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1.  Kidney Function and Mortality in Octogenarians: Cardiovascular Health Study All Stars 
To examine the association between kidney function and all-cause mortality in octogenarians.
Retrospective analysis of prospectively collected data.
Serum creatinine and cystatin C were measured in 1,053 Cardiovascular Health Study (CHS) All Stars participants.
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.
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).
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.
PMCID: PMC3902776  PMID: 22724391
octogenarians; kidney function; mortality
2.  Adipose Tissue Density, a Novel Biomarker Predicting Mortality Risk in Older Adults 
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.
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.
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.
VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
PMCID: PMC3859360  PMID: 23707956
Obesity; Aging; Leptin; Adiponectin.
3.  Body Composition Explains Sex Differential in Physical Performance Among Older Adults 
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.
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.
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.
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.
PMCID: PMC3859364  PMID: 23682159
Body composition; Physical performance; Epidemiology.
4.  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.
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.
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.
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).
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.
PMCID: PMC4269440  PMID: 25517117
5.  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.
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.
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.
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.
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 identifier NCT01072500.
PMCID: PMC4266388  PMID: 24866862
6.  Primary Prevention of Falls: Effectiveness of a Statewide Program 
American journal of public health  2014;104(5):e77-e84.
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.
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.
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.
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.
PMCID: PMC3987590  PMID: 24625164
7.  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.
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.
To examine the prevalence and correlates of self-reported medication nonadherence among community-dwelling elders with chronic cardiovascular conditions.
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.
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.
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.
PMCID: PMC3620923  PMID: 23291338
medication adherence; chronic disease; aged
8.  Genetic Epidemiology and Genome-Wide Linkage Analysis of Carotid Artery Ultrasound Traits in Multigenerational African Ancestry Families 
Atherosclerosis  2013;231(1):10.1016/j.atherosclerosis.2013.09.005.
Intima-media thickness, adventitial diameter and lumen diameter are indicators of cardiovascular disease risk. The influence of genetic factors on these measures in African ancestry populations is not well defined. Therefore, we estimated heritability and performed genome-wide linkage analysis of carotid ultrasound traits in 7 multigenerational families of African ancestry.
A total of 395 individuals (7 pedigrees; mean family size = 56; 2,392 relative pairs) aged ≥18 years had a common carotid artery ultrasound scan. Statistical analyses were conducted using pedigree-based maximum likelihood methods.
Significant covariates included age, sex, body mass index or height and waist, and systolic blood pressure. Residual heritabilities ranged from 0.35±0.10 to 0.64±0.12 (P<0.0001). We identified a novel quantitative trait locus for adventitial and lumen diameters on chromosome 11 (max LOD=4.09, 133cM).
Further fine mapping of this region may identify specific mutations predisposing to subclinical vascular disease among African ancestry individuals.
PMCID: PMC3837479  PMID: 24125421
carotid ultrasound; intima-media thickness; arterial diameter; genome-wide linkage; African ancestry
9.  Frailty and Risk for Heart Failure in Older Adults 
American heart journal  2013;166(5):10.1016/j.ahj.2013.07.032.
To assess the association between frailty and risk for heart failure (HF) in older adults.
Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known.
We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC battery) and the Gill index, and incident HF in 2825 participants aged 70-79 years.
Mean age of participants was 74±3years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (hazard ratio HR 1.36, 95%CI 1.08-1.71) and severe frailty (HR 1.88, 95%CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95%CI 1.13, 1.36 per SD decrease in score), and remained significant when controlled for death as a competing risk (HR 1.30; 95%CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95%CI 0.018-0.010) and appropriately reclassified 13.4% (NRI 0.073, 95%CI 0.021-0.125; P=0.006) of participants (8.3% who developed HF and 5.1% who did not).
Frailty is independently associated with risk of HF in older adults.
PMCID: PMC3844525  PMID: 24176445
Frailty; Heart Failure; Elderly
10.  The Relationship of Vitamin B12 and Sensory and Motor Peripheral Nerve Function in Older Adults 
To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults.
Health, Aging and Body Composition Study.
Two thousand two hundred eighty-seven adults aged 72–83 years [mean age: 76.5 ± 2.9 years; 51.4% female; 38.3% black].
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).
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.
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.
