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Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

Background: Bleeding is the major risk of aspirin treatment, especially in the elderly. A consensus definition for clinically significant bleeding (CSB) in aspirin primary prevention trials is lacking in the literature. Methods: This paper details the development, modification, application, and quality control of a definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial, a primary prevention trial of aspirin in 19,114 community-dwelling elderly men and women. In ASPREE a confirmed bleeding event needed to meet criteria both for substantiated bleeding and clinical significance. Substantiated bleeding was defined as: 1) observed bleeding, 2) a reasonable report of symptoms of bleeding, 3) medical, nursing or paramedical report, or 4) imaging evidence. Bleeding was defined as clinically significant if it: 1) required transfusion of red blood cells, 2) required admission to the hospital for >24 h, or prolonged a hospitalization, with bleeding as the principal reason, 3) required surgery to stop the bleeding, or 4) resulted in death. Bleeding sites were subclassified as upper gastrointestinal, lower gastrointestinal, intracranial (hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, extradural hematoma, or other), or other sites. Potential events were retrieved from medical records, self-report or notification from treating doctors. Two reviewers adjudicated each event using electronic adjudication software, and discordant cases were reviewed by a third reviewer. Adjudication rules evolved to become more strictly defined as the trial progressed and decision rules were added to assist with frequent scenarios such as post-operative bleeding. Conclusions: This paper provides a detailed methodologic description of the development of a standardized definition for clinically significant bleeding and provides a benchmark for development of a consensus definition for future aspirin primary prevention trials. Trial registration: ASPREE is registered on the International Standard Randomized Controlled Trial Number Register (ISRCTN83772183) and on clinicaltrials.gov (NCT01038583). Keywords: Aspirin, Primary prevention, Methods, Hemorrhage, Bleeding

OBJECTIVE: We assessed mobility disability trajectories before death in a large sample of very old adults using two analytic approaches to determine how well they correspond. DESIGN: Decedent sample from the Health, Aging and Body Composition Study (Health ABC). Data were collected between 1997 and 2015. SETTING: A population-based sample of 3075 participants, randomly selected from well-functioning White Medicare beneficiaries and all African American community residents meeting age criteria (70–79 years) in Pittsburgh, PA, and Memphis, TN. PARTICIPANTS: Of the 1991 participants who died by the end of the study, 1410 were interviewed for three years prior to death, including an interview six months before dying. EXPOSURES: Participants were interviewed in person or by phone at least every six months throughout the study. MEASUREMENTS: We analyzed self-reported mobility collected prospectively at six month intervals during the last three years of life. We derived trajectories in two ways: first by averaging decline within decedent groups pre-specified by clinical conditions and, second, by estimating trajectory models using maximum-likelihood semiparametric modeling. RESULTS: Classification by clinical conditions (sudden death, terminal, organ failure and frailty) accounted for 98% of decedents and produced groups with different characteristics. Five disability trajectories were identified: late decline, progressive disability, moderate disability, early decline, and persistent disability. Disability trajectory and clinical condition grouping both confirmed previous research but were only marginally related. CONCLUSIONS: Derived disability trajectories and grouping by clinical conditions both provide useful information about different facets of the end-of-life experience. The lack of fit between them suggests a need for greater attention to heterogeneity in disability in the period before death.

BACKGROUND: Age-related limitations in mobility and decreased physical activity appear to be linked cross-sectionally; however, large-scale, longitudinal analyses of the associations between age-related changes in mobility and engagement in physical activity are lacking. In this longitudinal study, we hypothesized that early mobility limitations would contribute to later decreases in physical activity to a larger degree than the reciprocal association of early decreases in physical activity to later mobility limitations. METHODS: Participants were 2,876 initially well-functioning community-dwelling older adults (aged 70–79 years at baseline; 52% women; 39% black) studied over a 9-year period. Usual walking speed and self-reported physical activity (based on minutes per week of walking) were assessed at Years 0 (ie, baseline), 4, and 9. A cross-lagged, longitudinal model assessed the bidirectional associations between walking speed and physical activity over time. RESULTS: Early change in walking speed between Years 0 and 4 predicted late change in physical activity between Years 4 and 9 (β = .13 p < .001). However, early change in physical activity did not predict late change in walking speed (β = −.01, p = .79). The difference between these two predictive associations was highly significant (p < .001). Associations were independent of baseline demographic and physical health variables, as well as longitudinal changes in grip and quadriceps strength. CONCLUSIONS: The results suggest declining walking speed as a precursor to declining engagement in physical activity, but the converse association was not evident. Improving walking speed may be a method to increase physical activity among elderly individuals.

Objectives: To examine the relationship between end-of-life (EOL) treatment preferences and recent hospitalization or emergency department (ED) care in the very old. Design: Quarterly telephone follow-up of participants in the EOL in the Very Old cohort. Setting: The EOL in the Very Old Age cohort drew from 1403 participants in the Health, Aging, and Body Composition (Health ABC) study who were alive in year 15 of follow-up. 87.5% (n = 1227) were successfully recontacted and enrolled. Participants: Preferences for treatment at the EOL and reported hospital and ED use were examined for 1118 participants (18% involving proxy reports) over 6 months, 1021 (16% with proxy reports) over 12 months, and 945 (23% with proxy reports) over 18 months in 6-month intervals. Measurements: Preferences for eight EOL treatments, elicited once each year; hospitalization and ED use reported every six months. Results: Preferences for more aggressive treatment (endorsing ≥5 of 8 options) were not significantly associa...

Background and objectives Although anthropometric measures of body fat are associated with development of CKD, they may not be able to distinguish between various forms of fat and therefore may be less accurate than computed tomography (CT) measures. We compared the association of CT and anthropometric measures of obesity with kidney outcomes in the Health Aging and Body Composition Study. Design, setting, participants, & measurements Participants were recruited from March of 1997 through July of 1998. CT measures included visceral abdominal fat (VAT), subcutaneous adipose tissue (SAT), and intermuscular fat area (IMAT), whereas anthropometric measures included waist circumference (WC) and body mass index (BMI). Kidney outcomes included kidney function (KF) decline (30% decrease in eGFRcysC in follow-up at either year 3 or 10) or incident CKD (follow-up eGFRcysC≤60 ml/min per 1.73 m2 in individuals with baseline GFR>60 ml/min per 1.73 m2). Multivariable logistic regression models and Poisson regression models were used to evaluate the association with decline in KF and incident kidney disease, respectively. We also assessed for the independent associations among the exposure measures by including them in the same model. Results Two-thousand four-hundred and eighty-nine individuals were included. Mean age was 74±3 years, 49% were men, 39% were black, 59% were hypertensive, and 15% were diabetic. KF decline occurred in 17% of the population, whereas incident CKD also occurred in 17% of those at risk. In continuous models, SAT, VAT, IMAT, BMI, and WC (per SD increase) were all significantly associated with KF decline. There was a significant interaction between VAT and CKD with regard to KF decline (P=0.01). Only VAT, BMI, and WC were associated with incident CKD. Only VAT remained a significant risk factor for incident CKD when other exposure variables were included in the same model. There was no association between any measure of obesity and kidney outcomes when creatinine values at years 3 and 10 were used to estimate changes in eGFR. Conclusions Anthropometric measures of body fat appear to provide as consistent estimates of KF decline risk as CT measures in elders.

