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1.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
OBJECTIVES:
To examine the association between kidney function and all-cause mortality in octogenarians.
DESIGN:
Retrospective analysis of prospectively collected data.
SETTING:
Community.
PARTICIPANTS:
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
MEASUREMENTS:
Estimated glomerular filtration rate (eGFR) was determined using the Chronic Kidney Disease Epidemiology Collaboration creatinine (eGFRCR) and cystatin C one-variable (eGFRCYS) equations. The association between quintiles of kidney function and all-cause mortality was analyzed using unadjusted and adjusted Cox proportional hazards models.
RESULTS:
Mean age of the participants was 85, 64% were female, 66% had hypertension, 14% had diabetes mellitus, and 39% had prevalent cardiovascular disease. There were 154 deaths over a median follow-up of 2.6 years. The association between eGFRCR and all-cause mortality was U-shaped. In comparison with the reference quintile (64–75 mL/min per 1.73 m2), the highest (≥75 mL/min per 1.73 m2) and lowest (≤43 mL/min per 1.73 m2) quintiles of eGFRCR were independently associated with mortality (hazard ratio (HR) = 2.49, 95% confidence interval (CI) = 1.36–4.55; HR = 2.28, 95% CI = 1.26–4.10, respectively). The association between eGFRCYS and all-cause mortality was linear in those with eGFRCYS of less than 60 mL/min per 1.73 m2, and in the multivariate analyses, the lowest quintile of eGFRCYS (<52 mL/min per 1.73 m2) was significantly associated with mortality (HR = 2.04, 95% CI = 1.12–3.71) compared with the highest quintile (>0.88 mL/min per 1.73 m2).
CONCLUSION:
Moderate reduction in kidney function is a risk factor for all-cause mortality in octogenarians. The association between eGFRCR and all-cause mortality differed from that observed with eGFRCYS; the relationship was U-shaped for eGFRCR, whereas the risk was primarily present in the lowest quintile for eGFRCYS. J Am Geriatr Soc 2012.
doi:10.1111/j.1532-5415.2012.04046.x
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
2.  Heritability of and Mortality Prediction With a Longevity Phenotype: The Healthy Aging Index 
Background.
Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI’s association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study.
Methods.
The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component–based family analysis using a polygenic model.
Results.
Cardiovascular Health Study participants with unhealthier index scores (7–10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0–2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring.
Conclusion.
The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.
doi:10.1093/gerona/glt117
PMCID: PMC3968826  PMID: 23913930
Epidemiology; Genetics; Longevity; Successful aging.
3.  Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS) 
Objective
Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark.
Methods
A total of 4,088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8,231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing.
Results
Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p < 5e–8). Of 25 suggestive (5e–8 < p < 1e–5) loci, one known (G6PC2 rs560887, replication p = 5e–5) and one novel (OR10R3P/SPTA1- rs12041363, replication p = 1e–17) loci were replicated (p < 0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P/SPTA1.
Conclusions
The analysis reconfirmed two known GWAS loci (GCK, HK1) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P/SPTA1. Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.
doi:10.1016/j.metabol.2013.11.018
PMCID: PMC3965585  PMID: 24405752
Genome-wide association study; Non-enzymatic glycation; Glucose, insulin resistance and diabetes; Premature aging processes
4.  Association Between Cerebellar Gray Matter Volumes, Gait Speed, and Information-Processing Ability in Older Adults Enrolled in the Health ABC Study 
Background.
The cerebellum plays an important role in mobility and cognition. However, it is unclear which regions of the cerebellum are associated with gait speed and information-processing ability in older adults without overt brain damage.
Methods.
Cross-sectional associations between cerebellar gray matter volumes (GMV), gait speed, and information-processing ability were explored in 231 community-dwelling adults (mean age: 83 years, 48% black, 58% female). We measured gait speed on an automated walkway and information-processing ability on the Digit Symbol Substitution test (DSST). Total and regional cerebellar GMV was measured on 3T-magnetic resonance imaging. Lobar GMV of the cerebellum, obtained by an automated parcellation process, were aggregated based on the cognitive (lobules VI, VII, VIII and crus I, II), sensorimotor (lobules II, IV, V), and vestibular (lobules IX and X) functions ascribed to the cerebellar regions.
Results.
Larger cerebellar GMV correlated with faster gait speed and superior DSST scores (both p < .001) independent of age, gender, atrophy, and small vessel disease. After adjusting for age, gender, and atrophy, larger cognitive cerebellar GMV correlated with both faster gait speed (p = .04) and higher DSST scores (p < .001), larger sensorimotor cerebellar GMV correlated significantly with DSST alone (p = .02), and the vestibular cerebellar GMV with neither. The association between cognitive cerebellar GMV and gait speed was no longer significant after adjusting for DSST score in the linear regression models.
Conclusions.
The relationship between gait speed and cerebellar GMV is influenced by information-processing ability, and this relationship is stronger in subregions ascribed to cognitive than vestibular or sensorimotor functions.
doi:10.1093/gerona/glt151
PMCID: PMC4095927  PMID: 24170673
Gait; Brain aging; Cognition; Imaging.