PMCID: PMC3376015  PMID: 22690982
low B12; deficient B12; sensory peripheral nerve function; motor nerve conduction; older adults
11.  Prediction of Severe, Persistent Activity-of-Daily-Living Disability in Older Adults 
American Journal of Epidemiology  2013;178(7):1085-1093.
In a prospective cohort of nondisabled adults aged 65 years or more in the Established Populations for Epidemiologic Studies of the Elderly (1981–1987 and 1985–1992), we used a competing risk approach to predict the 5-year risk of severe, persistent activities-of-daily-living (ADLs) disability, defined as dependence in ≥3 ADLs for 2 consecutive annual interviews or for 1 interview followed by death in the subsequent year. During 5 years, 6.8% developed severe, persistent ADL dependence, and 14.6% died without severe, persistent ADL dependence in the derivation cohort (n = 8,301); the corresponding percentages were 6.8% and 15.8% in the validation cohort (n = 4,177). A model based on age, current employment, visual impairment, self-rated health, diabetes mellitus, history of stroke or brain hemorrhage, cognitive function, and self-reported physical function showed good calibration. Discrimination, assessed by C statistics, for <70, 70–74, 75–79, and ≥80 years, was 0.75, 0.74, 0.65, and 0.66 in the derivation cohort and 0.70, 0.72, 0.70, and 0.65 in the validation cohort, respectively. In conclusion, a simple risk score based on routinely available clinical information can predict severe, persistent disability in 5 years. Future studies should examine whether physical performance measures can further improve prediction in the oldest old.
PMCID: PMC3783096  PMID: 23785110
activities of daily living; aged; prognosis
12.  The QT Interval and Risk of Incident Atrial Fibrillation 
Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.
To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.
We examined a prolonged QT corrected by the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae.
Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts.
A prolonged QT interval is associated with an increased risk of incident AF.
PMCID: PMC3787974  PMID: 23872693
atrial fibrillation; epidemiology; risk; QT interval; electrocardiography; ECG
13.  Mitochondrial DNA Sequence Variation Associated with Dementia and Cognitive Function in the Elderly 
Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increased neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10–12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia (OR = 1.86, 95% CI = 1.23, 2.82, p = 0.0008) and haplogroup J participants experienced a statistically significant 8-year decline in 3MS (β = −0.14, 95% CI = −0.27, −0.03, p = 0.0006), both compared with common haplogroup H. The m.15244A>G, p.G166G, CytB variant was associated with a significant decline in DSST score (β = −0.58, 95% CI −0.89, −0.28, p = 0.00019) and the m.14178T>C, p.I166V, ND6 variant was associated with a significant decline in 3MS score (β = −0.87, 95% CI −1.31, −3.86, p = 0.00012). Finally, we sequenced the complete ∼16.5 kb mtDNA from 135 Health ABC participants and identified several highly conserved and potentially functional nonsynonymous variants unique to 22 dementia cases and aggregate sequence variation across the hypervariable 2-3 regions that influences 3MS and DSST scores.
PMCID: PMC4156011  PMID: 22785396
Cognitive function; dementia; DNA sequencing; mitochondria; mtDNA; oxidative phosphorylation
14.  Decline in Health for Older Adults: Five-Year Change in 13 Key Measures of Standardized Health 
The health of older adults declines over time, but there are many ways of measuring health. It is unclear whether all health measures decline at the same rate or whether some aspects of health are less sensitive to aging than others.
We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity
strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, activities of daily living, instrumental activities of daily living, and gait speed. Each measure was standardized against self-rated health. We compared the 5-year change to see which of the 13 measures declined the fastest and the slowest.
The 5-year change in standardized health varied from a decline of 12 points (out of 100) for hospitalization to a decline of 17 points for gait speed. In most comparisons, standardized health from hospitalization and bed days declined the least, whereas health measured by activities of daily living, instrumental activities of daily living, and gait speed declined the most. These rankings were independent of age, sex, mortality patterns, and the method of standardization.
All of the health variables declined, on average, with advancing age, but at significantly different rates. Standardized measures of mental health, cognition, quality of life, and hospital utilization did not decline as fast as gait speed, activities of daily living, and instrumental activities of daily living. Public health interventions to address problems with gait speed, activities of daily living, and instrumental activities of daily living may help older adults to remain healthier in all dimensions.
PMCID: PMC3738029  PMID: 23666944
Aging; Cognition; ADL; IADL; Gait.