Background Musculoskeletal pain is highly prevalent and limits mobility in older adults. A potential mechanism by which pain affects mobility could be through its negative impact on the brain. We examined whether structural integrity of cerebral gray and white matter (WM) mediated the relationship between pain and mobility in community-dwelling older adults. Methods Musculoskeletal pain, gait speed, and neuroimaging data were obtained concurrently from the Health ABC study (mean age = 83/56% female, n = 212). Microstructural gray matter integrity was measured by mean diffusivity (MD), WM microstructure and macrostructure were measured by fractional anisotropy (FA) and WM hyperintensities (WMH), respectively. Regression models were adjusted for gray matter atrophy, age, gender, medication use, and obesity. Bootstrapped mediation methods were used (1,000 bootstrapped samples, 95% confidence intervals). Results The associations of musculoskeletal pain with WMH (β = .19, p < .05) and FA (β = -.18, p < .05) were robust to adjustment for gender, medication use, age, body mass index (BMI), and brain atrophy. Participants who experienced both knee and back pain had a significantly slower gait speed (~0.11 m/s) than those without knee or back pain (p < .05) independent of gender, medication, age, and BMI. WMH and FA significantly mediated the pain-gait speed relationship. Associations between pain and MD were not significant, and MD did not modify the association between pain and gait speed. Conclusions Cerebral WM integrity may contribute to the detrimental effects of musculoskeletal pain on mobility, although pre-existing WM integrity may also simultaneously amplify pain and decrease mobility. Future studies are needed to further understand whether successful pain management may significantly improve both brain health and mobility.

Background Olfactory impairment is common among older adults; however, data are largely limited to whites. Methods We conducted pooled analyses of two community-based studies: the Atherosclerosis Risk in Communities study (ARIC, 1,398 blacks and 4,665 whites), and the Health, Aging, and Body Composition study (Health ABC, 958 blacks and 1,536 whites) to determine the prevalence of anosmia and associated factors for black and white older adults in the United States. Results The overall prevalence of anosmia was 22.3% among blacks and 10.4% among whites. Blacks had a markedly higher odds of anosmia compared to whites in age and sex adjusted analyses (odds ratio [OR] 2.96, 95% confidence interval [CI] = 2.59-3.38). In both blacks and whites, higher anosmia prevalence was associated with older age and male sex. The highest prevalence was found in black men 85 years or older (58.3%), and the lowest in white women aged 65-69 years (2.4%). Higher education level, lower cognitive score, ApoE e4, daytime sleepiness, poorer general health status, lower body mass index, and Parkinson disease were associated with higher prevalence of anosmia in one or both races. However, the racial difference in anosmia remained statistically significant after adjusting for these factors (fully adjusted OR = 1.76, 95%CI: 1.50-2.07). Results were comparable between the two cohorts. Discussion Anosmia is common in older adults, particularly among blacks. Further studies are needed to identify risk factors for anosmia and to investigate racial disparities in this sensory deficit.

Objective: The objective of the study is was investigate the association between hearing impairment and anxiety. Method: We conducted a cross-sectional analysis of 1,732 community-based adults aged 76 to 85 years who participated in the Health Aging and Body Composition (ABC) study. Logistic regression models were adjusted for demographic and cardiovascular risk factors. Hearing impairment was defined by the speech-frequency pure tone average. Anxiety was defined as reporting two symptoms of at least “a little” or one symptom “quite a bit” on the three-item Hopkins Symptom Checklist. Results: Compared with individuals with no hearing impairment, the odds of prevalent anxiety were higher among individuals with mild hearing impairment (odds ratio [OR] = 1.32, 95% confidence interval [CI] = [1.01, 1.73]) and moderate or greater hearing impairment (OR = 1.59, 95% CI = [1.14, 2.22]). Hearing aid use was not significantly associated with lower odds of anxiety. Discussion: Hearing impairment is independently associated with greater odds of anxiety symptoms in older adults.

Few cohort studies have examined longitudinal associations between age-related changes in cognition and physical performance. Further, whether these associations differ for men versus women or can be attributed to differences in physical activity (PA) is unknown.Participants were 2,876 initially well-functioning community-dwelling older adults (aged 70-79 years at baseline; 52% female; 39% black) studied over a 9-year period. Usual gait speed, self-reported PA, and two cognitive measures-Digit Symbol Substitution Test (DSST) and Mini-Modified Mental State examination (3MS)-were assessed years 0 (ie, baseline), 4, and 9.Early decline between years 0 and 4 in gait speed predicted later decline between years 4 and 9 in performance on the 3MS (β = 0.10, p = .004) and on the DSST (β = 0.16, p.001). In contrast, the associations between early decline in cognition and later decline in gait speed were weaker and were non-significant after correcting for multiple comparisons (β = 0.08, p = .019 for 3MS and β = .06, p = .051 for DSST). All associations were similar for women and men and were unaltered when accounting for PA levels.The results indicate declining gait speed as a precursor to declining cognitive functioning, and suggest a weaker reciprocal process among older women and men.