5.  Weight Change, Body Composition and Risk of Mobility Disability and Mortality in Older Adults:A Population Based Cohort Study 
Objectives
To examine associations between weight change, body composition, risk of mobility disability and mortality in older adults.
Design
Prospective, longitudinal, population-based cohort.
Setting
The Health ABC Study.
Participants
Women (n=1044) and men (n=931) aged 70-79.
Measurements
Weight,lean and fat mass from DXA measured annually over 5 years. Weight was defined as stable (n=664, referent group), loss (n=662), gain (n=321) or cycling (gain and loss, n=328) using change of 5% from year to year or from year 1 to 6. Mobility disability (two consecutive reports of difficulty walking one-quarter mile or climbing 10 steps) and mortality were determined for 8 years subsequent to the weight change period. Associations were analyzed with cox proportional hazards regression adjusted for covariates.
Results
During follow-up, 313 women and 375 men developed mobility disability,322 women and 378 men were deceased. There was no risk of mobility disability or mortality with weight gain. Weight loss and weight cycling were associated with mobility disability in women:hazard ratio (HR)=1.88 (95% confidence interval (CI)=1.40-2.53),HR=1.59 (95% CI=1.11-2.29) and weight loss was associated in men:HR=1.30 (95% CI=1.01-1.69).Weight loss and weight cycling were associated with mortality risk in women:HR=1.47 (95% CI=1.07-2.01), HR=1.62 (95% CI=1.15-2.30) and in men:HR=1.41 (95% CI=1.09-1.83),HR=1.50 (95% CI=1.08-2.08). Adjustment for lean and fat mass and change in lean and fat mass from year 1 to 6 attenuated relationships between weight loss and mobility disability in men, and weight loss and mortality in men and women.
Conclusion
Weight cycling and weight loss predict impendingmobility disability and mortality in old age, underscoring the prognostic importance of weight history.
doi:10.1111/jgs.12954
PMCID: PMC4134405  PMID: 25039391
Aging; obesity; physical function; body composition; muscle loss
6.  Incident Physical Disability in People with Lower Extremity Peripheral Arterial Disease: The Role of Cardiovascular Disease 
Objective
To evaluate the risk of incident physical disability and the decline in gait speed over a six year follow-up associated with a low ankle-arm index (AAI) in older adults.
Design
Observational cohort study.
Setting
Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; or Allegheny County, Pennsylvania.
Participants
4705 older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study were included.
Measurements
The AAI was measured in 1992–93 (baseline). Self-reported mobility disability, activities of daily living (ADL) and instrumental activities of daily living (IADL) disability and gait speed were recorded at baseline and at 1 year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking ½ mile and ADL/IADL disability was defined as any difficulty with 11 specific ADL/IADL tasks. Individuals with mobility and/or ADL/IADL disability at baseline were excluded from the respective incident disability analyses.
Results
Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. These associations were partially explained by clinical cardiovascular disease (CVD), diabetes and interim CVD events for mobility disability and by clinical CVD and diabetes for ADL/IADL disability. Individuals with AAI < 0.90 had on average a mean decrease in gait speed of 0.02 m/s/year or a decline of 0.12 m/s over the 6 year follow-up. This decrease was partly explained by prevalent CVD but not further attenuated by interim CVD events.
Conclusions
Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.
doi:10.1111/j.1532-5415.2008.01719.x
PMCID: PMC4509641  PMID: 18384579
Peripheral arterial disease; disability; cardiovascular disease
7.  Race-related Differences in Depression Onset and Recovery in Older Persons Over Time: The Health, Aging, and Body Composition Study 
Objectives
To evaluate race-related differences in depression onset and recovery in older persons, overall and by sex, and examine race-related differences in mortality according to depression.
Design
Prospective cohort study.
Setting
General community in pre-designated zip code areas in Memphis, Tennessee, and Pittsburgh, Pennsylvania.
Participants
3,075 persons age 70-79 at baseline in the Health, Aging, and Body Composition study.
Measurements
Depression was assessed at 8 time points over 10 years using the 10-item Center for Epidemiologic Studies – Depression (CES-D) scale; scores of <8 and ≥8 denoted nondepressed and depressed, respectively. We created variables for transitions across each 18-month time interval, namely, from nondepressed or depressed to nondepressed, depressed, or death, and determined the association between race and the average likelihood of these transitions over time.
Results
A higher percentage of blacks than whites were depressed at nearly all time points. Adjusting for demographics, common chronic conditions, and body mass index, blacks had a higher likelihood of experiencing depression onset than whites (odds ratio, 1.22; 95% confidence interval, 1.03-1.43); among men, blacks were more likely to experience depression onset than whites (odds ratio, 1.44; 95% confidence interval, 1.24-2.89). Blacks also had a higher likelihood of transitioning from nondepressed to death (odds ratio, 1.79; 95% confidence interval, 1.30-2.46). Overall and in sex-stratified analyses, race was not associated with recovery from depression or with the transition from depression to death.
