=0.03, women: beta=-0.054, p=0.05). In addition, free testosterone levels in women, but not in men, were inversely associated with depressive symptoms (adjusted beta=-0.079, p=0.004). Men, but not women, in the lowest total testosterone quartile reported significantly more depressive symptoms than men in the other total testosterone quartiles (adjusted beta=-0.166, p=0.04).Our study is consistent with the idea that testosterone and DHEAS levels may play a role in mechanisms underlying depressive symptoms in old age.

Obesity in middle and old age predicts mobility limitation; however, the cumulative effect of overweight and/or obesity over the adult life course is unknown. The association between overweight and/or obesity in young, middle, and late adulthood and its cumulative effect on incident mobility limitation was examined among community-dwelling US adults aged 70-79 years at baseline (1997-1998) in the Health, Aging and Body Composition Study (n = 2,845). Body mass index was calculated by using recalled weight at ages 25 and 50 years and measured weight at ages 70-79 years. Mobility limitation (difficulty walking 1/4 mile (0.4 km) or climbing 10 steps) was assessed semiannually over 7 years of follow-up and was reported by 43.0% of men and 53.7% of women. Men and women who were overweight or obese at all 3 time points had an increased risk of mobility limitation (hazard ratio = 1.61, 95% confidence interval: 1.25, 2.06 and hazard ratio = 2.85, 95% confidence interval: 2.15, 3.78, respectively) compared with those who were normal weight throughout. Furthermore, there was a significant graded response (P < 0.0001) on risk of mobility limitation for the cumulative effect of obesity in men and overweight and/or obesity in women. Onset of overweight and obesity in earlier life contributes to an increased risk of mobility limitation in old age.

How serum albumin levels are associated with risk for heart failure (HF) in the elderly is unclear.We evaluated 2,907 participants without HF (age 73.6 +/- 2.9 years, 48.0% male, 58.7% white) from the community-based Health ABC Study. The association between baseline albumin and incident HF was assessed with standard and competing risks proportional hazards models controlling for HF predictors, inflammatory markers, and incident coronary events.During a median follow-up of 9.4 years, 342 (11.8%) participants developed HF. Albumin was a time-dependent predictor of HF, with significance retained for up to 6 years (baseline hazard ratio [HR] per -1 g/L 1.14, 95% CI 1.06-1.22, P < .001; annual rate of HR decline 2.1%, 95% CI 0.8%-3.3%, P = .001). This association persisted in models controlling for HF predictors, inflammatory markers, and incident coronary events (baseline HR per -1 g/L 1.13, 95% CI 1.05-1.22, P = .001; annual rate of HR decline 1.8%, 95% CI 0.5%-3.0%, P = .008) and when mortality was accounted for in adjusted competing risks models (baseline HR per -1 g/L 1.13, 95% CI 1.05-1.21, P = .001; annual rate of HR decline 1.9%, 95% CI 0.7%-3.1%, P = .002). The association of albumin with HF risk was similar in men (HR per -1 g/L 1.13, 95% CI 1.05-1.23, P = .002) and women (HR per -1 g/L 1.12, 95% CI 1.04-1.22, P = .005) and in whites and blacks (HR per -1 g/L 1.13, 95% CI 1.04-1.22, P< .01 for both races) in adjusted models.Low serum albumin levels are associated with increased risk for HF in the elderly in a time-dependent manner independent of inflammation and incident coronary events.

OBJECTIVES: To evaluate objective physical performance measures as predictors of survival and subsequent disability in older patients with cancer. DESIGN: Longitudinal cohort study. SETTING: Health, Aging and Body Composition (Health ABC) Study. PARTICIPANTS: Four hundred twenty‐nine individuals diagnosed with cancer during the first 6 years of follow‐up of the Health ABC Study. MEASUREMENTS: The associations between precancer measures of physical performance (20‐m usual gait speed, 400‐m long‐distance corridor walk (LDCW), and grip strength) and overall survival and a short‐term outcome of 2‐year progression to disability or death were evaluated. Cox proportional hazards and logistic regression models, stratified for metastatic disease, respectively, were used for outcomes. RESULTS: Mean age was 77.2, 36.1% were women, and 45.7% were black. Faster 20‐m usual walking speed was associated with a lower risk of death in the metastatic group (hazard ratio=0.89, 95% confidence interval (CI)=0.79–0.99) and lower 2‐year progression to disability or death in the nonmetastatic group (odds ratio (OR)=0.77, 95% CI=0.64–0.94). Ability to complete the 400‐m LDCW was associated with lower 2‐year progression to disability or death in the nonmetastatic group (OR=0.24, 95% CI=0.10–0.62). There were no associations between grip strength and disability or death. CONCLUSION: Lower extremity physical performance tests (usual gait speed and 400‐m LDCW) were associated with survival and 2‐year progression to disability or death. Objective physical performance measures may help inform pretreatment evaluations in older adults with cancer.