BACKGROUND:Depression and disability are closely linked. Less is known regarding clinical and subclinical depressive symptoms over time and risk of disability and mortality.METHODS:Responses to the Center for Epidemiologic Studies Short Depression scale (CES-D10) were assessed over a 4-year period in men (n = 1032) and women (n = 1070) aged 70-79 years initially free from disability. Depressive symptom trajectories were defined with group-based models. Disability (2 consecutive reports of severe difficulty walking one-quarter mile or climbing 10 steps) and mortality were determined for 9 subsequent years. Hazard ratios (HRs) were estimated using Cox proportional hazards adjusted for covariates.RESULTS:Three trajectories were identified: persistently nondepressed (54% of men, 54% of women, mean baseline CES-D10: 1.16 and 1.46), mildly depressed and increasing (40% of men, 38% of women, mean baseline CES-D10: 3.60 and 4.35), and depressed and increasing (6% of men, 8% of women, mean baseline CES-D10: 7.44 and 9.61). Disability and mortality rates per 1,000 person years were 41.4 and 60.3 in men and 45.8 and 41.9 in women. Relative to nondepressed, men in the mildly depressed (HR = 1.45, 95% confidence interval [CI] 1.11-1.89) and depressed trajectories (HR = 2.12, 95% CI 1.33-3.38) had increased disability; women in the depressed trajectory had increased disability (HR = 2.02, 95% CI 1.37-2.96). Men in the mildly depressed (HR = 1.24, 95% CI 1.01-1.52) and depressed trajectories (HR = 1.63, 95% CI 1.10-2.41) had elevated mortality risk; women exhibited no mortality risk.CONCLUSIONS:Trajectories of depressive symptoms without recovery may predict disability and mortality in apparently healthy older populations, thus underscoring the importance of monitoring depressive symptoms in geriatric care.

BACKGROUND White matter hyperintensities (WMH), a common marker of cerebral small vessel disease, and lower microstructural integrity of normal-appearing white matter are associated with slower gait. How these cerebral measures interact in relation to slower gait is unknown. We assessed whether microstructural integrity of normal-appearing white matter, measured by fractional anisotropy (FA), moderates the association of higher WMH with slower gait. METHODS WMH, FA, and gait speed were acquired for 265 community-dwelling older adults (average age = 82.9 years). RESULTS The inverse association between WMH and gait was robust to adjustment for age, gender, muscle strength, obesity, stroke, and hypertension (fully adjusted model: βs = -0.19, p = .001). The interaction between WMH and FA was significant; analyses stratified by FA showed that the inverse association between WMH and gait speed was significant only for those with low FA (FA < median, fully adjusted model: βs = -0.28, p = .001). Voxel-based results were similar for participants with FA less than median, there was an inverse association between gait speed and WMH which extended throughout the white matter (genu and body of corpus callosum, anterior limb of internal capsule, corona radiata, and superior longitudinal and fronto-occipital fasciculus). In contrast, for participants with FA ≥ median, the association was limited to the genu of corpus callosum, the cingulum, and the inferior longitudinal fasciculus. CONCLUSIONS Microstructural integrity is a moderating factor in the association between WMH and gait. Future studies should examine whether higher microstructural integrity represents a source of compensation in those with greater WMH burden to maintain function in late life.

BACKGROUND Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk. METHODS From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure). RESULTS Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P

OBJECTIVE: To determine if hip fracture patients would have smaller cross-sectional area (CSA) and lower radiological attenuation (suggesting greater fat infiltration) in all trunk muscles as compared to healthy older adults. DESIGN: Cross-sectional analysis of computed tomography scans. SETTING: Clinical imaging facility. PARTICIPANTS: Forty-one white participants (19 men, 22 women) from the Baltimore Hip Studies 7(th) cohort (BHS-7) at 2-months post-fracture were compared to 693 white participants (424 men, 269 women) from the Health, Aging and Body Composition Study (Health ABC) at the year 6 visit. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Trunk muscle CSA and attenuation values were obtained from a single 10 mm, axial computed tomography (CT) scan completed at the L4-L5 disc space in each participant. RESULTS: The hip fracture cohort had significantly smaller CSA for all trunk muscles (range: 12.1 to 38 % smaller) compared to the Health ABC cohort (p

BACKGROUND: Previous studies in HIV-infected individuals have demonstrated serum albumin to be strongly associated with kidney function decline, independent of urine albumin and inflammatory markers. Lower serum albumin concentrations may be an under-appreciated risk factor for kidney function decline in elders. METHODS: We performed a cohort analysis in the Health Aging and Body Composition Study, a cohort of well-functioning, bi-racial, community-dwelling elders between the age of 70 and 79 years. We examined the associations of serum albumin concentration with longitudinal kidney function decline by estimated glomerular filtration rate (eGFR). Outcomes included linear eGFR decline, rapid kidney function decline defined as >30% decrease in eGFR, defined as a final eGFR 60 mL/min/1.73 m(2) at baseline. Cystatin C-based eGFR was calculated at baseline, Year 3 and Year 10. RESULTS: Mean age was 74 years, and mean eGFR was 73 mL/min/1.73 m(2) at baseline. The mean rate of eGFR change was 1.81 mL/min/1.73 m(2) per year. After multivariate adjustment, lower serum albumin concentrations were strongly and independently associated with kidney function decline (−0.11 mL/min/1.73 m(2) per year for each standard deviation decrease serum albumin; −0.01 to − 0.20) with no attenuation after adjustment for urine albumin and inflammatory markers (−0.12, −0.03 to − 0.22). When divided into quartiles, serum albumin levels ≤3.80 g/dL were associated with increased odds of rapid kidney function decline (odds ratio 1.59; 1.12–2.26) and increased risk of incident chronic kidney disease (incident rate ratio 1.29; 1.03–1.62) relative to levels >4.21g/dL. Urine albumin to creatinine ratio (ACR) was also significantly and independently associated with kidney function decline (−0.08 mL/min/1.73 m(2) per year for urine ACR >30 mg/g; −0.82 to − 0.13). CONCLUSIONS: Lower serum albumin levels are strongly and independently associated with kidney function decline in elders, independent of clinical risk factors, urine albumin and measured inflammatory markers.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. METHODS: Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999–2000) and nerve function measurements at Year 4 (2000–01) were analyzed (n = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as ≤60 (CKD) or >60 mL/min/1.73 m(2) (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. RESULTS: Participants with CKD (n = 476) were older (77 ± 3 versus 75 ± 3 years; P

Fall injuries cause morbidity and mortality in older adults. We assessed if low blood pressure (BP) is associated with fall injuries, including sensitivity analyses stratified by antihypertensive medications, in community-dwelling adults from the Health, Aging and Body Composition Study (N = 1819; age 76.6 ± 2.9 years; 53% women; 37% black). Incident fall injuries (N = 570 in 3.8 ± 2.4 years) were the first Medicare claims event from clinic visit (7/00–6/01) to 12/31/08 with an ICD-9 fall code and non-fracture injury code, or fracture code with/without a fall code. Participants without fall injuries (N = 1249) were censored over 6.9 ± 2.1 years. Cox regression models for fall injuries with clinically relevant systolic BP (SBP; ≤ 120, ≤ 130, ≤ 140, > 150 mmHg) and diastolic BP (DBP; ≤ 60, ≤ 70, ≤ 80, > 90 mmHg) were adjusted for demographics, body mass index, lifestyle factors, comorbidity, and number and type of medications. Participants with versus without fall injuries had lower DBP (70.5 ± 11.2 vs. 71.8 ± 10.7 mmHg) and used more medications (3.8 ± 2.9 vs. 3.3 ± 2.7); all P