Conclusion
Our findings highlight race differences in depression in older persons and encourage further research on the course of depression in older blacks.
doi:10.1016/j.jagp.2013.09.001
PMCID: PMC3984378  PMID: 24125816
Aging; Depression; Depressive symptoms; Race differences; Epidemiology; Prospective studies
8.  Urinary Kidney Injury Molecule 1 (KIM-1) and Interleukin 18 (IL-18) as Risk Markers for Heart Failure in Older Adults: The Health, Aging, and Body Composition (Health ABC) Study 
Background
Kidney damage and reduced kidney function are potent risk factors for heart failure (HF), but existing studies are limited to assessing albuminuria or estimated glomerular filtration rate (eGFR). We evaluated the associations of urinary biomarkers of kidney tubular injury (interleukin 18 [IL-18] and kidney injury molecule 1 [KIM-1]) with future risk of HF.
Study Design
Retrospective cohort study.
Setting & Participants
2921 participants without HF in the Health, Aging, and Body Composition (Health ABC) cohort.
Predictors
Ratios of urine KIM-1, IL-18, and albumin to creatinine (KIM-1:Cr, IL-18:Cr, and ACR, respectively).
Outcomes
Incident HF over a median follow-up of 12 years.
Results
Median values of each marker at baseline were 812 (IQR, 497–1235) pg/mg for KIM-1:Cr, 31 (IQR, 19–56) pg/mg for IL-18:Cr, and 8 (IQR, 5–19) mg/g for ACR. 596 persons developed HF during follow-up. The top quartile of KIM-1:Cr was associated with risk of incident HF after adjustment for baseline eGFR, HF risk factors, and ACR (HR, 1.32; 95% CI, 1.02–1.70) in adjusted multivariate proportional hazards models. The top quartile of IL-18:Cr was also associated with HF in a model adjusted for risk factors and eGFR (HR, 1.35; 95% CI, 1.05–1.73), but was attenuated by adjustment for ACR (HR, 1.15; 95% CI, 0.89–1.48). The top quartile of ACR had a stronger adjusted association with HF (HR, 1.96; 95% CI, 1.53–2.51).
Limitations
Generalizability to other populations is uncertain.
Conclusions
Higher urine concentrations of KIM-1 were independently associated with incident HF risk, although the associations of higher ACR were of stronger magnitude.
doi:10.1053/j.ajkd.2014.01.432
PMCID: PMC4069223  PMID: 24656453
IL-18; KIM-1; cystatin C; heart failure; CKD; risk marker; cardiovascular disease (CVD); albuminuria; kidney tubular injury
9.  Sleep-Wake Disturbances in Sedentary Community-Dwelling Elders With Functional Limitations 
OBJECTIVES
To evaluate sleep-wake disturbances in sedentary community-dwelling elders with functional limitations.
DESIGN
Cross-sectional.
SETTING
Lifestyle Interventions and Independence in Elder (LIFE) Study.
PARTICIPANTS
1635 community-dwelling persons, mean age 78.9, who spent <20 minutes/week in the past month of regular physical activity and <125 minutes/week of moderate physical activity, and had a Short Physical Performance Battery (SPPB) score <10.
MEASUREMENTS
Mobility was evaluated by the 400-meter walk time (slow gait speed defined as <0.8 m/s) and SPPB score (≤7 defined moderate-to-severe mobility impairment). Physical inactivity was defined by sedentary time, as percent of accelerometry wear time with activity <100 counts/min); top quartile established high sedentary time. Sleep-wake disturbances were evaluated by the Insomnia Severity Index (ISI) (range 0–28; ≥8 defined insomnia), Epworth Sleepiness Scale (ESS) (range 0–24; ≥10 defined daytime drowsiness), Pittsburgh Sleep Quality Index (PSQI) (range 0–21; >5 defined poor sleep quality), and Berlin Questionnaire (high risk of sleep apnea).
RESULTS
Prevalence rates were 43.5% for slow gait speed and 44.7% for moderate-to-severe mobility impairment, with 77.0% of accelerometry wear time spent as sedentary time. Prevalence rates were 33.0% for insomnia, 18.1% for daytime drowsiness, 47.8% for poor sleep quality, and 32.9% for high risk of sleep apnea. Participants with insomnia, daytime drowsiness, and poor sleep quality had mean values of 12.1 for ISI, 12.5 for ESS, and 9.2 for PSQI, respectively. In adjusted models, measures of mobility and physical inactivity were generally not associated with sleep-wake disturbances, using continuous or categorical variables.
CONCLUSION
In a large sample of sedentary community-dwelling elders with functional limitations, sleep-wake disturbances were prevalent but only mildly severe, and were generally not associated with mobility impairment or physical inactivity.
doi:10.1111/jgs.12845
PMCID: PMC4057978  PMID: 24889836
mobility impairment; physical inactivity; sleep-wake disturbances
10.  Serum Carboxymethyl-Lysine, Disability, and Frailty in Older Persons: The Cardiovascular Health Study 
Background.
Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women.
Methods.
In 1996–1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 ± 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6–12 months for 14 years. Frailty was defined according to five standard criteria at the 1996–1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty.
Results.
Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95% CI 1.01–1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95% CI 1.14–1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women.
Conclusions.
Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML’s value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.
doi:10.1093/gerona/glt155
PMCID: PMC4022092  PMID: 24127427
Biomarkers; Disablement process; Epidemiology; Frailty; Metabolism.