Impaired kidney function has been associated with increased risk for death, myocardial infarction, stroke, and heart failure in high-risk populations. We evaluated whether impaired kidney function predicted risk of fatal cardiovascular disease independent of prevalent and incident cardiovascular events.The Health, Aging, and Body Composition study is a cohort of well-functioning, elderly participants aged 70 to 79 years at entry. We measured serum cystatin C and creatinine from baseline plasma samples of 3044 participants and followed them over 6 years, examining the associations among kidney function, cardiovascular death, and incident cardiovascular events. Cystatin C was categorized as low (< 0.84 mg/L), medium (0.84-1.18 mg/L), or high (> or = 1.19 mg/L); serum creatinine (cutoff value of > or = 1.3 in women and > or = 1.5 in men) and estimated glomerular filtration rate (eGFR; greater and less than 60 mL/min per 1.73 m2) were dichotomized.During follow-up, 242 cardiovascular deaths occurred, of which 69 were in participants without prior cardiovascular events; 294 incident cardiovascular events occurred including 135 myocardial infarctions and 163 strokes. Higher cystatin C concentrations were significantly associated with cardiovascular death (adjusted hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.05-2.76 for the medium cystatin C group; and HR 2.24, 95% CI 1.30-3.86 for the high cystatin C group, relative to the low cystatin C group). The point estimate was of greater magnitude in the analysis that excluded prevalent cardiovascular disease (adjusted HR 2.68, 95% CI 0.94-7.70 for the medium cystatin C group; and HR 4.91, 95% CI, 1.55-15.54 for the high cystatin C group). Elevated creatinine levels (adjusted HR 1.54, 95% CI 1.02-2.33, and HR 2.28, 95% CI 1.10-4.73 among participants without a history of cardiovascular disease) were also associated with cardiovascular death. No significant association was found between low eGFR and cardiovascular death. In addition, cystatin C, low eGFR, or elevated creatinine levels were not associated with other cardiovascular events.Impaired kidney function is a strong predictor of cardiovascular death, particularly among participants without prior history of cardiovascular disease.

To examine joint associations of physical activity and adiposity measures (body mass index (BMI), waist circumference, percentage body fat) with incident mobility limitation.Prospective observational cohort study.Memphis, Tennessee and Pittsburgh, Pennsylvania.Two thousand nine hundred and eighty-two black and white men and women aged 70 to 79 participating in the Health, Aging and Body Composition (Health ABC) study.Mobility limitation was defined as reported difficulty walking one-quarter of a mile or climbing 10 steps during two consecutive semiannual assessments over 6.5 years. Three measures of adiposity were included in this study: BMI, total percentage body fat, and waist circumference. Physical activity was assessed using a modified leisure-time physical activity questionnaire.Forty-six percent of the cohort developed mobility limitation. White and black men with a high BMI (> or = 30 kg/m(2)), high total percentage body fat (> 31.3%), or high waist circumference (> or = 102 cm) had an approximately 60%, 40%, and 40%, respectively, higher risk of incident mobility limitation than those with low adiposity. In women, high adiposity was also associated with a significantly higher mobility limitation risk than in those with low adiposity. Low physical activity (lowest quartile) was associated with a 70% higher risk of mobility limitation in all groups. Persons with high adiposity and low physical activity were at particularly high risk of mobility limitation. People with high adiposity who were physically active had an equally high risk of mobility limitation as inactive people with low adiposity.High adiposity and low self-reported physical activity predicted the onset of mobility limitation in well-functioning older persons. Preventing weight gain in old age and promoting physical activity in obese and non-obese older persons may therefore be effective strategies to prevent mobility loss and future disability.