Elevated levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) have been linked to greater risk of fractures in some studies, especially among individuals with chronic kidney disease (CKD). We evaluated FGF23 as a risk factor for bone loss and fractures in the Health, Aging, and Body Composition (Health ABC) study, which is a prospective biracial cohort of well-functioning adults aged 70 to 79 years recruited at two clinical centers in the United States. The sample for the bone mineral density (BMD) analyses consisted of 2234 participants who had at least two serial total hip areal BMD measures. The fracture analyses included 2786 participants, 567 of whom sustained a fracture during a median follow up of 4.95 years. Linear mixed-effects models were used for longitudinal measurements of total hip areal BMD and the proportional subdistribution hazard regression model subject to competing risks of death was used for risk of fracture. The median FGF23 was 46.7 (interquartile range [IQR] 36.7 to 60.2) pg/mL. The mean annualized percent change in total hip areal BMD did not vary significantly according to FGF23 quartile in all participants (p for trend = 0.70), but the effect was modified by CKD status (adjusted p for interaction

Evidence of the association between chronic inflammation and the risk of colorectal cancer (CRC) and other obesity-related cancers (OBRC) remains inconsistent, possibly due to a paucity of studies examining repeated measures of inflammation. In the Health ABC prospective study of 2,490 adults aged 70-79 years at baseline, we assessed whether circulating levels of three markers of systemic inflammation, IL-6, CRP and TNF-α, were associated with the risk of CRC and OBRC, a cluster including cancers of pancreas, prostate, breast and endometrium. Inflammatory markers were measured in stored fasting blood samples. While only baseline measures of TNF-α were available, IL-6 and CRP were additionally measured at Years 2, 4, 6 and 8. Multivariable Cox models were fit to determine whether tertiles and log-transformed baseline, updated and averaged measures of CRP and IL-6 and baseline measures of TNF-α were associated with the risk of incident cancer(s). During a median follow-up of 11.9 years, we observed 55 and 172 cases of CRC and OBRC, respectively. The hazard of CRC in the highest tertile of updated CRP was more than double that in the lowest tertile (HR = 2.29; 95% CI: 1.08-4.86). No significant associations were seen between colorectal cancer and IL-6 or TNF-α. Additionally, no significant associations were found between obesity-related cancers and the three inflammatory markers overall, but we observed a suggestion of effect modification by BMI and NSAID use. In summary, in this population, higher CRP levels were associated with increased risk of CRC, but not of OBRC. The findings provide new evidence that chronically elevated levels of CRP, as reflected by repeated measures of this marker, may play a role in colorectal carcinogenesis in older adults.

BackgroundInflammation, slow gait, and depression individually are associated with mortality, yet little is known about the trajectories of these measures, their interrelationships, or their collective impact on mortality.MethodsLongitudinal latent class analysis was used to evaluate trajectories of depression (Center for Epidemiologic Studies Depression ≥ 10), slow gait ( 3.2 pg/mL) using data from the Health Aging and Body Composition Study. Logistic regression was used to identify their associations with mortality.ResultsFor each outcome, low-probability (n inflammation = 1,656, n slow gait = 1,471, n depression = 1,458), increasing-probability (n inflammation = 847, n slow gait = 880, n depression = 1,062), and consistently high-probability (n inflammation = 572, n slow gait = 724, n depression = 555) trajectories were identified, with 22% of all participants classified as having increasing or consistently high-probability trajectories on inflammation, slow gait, and depression (meaning probability of impairment on each outcome increased from low to moderate/high or remained high over 10 years). Trajectories of slow gait were associated with inflammation (r = .40, p < .001) and depression (r = .49, p < .001). Although worsening trajectories of inflammation were independently associated with mortality (p < .001), the association between worsening trajectories of slow gait and mortality was only present in participants with worsening depression trajectories (p < .01). Participants with increasing/consistently high trajectories of depression and consistently high trajectories of inflammation and slow gait (n = 247) have an adjusted-morality rate of 85.2%, greater than all other classification permutations.ConclusionsComprehensive assessment of older adults is warranted for the development of treatment strategies targeting a high-mortality risk phenotype consisting of inflammation, depression, and slow gait speed.

Background. Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function. Methods. We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking ¼ – ½ mile or climbing 10 steps within 3 years. Results. Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from

Objectives This study sought to determine the degree to which racial differences in atrial fibrillation (AF) risk are explained by differences in inflammation and adiposity. Background Despite having a lower prevalence of established AF risk factors, whites exhibit substantially higher rates of this arrhythmia than blacks. The mechanism underlying this observation is not known. Both inflammation and obesity are risk factors for AF, and adipose tissue is a known contributor to systemic inflammation. Methods Baseline serum inflammatory biomarker concentrations and abdominal adiposity (assessed by computed tomography) were quantified in a subset of black and white participants without prevalent AF in the Health ABC (Health, Aging, and Body Composition) study. Participants were prospectively followed for the diagnosis of AF, using study electrocardiography and Medicare claims data. Cox proportional hazards models were used to determine the adjusted relative hazard of incident AF between races before and after biomarker adjustment. Results Among 2,768 participants (43% black), 721 participants developed incident AF over a median follow-up of 10.9 years. White race was associated with a heightened adjusted risk of incident AF (HR: 1.55; 95% confidence interval [CI]: 1.30 to 1.84, p Conclusions Systemic inflammatory pathways significantly mediate the heightened risk of AF among whites. The higher level of systemic inflammation and concomitant increased AF risk in whites is not explained by racial differences in abdominal adiposity or the presence of other proinflammatory cardiovascular comorbidities.