11.  Transition to Sarcopenia and Determinants of Transitions in Older Adults: A Population-Based Study 
Background.
Diagnostic criteria for sarcopenia from appendicular lean mass (ALM), strength, and performance have been proposed, but little is known regarding the progression of sarcopenia.
We examined the time course of sarcopenia and determinants of transitioning toward and away from sarcopenia.
Methods.
ALM, gait speed, and grip strength were assessed seven times over 9 years in 2,928 initially well-functioning adults aged 70–79. Low ALM was defined as less than 7.95 kg/m2 (men) or less than 6.24 kg/m2 (women), low performance as gait speed less than 1.0 m/s, low strength as grip strength less than 30 kg (men) or less than 20 kg (women). Presarcopenia was defined as low ALM and sarcopenia as low ALM with low performance or low strength. Hidden Markov modeling was used to characterize states of ALM, strength, and performance and model transitions leading to sarcopenia and death. Determinants of transitioning toward and away from sarcopenia were examined with logistic regression.
Results.
Initially, 54% of participants had normal ALM, strength, and performance; 21% had presarcopenia; 5% had sarcopenia; and 20% had intermediate characteristics. Of participants with normal ALM, strength, and performance, 1% transitioned to presarcopenia and none transitioned to sarcopenia. The greatest transition to sarcopenia (7%) was in presarcopenic individuals. Low-functioning and sarcopenia states were more likely to lead to death (12% and 13%). Higher body mass index (p < .001) and pain (p = .05) predicted transition toward sarcopenia, whereas moderate activity predicted transition from presarcopenia to more normal states (p = .02).
Conclusions.
Pain, physical activity, and body mass index, potentially modifiable factors, are determinants of transitions. Promotion of health approaching old age is important as few individuals transition away from their initial state.
doi:10.1093/gerona/glt131
PMCID: PMC4022098  PMID: 24013673
Muscle; Aging; Physical function; Sarcopenia; Epidemiology.
12.  Comparison Between Southern Blots and qPCR Analysis of Leukocyte Telomere Length in the Health ABC Study 
Only a few studies, primarily limited to small samples, have examined the relationship between leukocyte telomere length (LTL) data generated by Southern blots, expressed in kilobases, versus quantitative PCR data, expressed in the telomere product/a single gene product (T/S). In the present study, we compared LTL data generated by the two methods in 681 elderly participants (50% African Americans, 50% of European origin, 49.2% women, mean age 73.7±2.9 years) in the Health Aging and Body Composition Study. The correlation between the data generated by the two methods was modest (R 2 = .27). Both methods captured the age effect on LTL and the longer LTL in women than in men. However, only the Southern blot method showed a significantly longer LTL in African Americans than in European decent individuals, which might be attributed to the larger measurement error of the quantitative PCR–based method than the Southern blots.
doi:10.1093/gerona/glt121
PMCID: PMC4049151  PMID: 23946336
Leukocyte telomere length; Quantitative PCR; Southern blots.
13.  Higher Step Length Variability Indicates Lower Grey Matter Integrity of Selected Regions in Older Adults 
Gait & posture  2014;40(1):225-230.
Step length variability (SLV) increases with age in those without overt neurologic disease, is higher in neurologic patients, is associated with falls, and predicts dementia. Whether higher SLV in older adults without neurologic disease indicates presence of neurologic abnormalities is unknown. Our objective was to identify whether SLV in older adults without overt disease is associated with findings from multimodal neuroimaging. A well-characterized cohort of 265 adults (79–90 years) was concurrently assessed by gait mat, magnetic resonance imaging with diffusion tensor, and neurological exam. Linear regression models adjusted for gait speed, demographic, health, and functional covariates assessed associations of MRI measures (grey matter volume, white matter hyperintensity volume, mean diffusivity, fractional anisotropy) with SLV. Regional distribution of associations was assessed by sparse partial least squares analyses. Higher SLV (mean: 8.4, SD: 3.3) was significantly associated with older age, slower gait speed, and poorer executive function and also with lower grey matter integrity measured by mean diffusivity (standardized beta=0.16; p=0.02). Associations between SLV and grey matter integrity were strongest for the hippocampus and anterior cingulate gyrus (both β=0.18) as compared to other regions. Associations of SLV with other neuroimaging markers were not significant. Lower integrity of normal-appearing grey matter may underlie higher SLV in older adults. Our results highlighted the hippocampus and anterior cingulate gyrus, regions involved in memory and executive function. These findings support previous research indicating a role for cognitive function in motor control. Higher SLV may indicate focal neuropathology in those without diagnosed neurologic disease.
doi:10.1016/j.gaitpost.2014.03.192
PMCID: PMC4071448  PMID: 24792638
gait disorders; diffusion tensor imaging; aging; brain
14.  Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects 
Objectives
To determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular (CVD) events beyond conventional risk factors.
Background
Several studies have shown that aPWV may be a useful risk factor for predicting CVD but have been underpowered to examine whether this is true for different sub-groups.
Methods
We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with cardiovascular outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects.