Objectives To examine the association between 25‐hydroxyvitamin D (25( OH ) D ) and physical function in adults of advanced age. Design Cross‐sectional and longitudinal analysis of physical function over 3 years of follow‐up in the Cardiovascular Health Study All Stars. Setting F orsyth County, N orth C arolina; S acramento County, C alifornia; W ashington County, M aryland; and A llegheny County, P ennsylvania. Participants Community‐dwelling adults aged 77 to 100 (N = 988). Measurements Serum 25‐hydroxyvitamin D 25( OH ) D ), Short Physical Performance Battery ( SPPB ), and grip and knee extensor strength assessed at baseline. Mobility disability (difficulty walking half a mile or up 10 steps) and activities of daily living ( ADL s) disability were assessed at baseline and every 6 months over 3 years of follow‐up. Results Almost one‐third (30.8%) of participants were deficient in 25( OH ) D (&lt;20 ng/mL). SPPB scores were lower in those with deficient 25( OH ) D (mean (standard error) 6.53 (0.24)) than in those with sufficient 25( OH ) D (≥30 ng/mL) (7.15 (0.25)) after adjusting for sociodemographic characteristics, season, health behaviors, and chronic conditions ( P = .006). Grip strength adjusted for body size was also lower in those with deficient 25( OH ) D than in those with sufficient 25(OH)D (24.7 (0.6) kg vs 26.0 (0.6) kg, P = .02). Participants with deficient 25( OH ) D were more likely to have prevalent mobility ( OR = 1.44, 95% confidence interval ( CI )) = 0.96–2.14) and ADL disability ( OR = 1.51, 95% CI = 1.01–2.25) at baseline than those with sufficient 25( OH ) D . Furthermore, participants with deficient 25( OH ) D were at greater risk of incident mobility disability over 3 years of follow‐up (hazard ratio = 1.56, 95% CI = 1.06–2.30). Conclusion Vitamin D deficiency was common and was associated with poorer physical performance, lower muscle strength, and prevalent mobility and ADL disability in community‐dwelling older adults. Moreover, vitamin D deficiency predicted incident mobility disability.

Adult height is a classic polygenic trait of high heritability (h(2) approximately 0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain approximately10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10(-12) and 2p14-rs4315565, P = 1.2×10(-8)). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10(-4) for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.

Matrix Gla protein (MGP) is a calcification inhibitor in vascular tissue that must be carboxylated by vitamin K to function. Evidence suggests circulating uncarboxylated MGP (ucMGP) is elevated in persons with disease characterized by vascular calcification. The primary purpose of this study was to determine cross-sectional and longitudinal associations between plasma ucMGP, vitamin K status, and coronary artery calcium (CAC) in older adults without coronary heart disease. Genetic determinants of ucMGP were also explored. Cross-sectional associations among baseline plasma ucMGP, vitamin K status biomarkers [plasma phylloquinone, uncarboxylated prothrombin (PIVKA-II), serum uncarboxylated osteocalcin (%ucOC)], CAC, and plausible genetic polymorphisms were examined in 438 community-dwelling adults (60-80 y, 59% women). The effect of phylloquinone supplementation (500 μg/d) for 3 y on plasma ucMGP was determined among 374 participants. At baseline, plasma phylloquinone was lower and %ucOC and PIVKA-II were greater across higher plasma ucMGP quartiles (all P < 0.001, age-adjusted). Major allele homozygotes for MGP rs1800801 and rs4236 had higher plasma ucMGP than heterozygotes or minor allele homozygotes. (P ≤ 0.004). The decrease in plasma ucMGP was greater in the 190 participants who received phylloquinone (mean ± SD) (-345 ± 251 pmol/L) than in the 184 who did not (-40 ± 196 pmol/L) (P < 0.0001). CAC did not differ according to ucMGP quartile (P = 0.35, age-adjusted). In the phylloquinone-supplemented group, the 3-y change in ucMGP was not associated with the 3-y change in CAC [unstandard β (SE) = -0.02 (0.02); P = 0.44]. Plasma ucMGP was associated with vitamin K status biomarkers and was reduced following phylloquinone supplementation, suggesting it may be a useful marker of vitamin K status in vascular tissue. Plasma ucMGP did not reflect CAC in healthy older adults.

OBJECTIVE Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants. RESEARCH DESIGN AND METHODS We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes. RESULTS We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant. CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.