Objectives To determine the association between hearing impairment (HI) and risk and duration of hospitalization in community-dwelling older adults in the United States. Design Prospective observational study. Setting Health, Aging and Body Composition Study. Participants Well-functioning community-dwelling white and black Medicare beneficiaries aged 70 to 79 at study enrollment in 1997–98 were followed for a median of 12 years. Measurements Incidence, annual rate, and duration of hospitalization were the primary outcomes. Hearing was defined as the pure-tone average (PTA) of hearing thresholds in decibels re: hearing level (dB HL) at octave frequencies from 0.5 to 4.0 kHz. Mild HI was defined as a PTA from 25 to 40 dB HL, and moderate or greater HI was defined as a PTA greater than 40 dB HL. Results Of the 2,148 participants included in the analysis, 1,801 (83.5%) experienced one or more hospitalizations, with 7,007 adjudicated hospitalization events occurring during the study period. Eight hundred eighty-two (41.1%) participants had normal hearing, 818 (38.1%) had mild HI, and 448 (20.9%) had moderate or greater HI. After adjusting for demographic characteristics and cardiovascular comorbidities, persons with mild HI experienced a 16% (hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.04–1.29) greater risk of incident hospitalization and a 17% (incidence rate ratio (IRR) = 1.17, 95% CI = 1.04–1.32) greater annual rate of hospitalization, and those with moderate or greater HI experienced a 21% (HR = 1.21, 95% CI = 1.06–1.38) greater risk of incident hospitalization and a 19% (IRR = 1.19, 95% CI = 1.04–1.38) greater annual rate of hospitalization than persons with normal hearing. There was no significant association between HI and mean duration of hospitalization. Conclusion Hearing-impaired older adults experience a greater incidence and annual rate of hospitalization than those with normal hearing. Investigating whether rehabilitative therapies could affect the risk of hospitalization in older adults requires further study.

Mid-thigh cross-sectional muscle area (CSA), muscle attenuation, and greater trochanter soft tissue thickness have been shown to be independent risk factors of hip fracture. Our aim was to determine whether muscle and adipose tissue measures derived from dual-energy X-ray absorptiometry (DXA) scans would have a similar risk association as those measured using other imaging methods. Using a case-cohort study design, we identified 169 incident hip fracture cases over an average of 13.5 years among participants from the Health ABC Study, a prospective study of 3075 individuals initially aged 70 to 79 years. We modeled the thigh 3D geometry and compared DXA and computed tomography (CT) measures. DXA-derived thigh CSA, muscle attenuation, and subcutaneous fat thickness were found to be highly correlated to their CT counterparts (Pearson's r = 0.82, 0.45, and 0.91, respectively; p < 0.05). The fracture risk of men and women were calculated separately. We found that decreased subcutaneous fat, CT thigh muscle attenuation, and appendicular lean mass by height squared (ALM/Ht2) were associated with fracture risk in men; hazard ratios (HR) = 1.44 (1.02, 2.02), 1.40 (1.05, 1.85), and 0.58 (0.36, 0.91), respectively, after adjusting for age, race, clinical site, body mass index (BMI), chronic disease, hip bone mineral density (BMD), self-reported health, alcohol use, smoking status, education, physical activity, and cognitive function. In a similar model for women, only decreases in subcutaneous fat and DXA CSA were associated with hip fracture risk; HR = 1.39 (1.07, 1.82) and 0.78 (0.62, 0.97), respectively. Men with a high ALM/Ht2 and low subcutaneous fat thickness had greater than 8 times higher risk for hip fracture compared with those with low ALM/Ht2 and high subcutaneous fat. In women, ALM/Ht2 did not improve the model when subcutaneous fat was included. We conclude that the DXA-derived subcutaneous fat thickness is a strong marker for hip fracture risk in both men and women, especially in men with high ALM/Ht2. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research

The objective of this study is to examine the relationship of serum carboxymethyl-lysine (CML), an advanced glycation end product (AGE), with pulse pressure (PP), aortic pulse wave velocity (aPWV) and hypertension in older adults.AGEs are bioactive molecules that accumulate in tissues with ageing and can both cross-link collagen and induce inflammation in model systems. The relationship of AGEs with arterial stiffness and hypertension has not been well characterized in community-dwelling older adults.We measured serum CML and blood pressure in 3044 adults, aged 70-79 years, who participated in the Health, Aging and Body Composition Study, a population-based study of ageing in Pittsburgh, Pennsylvania and Memphis, Tennessee. aPWV was measured in 2468 participants.Participants in the highest tertile of serum CML had higher PP (highest tertile: beta = 2.85, SE = 0.82, P = 0.0005; middle tertile: beta = 0.60, SE = 0.80, P = 0.45), and higher aPWV (highest tertile: beta = 51.4, SE = 20.1, P = 0.01; middle tertile: beta = 3.2, SE = 19.8, P = 0.87) than those in the lowest tertile in multivariable linear regression models adjusting for age, sex, race, education, BMI, smoking, alcohol use, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes, cardiovascular disease and chronic kidney disease. Participants in the highest and middle tertiles of serum CML had higher odds of hypertension [odds ratio (OR) 1.32, 95% confidence interval (95% CI) 1.06-1.60, P = 0.005; OR 1.27, 95% CI 1.05-1.53, P = 0.01, respectively] than those in the lowest tertile in a multivariable logistic regression model adjusting for the same covariates.Elevated serum CML was associated with arterial stiffness, as reflected by higher PP and aPWV, in older, community-dwelling adults.

Objective: We sought to develop and validate a risk index for prospective cognitive decline in older adults based on blood-derived markers. Methods: The index was based on 8 markers that have been previously associated with cognitive aging: APOE genotype, plasma β-amyloid 42/40 ratio, telomere length, cystatin C, glucose, C-reactive protein, interleukin-6, and albumin. The outcome was person-specific cognitive slopes (Modified Mini-Mental State Examination) from 11 years of follow-up. A total of 1,445 older adults comprised the development sample. An index based on dichotomized markers was divided into low-, medium-, and high-risk categories; the risk categories were validated with the remaining sample (n = 739) using linear regression. Amyloid was measured on a subsample (n = 865) and was included only in a secondary index. Results: The risk categories showed significant differences from each other and were predictive of prospective cognitive decline in the validation sample, even after adjustment for age and baseline cognitive score: the low-risk group (24.8%) declined 0.32 points/y (95% confidence interval [CI]: −0.46, −0.19), the medium-risk group (58.7%) declined 0.55 points/y (95% CI: −0.65, 0.45), and the high-risk group (16.6%) declined 0.69 points/y (95% CI: −0.85, −0.54). Using the secondary index, which included β-amyloid 42/40 (validation n = 279), the low-risk group (26.9%) declined 0.20 points/y (95% CI: −0.42, 0.01), the medium-risk group (61.3%) declined 0.55 points/y (95% CI: −0.72, −0.38), and the high-risk group (11.8%) declined 0.83 points/y (95% CI: −1.14, −0.51). Conclusions: A risk index based on 8 blood-based markers was modestly able to predict cognitive decline over an 11-year follow-up. Further validation in other cohorts is necessary.