Results
Of 17,635 participants, 1,785 (10%) had a cardiovascular (CVD) event. The pooled age- and sex-adjusted hazard ratio [95% CI] per SD change in loge aPWV was 1.35 [1.22, 1.50, p<0.001] for coronary heart disease (CHD), 1.54 [1.34, 1.78, p<0.001] for stroke, and 1.45 [1.30, 1.61, p<0.001) for CVD. Associations stratified by sex, diabetes and hypertension were similar, but decreased with age (1.89, 1.77, 1.36 and 1.23 for ≤50, 51–60, 61–70 and >70 years respectively, pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor: CHD 1.23, [1.11, 1.35 p<0.001]; stroke 1.28, [1.16, 1.42 p<0.001]; cardiovascular events 1.30 [1.18, 1.43, p<0.001]. Reclassification indices showed the addition of aPWV improved risk prediction (13% for 10 year CVD risk for intermediate risk) for some sub-groups.
Conclusions
Consideration of aPWV improves model fit and reclassifies risk for future cardiovascular events in models that include standard risk factors. aPWV may enable better identification of high-risk populations who may benefit from more aggressive cardiovascular risk factor management.
doi:10.1016/j.jacc.2013.09.063
PMCID: PMC4401072  PMID: 24239664
pulse wave velocity; meta-analysis; cardiovascular disease; prognostic factor
15.  Peripheral Nerve Function and Lower Extremity Muscle Power in Older Men 
OBJECTIVE
To assess whether sensorimotor peripheral nerve function is associated with muscle power in community-dwelling older men.
DESIGN
Longitudinal cohort study with 2.3 ± 0.3 years of follow-up.
SETTING
One clinical site.
PARTICIPANTS
Three hundred seventy-two participants at the Pittsburgh site of the Osteoporotic Fractures in Men (MrOS) Study (N = 5994, age = 77.2 ± 5.1 years, 99.5% white, BMI = 27.9 ± 3.7kg/m2, power = 1.88 ± 0.6watts/kg).
INTERVENTIONS
Not applicable.
MAIN OUTCOME MEASURES
A nerve function ancillary study was performed 4.6 ± 0.4 years after baseline. Muscle power was measured using a power rig. Peroneal motor nerve conduction amplitude, distal motor latency, and mean f-wave latency were measured. Sensory nerve function was assessed using 10-g and 1.4-g monofilaments and sural sensory nerve conduction amplitude and distal latency. Peripheral neuropathy symptoms at the leg and feet were assessed by self-report.
RESULTS
Adjusting for age, height, total body lean and fat mass, one standard deviation lower motor (β = −0.07, p<0.05) and sensory amplitude (β = −0.09, p<0.05) and 1.4-g (β = -0.11, p<0.05) and 10-g monofilament insensitivity (β = −0.17 both p<0.05) were associated with lower muscle power/kg. Compared to the effect of age on muscle power (β per year = −0.05 , p<0.0001), this was equivalent to aging 1.4 years for motor amplitude, 1.8 years for sensory amplitude, 2.2 years for 1.4-g monofilament detection, and 3.4 years for 10-g detection. Baseline 1.4-g monofilament detection predicted greater decline in power/kg. Short-term change in nerve function was not associated with concurrent short-term change in power/kg.
CONCLUSION
Worse sensory and motor nerve function were associated with lower power/kg and are likely important for impaired muscle function in older men. Monofilament sensitivity was associated with greater decline in power/kg and screening may identify early risk for muscle function decline in late-life, which has implications for disability.
doi:10.1016/j.apmr.2013.11.018
PMCID: PMC3972273  PMID: 24355427
muscle power; older adults; peripheral nerve function; sensory nerve function; motor nerve function
16.  Common Genetic Variants on 6q24 Associated With Exceptional Episodic Memory Performance in the Elderly 
JAMA neurology  2014;71(12):1514-1519.
IMPORTANCE
There aregenetic influences on memory ability as we age. but no specific genes have been identified.
OBJECTIVE
To use a cognitive endophenotype. exceptional episodic memory(EEM) performance. derived from nondemented offspring from the Long Life FamilyStudy(LLFS) to identify genetic variants that may be responsible for the high cognitive performance of LLFS participants and further replicate these variants using an additional 4006 nondemented individuals from 4 independent elderly cohorts
DESIGN, SETTING, AND PARTICIPANTS
A total of 467 LLFS participants from 18 families with 2 or more offspring that exhibited exceptional memory performance were used for genome-wide linkage analysis Adjusted multivariate linear analyses in the 40-megabase region encompassing the linkage peak were conducted using 4 independent replication data sets that included 4006 nondemented elderly individuals. Results of the individual replication cohorts were combined by meta-analysis
MAIN OUTCOME MEASURE
Episodic memory scores computed as the mean of the 2 standardized measures of Logical Memory IA and IIA
RESULTS
Heritability estimates indicated a significant genetic component for E EM (h2 = 0.21; SE = 0.09) Genome-wide linkage analysis revealed that EEM was linked to the 6q24 region (maximum logarithm of odds score, 3.64) Association analysis in LLFS families identified single-nucleotide polymorphisms (SNPs) nominally associated with EEM in the 40-megabase window encompassing the linkage peak Replication in one cohort identified a set of 26 SNPs associated with episodic memory (P ≤ 05) Meta-analysis of the 26 SNPs using the 4 independent replication cohorts found SN Ps rs9321334 and rs6902875 to be nominally significantly associated with episodic memory (P= .009 and P = .013. respectively). With meta-analysis restricted to individuals lacking an APOE ε4 allele. SNP rs6902875 became statistically significant (meta-analysis. P = 6.7 × 10−5) Haplotypeanalysis incorporating the 2 SNPs flanking rs6902875 (rs9321334 and rs48975 74) revealed that the A-A-Chap lotype was significantly associated with episodic memory performance (P = 2.4 × 10−5). This genomic region harbors monooxygenase dopamine β-hydroxylase-1ike 1gene (MOXD1). implicated in the biosynthesis of norepinephrine. which is prominently involved in cognitive functions.
CONCLUSIONS AND RELEVANCE
The results provide strong evidence for potential candidate genes related to EE Mon 6q24 Identifying the genes will help in understanding the biological basis of memory performance and allow interventions for enhancement of cognitive function.
doi:10.1001/jamaneurol.2014.1663
PMCID: PMC4355405  PMID: 25317765
17.  Statin Use and Gait-Speed Decline in Community-Dwelling Older Adults 
BACKGROUND/OBJECTIVES
The association between statin use and physical function is uncertain. The objective of this study was to examine the association between statin use and objectively assessed gait-speed decline in community-dwelling older adults.
DESIGN
Longitudinal cohort study.
SETTING
Health, Aging, and Body Composition (Health ABC) study.
PARTICIPANTS
Two thousand five participants aged 70–79 years at baseline, with medication and gait speed data at years 1998–1999, 1999–2000, 2001–2002 and 2002–2003.
MEASUREMENTS
The independent variables were any statin use, their standardized daily doses (low, moderate, high) and lipophilicity. The primary outcome measure was gait speed decline ≥ 0.1 m/s in the following year of statin use. Multivariable generalized estimating equations were used, adjusting for demographic, health-related behaviors, health status and access to health care factors.
RESULTS
Statin use increased from 16.2% in 1998–1999 to 25.6% in 2002–2003. The overall proportions of those with gait speed decline ≥ 0.1 m/s increased from 22.2 to 23.9% between 1998–2003. Compared to non-users, any statin use was not associated with gait speed decline ≥ 0.1 m/s (adjusted odds ratio [AOR] = 0.90, 95% CI [0.77, 1.06]). Similar non-significant trends were also seen with the use of hydrophilic or lipophilic statins. Only low-dose statin users were found to have a 22% lower risk of gait speed decline (AOR = 0.78, 95% CI [0.61, 0.99]), which was mainly driven by the results from 1999–2000 follow-up.
CONCLUSION
These results suggest no detrimental effects of statin use on gait speed decline in community-dwelling older adults.
doi:10.1111/jgs.13134
PMCID: PMC4300263  PMID: 25537649
hydroxymethylglutaryl-CoA reductase inhibitors; statins; gait speed; physical function; aged
18.  Adipose Tissue Density, a Novel Biomarker Predicting Mortality Risk in Older Adults 
Background.
Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.
Methods.
VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4–13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.
Results.
Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36–2.80; Health ABC) and 1.88 (1.31–2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35–2.28; Health ABC) and 1.56 (1.15–2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12–2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21–2.07), and AGES-Reykjavik, 1.43 (1.07–1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.
Conclusion.
VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
doi:10.1093/gerona/glt070
PMCID: PMC3859360  PMID: 23707956
Obesity; Aging; Leptin; Adiponectin.
19.  Body Composition Explains Sex Differential in Physical Performance Among Older Adults 
Background.
Older women have higher percent body fat, poorer physical function, lower strength, and higher rates of nonfatal chronic conditions than men. We sought to determine whether these differences explained physical performance differences between men and women.
Methods.
Physical performance was assessed in the Health, Aging and Body Composition study in 2,863 men and women aged 70–79 with a composite 0–4 point score consisting of chair stands, standing balance including one-leg stand, and 6-m usual and narrow walk tests. Total body composition was measured by dual x-ray absorptiometry, thigh composition by computed tomography, and knee extensor strength by isokinetic dynamometer. Analysis of covariance estimated least square mean performance scores for men and women.
Results.
Men had higher performance scores than women (least square means: 2.33±0.02 vs 2.03±0.02, p < .0001), adjusted for race, study site, age, and height. Body composition measures (total body fat and thigh muscle area, muscle density, subcutaneous fat, and intermuscular fat) accounted for differences between men and women (least square means: 2.15±0.02 vs 2.17±0.02, p = .53). Higher strength in men partly explained the sex difference (least square means: 2.28±0.02 vs 2.12±0.02, p < .0001). Strength attenuated the association of thigh muscle mass with performance. Chronic health conditions did not explain the sex difference.
Conclusions.
In a well-functioning cohort, poorer physical function in women compared with men can be explained predominantly by their higher fat mass, but also by other body composition differences. The higher proportion of body fat in women may put them at significant biomechanical disadvantage for greater disability in old age.
doi:10.1093/gerona/glt027
PMCID: PMC3859364  PMID: 23682159
Body composition; Physical performance; Epidemiology.