Background Metabolic pathways that give rise to functional decline and mobility disability in older adults are incompletely understood. Methods To identify metabolic perturbations that may affect functional decline, nontargeted metabolomics was used to measure 350 metabolites in baseline plasma from 313 black men in the Health ABC Study (median age 74 years). Usual gait speed was measured over 20 m. Cross-sectional relationships between gait speed and metabolites were explored with partial correlations adjusted for age, study site, and smoking status. Risk of incident mobility disability (two consecutive reports of severe difficulty walking quarter mile or climb 10 stairs) over 13 years of follow-up was explored with Cox regression models among 307 men who were initially free of mobility disability. Significance was determined at p ≤ .01 and q (false discovery rate) ≤ 0.30. Results Two metabolites were correlated with gait speed: salicylurate (r = -.19) and 2-hydroxyglutarate (r = -.18). Metabolites of amino acids and amino acid degradation (indoxy sulfate; hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.09-2.03, symmetric dimethylarginine; HR = 3.58, 95% CI = 1.57-8.15, N-carbamoyl beta-alanine; HR = 1.91, 95% CI = 1.16-3.14, quinolinate; HR = 2.56, 95% CI = 1.65-3.96) and metabolites related to kidney function (aforementioned symmetric dimethylarginine and indoxy sulfate as well as creatinine; HR = 5.91, 95% CI = 2.06-16.9, inositol; HR = 2.70, 95% CI = 1.47-4.97) were among the 23 metabolites associated with incident mobility disability. Conclusions This study highlights the potential role of amino acid derivatives and products and kidney function early in the development of mobility disability and suggests metabolic profiles could help identify individuals at risk of functional decline.

Objective:To investigate olfaction in relation to incident Parkinson disease (PD) in US white and black older adults.Methods:The study included 1,510 white (mean age 75.6 years) and 952 black (75.4 years) participants of the Health, Aging, and Body Composition study. We evaluated the olfaction of study participants with the Brief Smell Identification Test (BSIT) in 1999–2000. We retrospectively adjudicated PD cases identified through August 31, 2012, using multiple data sources. We used multivariable Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).Results:During an average of 9.8 years of follow-up, we identified a total of 42 incident PD cases, including 30 white and 12 black participants. Overall, poor sense of smell, as indicated by a lower BSIT score, was associated with higher risk of PD. Compared with the highest tertile of BSIT (t3), the HR was 1.3 (95% CI 0.5–3.6) for the second tertile (t2) and 4.8 (95% CI 2.0–11.2) for the lowest tertile (t1) (ptrend < 0.00001). Further analyses revealed significant associations for incident PD in both the first 5 years of follow-up (HRt1/[t2+t3] 4.2, 95% CI 1.7–10.8) and thereafter (HRt1/[t2+t3] 4.1, 95% CI 1.7–9.8). This association appeared to be stronger in white (HRt1/[t2+t3] 4.9, 95% CI 2.3–10.5) than in black participants (HRt1/[t2+t3] 2.5, 95% CI 0.8–8.1), and in men (HRt1/[t2+t3] 5.4, 95% CI 2.3–12.9) than in women (HRt1/[t2+t3] 2.9, 95% CI 1.1–7.8).Conclusions:Poor olfaction predicts PD in short and intermediate terms; the possibility of stronger associations among men and white participants warrants further investigation.

Background: Prevalence of heart failure (HF) increases significantly with age, coinciding with age-related changes in body composition that are common and consequential. Still, body composition is rarely factored in routine HF care. Methods and Results: The Health, Aging, and Body Composition study is a prospective cohort study of nondisabled adults. Using yearly dual-energy x-ray absorptiometry, body composition was assessed in the Health, Aging, and Body Composition study over 6 years, comparing those who developed incident HF versus those who did not. Among 2815 Health, Aging, and Body Composition participants (48.5% men; 59.6% whites; mean age, 73.6±2.9 years), 111 developed incident HF over the 6-year study period. At entry into the Health, Aging, and Body Composition study, men and women who later developed HF had higher total body mass when compared with those versus those who did not develop HF (men, 80.9±10 versus 78.6±12.9 kg, P =0.05; women, 72.7±15.0 versus 68.2±14.2 kg, P =0.01, respectively). However, after developing HF, loss of total lean body mass was disproportionate; men with HF lost 654.6 versus 391.4 g/y in non-HF participants, P =0.02. Loss of appendicular lean mass was also greater with HF (−419.9 versus −318.2 g/y; P =0.02), even after accounting for total weight change. Among women with HF, loss of total and appendicular lean mass were also greater than in non-HF participants but not to the extent seen among men. Conclusions: Incident HF in older adults was associated with disproportionate loss of lean mass, particularly among men. Prognostic implications are significant, with key sex-specific inferences on physical function, frailty, disability, and pharmacodynamics that all merit further investigation.

Objectives To determine the association between catechol-O-methyltransferase (COMT) genotype and 6-m walk time and to determine whether these associations are quadratic in nature, similar to previously reported U-shaped associations between dopamine and gait and cognition. Design Prospective cohort study. Setting Health, Aging and Body Composition Study. Participants Black (n = 850) and white (n = 1,352) men and women with a mean age of 73.5 ± 2.85 at baseline. Measurements Mixed models were used to assess the association between the COMT genotype and 6-m walk time, cross-sectionally and longitudinally over 10 years. Models were assessed unstratified and stratified according to race because allele distributions were different between white and black participants. Results There was a significant U-shaped association between COMT genotype and 6-m walk time: those with higher (Val/Val) and lower (Met/Met) dopamine slowed more over 10 years (0.22 ± 0.02 seconds per visit and 0.23 ± 0.02 seconds per visit, respectively) than those with the intermediate (Met/Val) dopamine (0.20 ± 0.02 seconds per visit) (P = .005). Stratified results showed a significant relationship in black (P = .01) but not white (P = .15) participants. Conclusion These findings indicate a role of dopaminergic regulation of gait speed in community-dwelling older adults and of prefrontal cortex involvement in gait performance. Future work should investigate the molecular integrity of dopaminergic networks and gait changes over time and structural changes in the brain with COMT and gait decline in older adults.