20.  Resting Heart Rate and Risk of Incident Heart Failure: Three Prospective Cohort Studies and a Systematic Meta‐Analysis 
Background
The relationship between resting heart rate (RHR) and incident heart failure (HF) has been questioned.
Methods and Results
RHR was assessed at baseline in 7073 participants in 3 prospective cohorts (Cardiovascular Health Study, Health ABC study and Kuopio Ischemic Heart Disease Study) that recorded 1189 incident HF outcomes during 92 702 person‐years of follow‐up. Mean age of participants was 67 (9.9) years and mean RHR was 64.6 (11.1) bpm. Baseline RHR correlated (P<0.001) positively with body mass index (r=0.10), fasting glucose (r=0.18), and C‐reactive protein (r=0.20); and inversely with serum creatinine (r=−0.05) and albumin (r=−0.05). Baseline RHR was non‐linearly associated with HF risk. The age and sex‐adjusted hazard ratio for HF comparing the top (>72 bpm) versus the bottom (<57 bpm) quartile of baseline RHR was 1.48 (95% confidence interval [CI] 1.26 to 1.74) and was modestly attenuated (1.30, 95% CI 1.10 to 1.53) with further adjustment for body mass index, history of diabetes, hypertension, smoking status, serum creatinine, and left ventricular hypertrophy. These findings remained consistent in analyses accounting for incident coronary heart disease, excluding individuals with prior cardiovascular events, or those taking beta‐blockers; and in subgroups defined by several individual participant characteristics. In a pooled random effects meta‐analysis of 7 population‐based studies (43 051 participants and 3476 HF events), the overall hazard ratio comparing top versus bottom fourth of RHR was 1.40 (95% CI: 1.19 to 1.64).
Conclusions
There is a non‐linear association between RHR and incident HF. Further research is needed to understand the physiologic foundations of this association.
doi:10.1161/JAHA.114.001364
PMCID: PMC4330063  PMID: 25589535
heart failure; heart rate; risk factor
21.  The Relationship of Vitamin B12 and Sensory and Motor Peripheral Nerve Function in Older Adults 
Objectives
To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults.
Design
Cross-sectional.
Setting
Health, Aging and Body Composition Study.
Participants
Two thousand two hundred eighty-seven adults aged 72–83 years [mean age: 76.5 ± 2.9 years; 51.4% female; 38.3% black].
Measurements
Low serum B12 was defined based solely on serum B12 of <260 pmol/L, whereas deficient B12 status was defined as B12 <260 pmol/L, methylmalonic acid [MMA] >271 nmol/L and MMA >2-methylcitrate. Peripheral nerve function was assessed by peroneal nerve conduction amplitude and velocity [NCV] (motor); 1.4g/10g monofilament detection; average vibration threshold detection; and peripheral neuropathy symptoms [numbness; aching/burning pain] (sensory).
Results
B12 deficient status was found in 7.0% and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4g) touch (OR: 1.50; 95% CI: [1.06, 2.13]) and worse NCV [42.3 m/s vs. 43.5 m/s] (β =−1.16; p=0.01), after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms.
Conclusion
Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate.
doi:10.1111/j.1532-5415.2012.03998.x
PMCID: PMC3376015  PMID: 22690982
low B12; deficient B12; sensory peripheral nerve function; motor nerve conduction; older adults
22.  Impact of Visceral Fat on Skeletal Muscle Mass and Vice Versa in a Prospective Cohort Study: The Korean Sarcopenic Obesity Study (KSOS) 
PLoS ONE  2014;9(12):e115407.
Objectives
Sarcopenia and visceral obesity have been suggested to aggravate each other, resulting in a vicious cycle. However, evidence based on prospective study is very limited. Our purpose was to investigate whether visceral fat promotes a decrease in skeletal muscle mass and vice versa.
Methods
We observed changes in anthropometric and body composition data during a follow-up period of 27.6±2.8 months in 379 Korean men and women (mean age 51.9±14.6 years) from the Korean Sarcopenic Obesity Study (KSOS). Appendicular lean soft tissue (ALST) mass was calculated using dual-energy X-ray absorptiometry, and visceral fat area (VFA) was measured using computed tomography at baseline and follow-up examination.
Results
ALST mass significantly decreased, whereas trunk and total fat mass increased in both men and women despite no significant change in weight and body mass index. In particular, women with visceral obesity at baseline had a greater decrease in ALST mass than those without visceral obesity (P = 0.001). In multiple linear regression analysis, baseline VFA was an independent negative predictor of the changes in ALST after adjusting for confounding factors including age, gender, life style and body composition parameters, insulin resistance, high sensitivity C-reactive protein and vitamin D levels (P = 0.001), whereas the association between baseline ALST mass and changes in VFA was not statistically significant (P = 0.555).
Conclusions
This longitudinal study showed that visceral obesity was associated with future loss of skeletal muscle mass in Korean adults. These results may provide novel insight into sarcopenic obesity in an aging society.
doi:10.1371/journal.pone.0115407
PMCID: PMC4269440  PMID: 25517117
23.  Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE Study randomized clinical trial 
JAMA  2014;311(23):2387-2396.