PURPOSE: We assessed the discrimination of lean mass estimates that have been adjusted for adiposity for physical functioning deficits and prediction of incident disability. METHODS: Included were 2,846 participants from the Health, Aging and Body Composition Study with available whole-body dual energy absorptiometry measures of appendicular lean mass index (ALMI, kg/m(2)) and fat mass index (FMI, kg/m(2)). Age-, sex-, and race-specific Z-Scores and T-Scores were determined by comparison to published reference ranges. ALMI values were adjusted for FMI (ALMI(FMI)) using a novel published method. Sex-stratified analyses assessed associations between lean mass estimates and the physical performance score, ability to complete a 400-meter walk, grip strength, and incident disability. Dichotomized definitions of low lean for age and sarcopenia were examined and their performance compared to the ALM-to-BMI ratio. RESULTS: Compared to ALMI T-Scores and Z-Scores, the ALMI(FMI) scores demonstrated stronger associations with physical functioning, and were similarly associated with grip strength. Greater FMI Z-Scores and T-Scores were associated with poor physical functioning and incident disability. Definitions of low lean for age and sarcopenia using ALMI(FMI) (compared to ALMI) better discriminated those with poor physical functioning and a greater risk of incident disability. The ALM-to-BMI ratio was modestly associated with grip strength and physical performance, but was not associated with completion of the 400-meter walk or incident disability, independent of adiposity and height. CONCLUSION: Estimation of skeletal muscle mass relative to adiposity improves correlations with physical performance and prediction of incident disability suggesting it is an informative outcome for clinical studies.

U.S. blacks have a higher risk of death than whites. This varies by cause of death; stroke, kidney disease and some cancers are higher in blacks. We evaluated cause-specific mortality risk factors in Health ABC to determine whether specific risk factors are more important for these causes of death in blacks than whites. Potential risk factors included: demographics, smoking, body mass index, chronic disease, physical function, and cognition. Among N=3075 participants ages 70–79 (41.7% black), average follow-up was 11.9 years. Underlying cause of death was adjudicated by committee and categorized as: cardiovascular disease, stroke, cancer, dementia, pulmonary, infection, kidney, and other cause. Median survival (95% confidence interval) among black men, white men, black women, and white women was 10.6 (10.0, 11.5), 12.8 (12.4, 13.4), 13.4 (12.6, 14.6), and 15.3 (14.8, 16.2) years, respectively. Adjusting for age and sex, blacks had higher risks of dying from: any cause (hazard ratio=1.32 (1.21, 1.44)), kidney disease (HR=2.10 (1.17, 3.78)), cancer (HR=1.35 (1.13, 1.62)), and stroke (HR=1.32 (0.97, 1.75)). Higher all-cause mortality risk among blacks was attenuated by further adjustment for gait speed (black race adjusted HR=1.06 (0.95, 1.17)) or digit symbol substitution test (black race adjusted HR=1.01 (0.91, 1.12)), but minimally by prevalent diseases (black race adjusted HR=1.25 (1.13, 1.38)). Gait speed also attenuated higher risk of kidney and stroke deaths among blacks, but not cancer deaths. Factors contributing to poorer physical and cognitive function in similarly aged community-dwelling ambulatory black men and women could be targets to reduce disparity and excess mortality.

Previous studies have shown that more active older adults have better cognition and brain health based on a variety of structural neuroimaging measures. Nevertheless, the effects of maintaining physical activity over an extended period of time on future changes in older adults’ cognition and brain structure are unknown. Participants were 141 initially well-functioning community-dwelling older adults (aged 70–79 years at baseline; 60% female; 42% black) studied over a 13-year period. Physical activity (self-reported time spent walking) was assessed annually from years 1 to 10. Magnetic resonance imaging with diffusion tensor was performed at years 10 and 13. Time spent walking decreased on average by 8.4% annually from year 1 to year 10. Independent of initial time spent walking, demographics, and APOE e4 status, better maintenance of time spent walking over the decade predicted less reduction in hippocampal volume (p = .03), smaller increases in global gray matter mean diffusivity and white matter axial diffusivity (p < .01), and maintenance of general cognitive performance (p < .01). Maintenance of cognitive performance was associated with smaller increases in white matter axial diffusivity (p < .01). PA at baseline and at year 10, as well as changes in PA over a five-year period were less predictive of future changes in brain structure and cognition. Thus, how physical activity levels change over longer periods of aging may be an important contributor to cognitive and neural protection.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p, We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland’s Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI’s Atherosclerosis Risk in Communities (ARIC) Study, and Iceland’s Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community’s Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg’s Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the “Center of Knowledge Interchange” program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer’s Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study “GWAS in MrOS and SOF” under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women’s Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129.

The prevalence of hearing impairment doubles with every age decade such that nearly two-thirds of adults aged 70 and older in the United States have a clinically significant hearing impairment that hinders daily communication (1). Recent epidemiologic studies have demonstrated that hearing impairment is independently associated with poorer physical functioning (2,3) and falls (4,5) in older adults. These associations may be explained by concomitant vestibular dysfunction, (6,7) a shared pathologic etiology (eg microvascular disease; inflammation), or through the effects of hearing impairment on cognitive load, (8,9) social isolation, (10) and reduced awareness of the auditory environment. Maintaining an optimal level of physical functioning is a critical aspect of healthy aging, and objective physical performance tests predict the onset of dependence and mortality in older adults (11). Currently, there are no longitudinal studies that examine whether hearing impairment is associated with poorer objective physical functioning in older adults. Identifying potentially modifiable risk factors for poorer physical functioning in the elderly is a critical public health priority given the aging of the population. In this study, we investigate whether hearing impairment is independently associated with declines in physical functioning in older adults. We use a well-established physical performance battery to assess objective physical functioning over an 11-year period. To better understand the clinical and public health significance of these results, we also investigate the association of hearing impairment with the risk of incident disability and requirement for nursing care.