SUMMARY
Importance
In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining if physical activity prevents or delays mobility disability.
Objective
To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability.
Design, Setting, and Participants
The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban and rural communities at 8 field centers throughout the US. We randomized a volunteer sample of 1,635 sedentary men and women aged 70–89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m.
Interventions
Participants were randomized to a structured moderate intensity physical activity program (n=818) done in a center and at home that included including aerobic, resistance and flexibility training activities or to a health education program (n=817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises.
Main Outcomes and Measures
The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m.
Results
Incident major mobility disability occurred in 30.1% (n=246/818) of physical activity and 35.5% (n=290/817) of health education participants (HR=0.82, 95%CI=0.69–0.98, p=0.03). Persistent mobility disability was experienced by 120/818 (14.7%) physical activity and 162/817 (19.8%) health education participants (HR=0.72; 95%CI=0.57–0.91; p=0.006). Serious adverse events were reported by 404/818 (49.4%) of the physical activity and 373/817 (45.7%) of the health education participants (Risk Ratio=1.08; 95%CI=0.98–1.20).
Conclusions and Relevance
A structured moderate intensity physical activity program, compared with a health education program, reduced major mobility disability over 2.6 years among older adults at risk of disability. These findings suggest mobility benefit from such a program in vulnerable older adults.
Registration
ClinicalsTrials.gov identifier NCT01072500.
doi:10.1001/jama.2014.5616
PMCID: PMC4266388  PMID: 24866862
24.  Primary Prevention of Falls: Effectiveness of a Statewide Program 
American journal of public health  2014;104(5):e77-e84.
Objective
We examined a population-wide program to reduce falls incidence, Pennsylvania’s Healthy Steps for Older Adults (HSOA), which, to date, has been completed by 32,000 people aged 50 or older. Older adults completing HSOA are screened and educated regarding falls risk, with those identified as high risk referred to primary care providers and home safety resources.
Methods
In 2010-2011 older adults who completed HSOA (n=814) or who did not but attended the same senior center sites (n=1019) were enrolled and followed monthly for up to 12 months. Falls were defined as any occasion when a person ends up on the floor or ground without being able to stop or prevent it. While participants were not randomly allocated to study conditions, the two groups did not differ in falls risk at baseline or attrition over follow-up. We ascertained falls each month using a telephone interactive voice response system.
Results
In multivariate models, adjusted falls incidence rate ratios among HSOA participants were lower than in the comparator group for both total (IRR = 0.83, 95% confidence interval [CI], 0.72-0.96) and activity-adjusted (IRR= 0.81, 95% CI, 0.70-0.93) months of follow-up.
Conclusions
Primary prevention of falls using existing aging services infrastructure is feasible and resulted in a 17% reduction in the rate of falls over a median of 7.5 months of follow-up.
doi:10.2105/AJPH.2013.301829
PMCID: PMC3987590  PMID: 24625164
25.  Prevalence and Correlates of Self-Reported Medication Non-Adherence among Older Adults with Coronary Heart Disease, Diabetes Mellitus, and/or Hypertension 
Research in social & administrative pharmacy : RSAP  2013;9(6):10.1016/j.sapharm.2012.12.002.
Background
Information about the about the prevalence and correlates of self-reported medication nonadherence using multiple measures in older adults with chronic cardiovascular conditions is needed.
Objective
To examine the prevalence and correlates of self-reported medication nonadherence among community-dwelling elders with chronic cardiovascular conditions.
Methods
Participants (n=897) included members from the Health, Aging and Body Composition study with coronary heart disease, diabetes mellitus, and/or hypertension at year 10. Self-reported nonadherence was measured by the 4-item Morisky Medication Adherence Scale (MMAS-4) and 2-item cost-related nonadherence (CRN-2) scale at year 11. Factors (demographic, health status, and access to care) were examined for association with the MMAS-4 and then for association with the CRN-2 scale.
Results
Nonadherence per the MMAS-4 and CRN-2 scale was reported by 40.7% and 7.7% of participants, respectively, with little overlap (3.7%). Multivariable logistic regression analyses found that black race was significantly associated with nonadherence per the MMAS-4 (p=0.002) and the CRN-2 scale (p=0.005). Other correlates of nonadherence per the MMAS-4 (with independent associations) included having cancer (p=0.04), a history of falls (p=0.02), sleep disturbances (p=0.04) and having a hospitalization in the previous 6 months (p=0.005). Conversely, being unmarried (p=0.049), having worse self-reported health (p=0.04) and needs being poorly met by income (p=0.02) showed significant independent associations with nonadherence per the CRN-2 scale.
Conclusions
Self-reported medication nonadherence was common in older adults with chronic cardiovascular conditions and only one factor – race – was associated with both types. The research implication of this finding is that it highlights the need to measure both types of self-reported nonadherence in older adults. Moreover, the administration of these quick measures in the clinical setting should help identify specific actions such as patient education or greater use of generic medications or pill boxes that may address barriers to medication nonadherence.
doi:10.1016/j.sapharm.2012.12.002
PMCID: PMC3620923  PMID: 23291338
medication adherence; chronic disease; aged

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