Hypertension and long-term exposure to higher systolic blood pressure (SBP) are risk factors for dementia and disability among older adults living in the community.1–3 Although the beneficial effects of antihypertensive treatments have been shown for major cardiovascular events,4 the effects of antihypertensive strategies to reduce the excess risk of dementia attributable to higher SBP have yielded mixed results.5–8 Moreover, several studies have shown lower blood pressure (BP), but not high BP, relates to cognitive impairment.9,10 The strongest evidence that lowering SBP can reduce cerebral small vessel disease is for selected cohorts of stroke patients or for adults aged 80 years who are otherwise without a remarkable cardiovascular history would have neuroprotective effects.7,8,11 We have limited knowledge of which SBP characteristics may be most detrimental to the central nervous system. Similarly, the brain areas and parenchyma that are most vulnerable to higher SBP in older age are not entirely identified. Although several cross-sectional studies of older adults report that higher SBP is associated with generalized white matter hyperintensities and gray matter atrophy,6,12–15 there are few longitudinal studies of repeated SBP measures combined with neuroimaging, and associations with specific brain networks are not consistent across reports.14–18 Longitudinal variations in SBP, in addition to higher absolute levels, are emerging as risk factors for brain structural abnormalities, but evidence is derived largely from studies of patients with clinically overt vascular conditions16,19,20 rather than older adults living in the community. Quantifying the associations between longitudinal measures of SBP and the spatial distribution of brain abnormalities can help understand the mechanisms underlying the effects of SBP on risk of dementia and disability. Careful characterization and estimates of these associations can also provide biomarkers of brain health to monitor the possible neuroprotective effects of SBP management. This knowledge could lend insight and help in designing intervention trials targeting very old adults, a topic that is especially timely in light of the growing number of adults surviving past age 80 years. We hypothesized that, if higher SBP is related to higher risk of dementia and disability, as prior works suggest, then that the harmful SBP-related effects on the central nervous system should be primarily localized in brain areas most related to memory and executive function—that is, medial temporal, prefronto-parietal, and basal ganglia. Because of their watershed vascularization, these areas are also most vulnerable to the perfusion changes and small vessel disease that accompany higher SBP.21 In this study, careful characterization of SBP and antihypertensive medications over 10 years were examined in relationship to neuroimaging markers of brain integrity at the macro- and microstructural level in multiple regions and tracts. The relationship between higher variability of SBP over time and neuroimaging markers was also explored using coefficient of variation and trajectories analyses.

Hearing impairment (HI) affects 16.1 million or nearly two of every three adults aged 70 and older in the United States (1). Epidemiologic studies have demonstrated that HI is independently associated with poorer hearing-related quality of life (2), depression (3), cognitive decline (4), incident dementia (5), impaired activities of daily living (6), increased falls (7), and increased hospitalizations (8). Hypothesized mechanisms to explain these observed associations include residual confounding from shared pathologies (eg, microvascular disease), cognitive load from increased auditory central processing required to decode degraded auditory signals (9), or social isolation (10). Importantly, these mechanisms are not mutually exclusive, and multiple pathways likely coexist and contribute to poorer cognitive and social functioning in older adults with HI. Whether HI is associated with mortality, possibly through similar pathways, is unclear. Previous studies have examined an association of HI with mortality but with inconsistent results (11–17). Most previous studies (12–15) subjectively measured hearing through self-report, and this imprecision in diagnostic assessment might have resulted in decreased sensitivity to detect associations. However, two Australian studies (16,18) determined hearing objectively through audiometric testing, with one finding an association between HI and mortality that was mediated through cognitive impairment and walking disability (16). Additionally, a study of older adults in Iceland demonstrated that HI was independently associated with increased cardiovascular mortality (17). In the present study, we investigated whether HI defined according to World Health Organization criteria (19) was associated with mortality in a longitudinal sample of community-dwelling older adults living in the United States followed in the Health, Aging, and Body Composition study. We hypothesized that greater HI is associated with increased mortality, independent of demographics and cardiovascular risk factors.

Kidney damage is a common sequela of several chronic pathologic conditions. Whether biomarkers of kidney damage are prognostic for more severe outcomes is unknown. We measured three urinary biomarkers (kidney injury molecule-1 [KIM-1], IL-18, and albumin) in 3010 individuals enrolled in the Health, Aging and Body Composition (Health ABC) study and used Cox proportional hazards models to investigate the associations of urinary KIM-1/creatinine (cr), IL-18/cr, and albumin/cr (ACR) with all-cause mortality and cardiovascular disease (CVD). Multivariable models adjusted for demographics, traditional CVD risk factors, and eGFR. Mean age of participants was 74 years, 49% of participants were men, and 41% of participants were black. During the median 12.4 years of follow-up, 1450 deaths and 797 CVD outcomes occurred. Compared with the lowest quartile, successive quartiles had the following adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) for mortality: KIM-1/cr: (1.21; 1.03 to 1.41), (1.13; 0.96 to 1.34), and (1.28; 1.08 to 1.52); IL-18/cr: (1.02; 0.88 to 1.19), (1.16; 0.99 to 1.35), and (1.06; 0.90 to 1.25); ACR: (1.08; 0.91 to 1.27), (1.24; 1.06 to 1.46), and (1.63; 1.39 to 1.91). In similar analyses, only ACR quartiles associated with CVD: (1.19; 0.95 to 1.48), (1.35; 1.08 to 1.67), and (1.54; 1.24 to 1.91). Urinary KIM-1 had a modest association with all-cause mortality but did not associate with CVD, and urinary IL-18 did not associate with either outcome. In contrast, albuminuria strongly associated with all-cause mortality and CVD. Future studies should evaluate reasons for these differences in the prognostic importance of individual kidney injury markers.

Background: Whether apolipoprotein E (APOE) E4 allele status which is associated with an increased risk of cognitive decline is also associated with hearing impairment is unknown. Methods: We studied 1833 men and women enrolled in the Health, Aging and Body Composition study. Regression models adjusted for demographic and cardiovascular risk factors were used to assess the cross-sectional association of APOE-E4 status with individual pure tone hearing thresholds and the 4-frequency pure tone average (0.5-4 kHz) in the better hearing ear. Results: Compared to participants with no APOE-E4 alleles, participants with 1 allele had better thresholds at 4.0 kHz (β = −2.72 dB, P = .013) and 8.0 kHz (β = −3.05 kHz, P = .006), and participants with 2 alleles had better hearing thresholds at 1.0 kHz (β = −8.56 dB, P = .021). Conclusion: Our results suggest that APOE-E4 allele status may be marginally associated with better hearing thresholds in older adults.

Background: Obesity is a risk factor for disability, but risk of specific adipose depots is not completely understood. Objective: We investigated associations between mobility limitation, performance, and the following adipose measures: body mass index (BMI) and areas and densities of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) in older adults. Design: This was a prospective population-based study of men (n = 1459) and women (n = 1552) initially aged 70–79 y and free from mobility limitation. BMI was determined from measured height and weight. Adipose tissue area and density in Hounsfield units were measured in the thigh and abdomen by using computed tomography. Mobility limitation was defined as 2 consecutive reports of difficulty walking one-quarter mile or climbing 10 steps during semiannual assessments over 13 y. Poor performance was defined as a gait speed