15.  Long-term Survival in Adults Aged 65 and Older With White Matter Hyperintensity: Association With Performance on the Digit Symbol Substitution Test 
Psychosomatic medicine  2013;75(7):10.1097/PSY.0b013e31829c1df2.
White matter hyperintensity (WMH) confers increased mortality risk in patients with cardiovascular diseases. However, little is known about differences in survival times among adults 65 years and older who have WMH and live in the community. To characterize the factors that may reduce mortality risk in the presence of WMH, measures of race, sex, ApoE4, neuroimaging, cardiometabolic, physiological and psychosocial characteristics were examined, with a particular focus on information processing as measured by the Digit Symbol Substitution Test(DSST).
Cox-proportional models were used to estimate mortality risks in a cohort of 3513 adults (74.8years, 58%women, 84%white) with WMH (0–9 points), DSST (0–90 points), risk factor assessment in 1992–94 and data on mortality and incident stroke to 2009 (median follow-up [range]:14.2[0.5–18.1]years).
WMH predicted a 48% greater mortality risk (age-adjusted hazard ratio (HR)[95% confidence interval(CI)] for WMH>3 points=1.48[1.35–1.62]). This association was attenuated after adjustment for DSST (HR[CI]: 1.38[1.27–1.51]) or lacunar infarcts (HR[CI]: 1.37[1.25,1.50]) but not after adjustment for other factors. The interaction between DSST and WMH was significant (p=0.011). In fully adjusted models stratified by WMH>3, participants with DSST>median had a 34% lower mortality risk among those with WMH>3 (n=532/1217) and a 28% lower mortality risk among those with WMH<3 (n=1364/2296), compared to participants with DSST
WMH is associated with increased long-term mortality risk in community-dwelling adults aged 65 and older. The increased risk is attenuated for those with higher DSST. Assessment of cognitive function with DSST may improve risk stratification of individuals with WMH.
PMCID: PMC3809761  PMID: 23886735
mortality; information processing; white matter hyperintensity
Rationale: Relationships between chronic health conditions and acute infections remain poorly understood. Preclinical studies suggest crosstalk between nervous and immune systems.
Objectives: To determine bidirectional relationships between cognition and pneumonia.
Methods: We conducted longitudinal analyses of a population-based cohort over 10 years. We determined whether changes in cognition increase risk of pneumonia hospitalization by trajectory analyses and joint modeling. We then determined whether pneumonia hospitalization increased risk of subsequent dementia using a Cox model with pneumonia as a time-varying covariate.
Measurements and Main Results: Of the 5,888 participants, 639 (10.9%) were hospitalized with pneumonia at least once. Most participants had normal cognition before pneumonia. Three cognition trajectories were identified: no, minimal, and severe rapid decline. A greater proportion of participants hospitalized with pneumonia were on trajectories of minimal or severe decline before occurrence of pneumonia compared with those never hospitalized with pneumonia (proportion with no, minimal, and severe decline were 67.1%, 22.8%, and 10.0% vs. 76.0%, 19.3%, and 4.6% for participants with and without pneumonia, respectively; P < 0.001). Small subclinical changes in cognition increased risk of pneumonia, even in those with normal cognition and physical function before pneumonia (β = −0.02; P < 0.001). Participants with pneumonia were subsequently at an increased risk of dementia (hazard ratio, 2.24 [95% confidence interval, 1.62–3.11]; P = 0.01). Associations were independent of demographics, health behaviors, other chronic conditions, and physical function. Bidirectional relationship did not vary based on severity of disease, and similar associations were noted for those with severe sepsis and other infections.
Conclusions: A bidirectional relationship exists between pneumonia and cognition and may explain how a single episode of infection in well-appearing older individuals accelerates decline in chronic health conditions and loss of functional independence.
PMCID: PMC3827700  PMID: 23848267
pneumonia; dementia; cognitive function
American Journal of Hypertension  2013;26(8):1037-1044.
Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.
We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.
Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (–0.19, –0.08, P < 0.001) and 0.15-ml/min/year faster decline (–0.21, –0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, –0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.
Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.
PMCID: PMC3816322  PMID: 23709568
blood pressure; cystatin C; diastolic blood pressure; elderly; hypertension; kidney function; systolic blood pressure.
Pneumonia requiring hospitalization remains a major public health problem among community-dwelling older adults. Impaired oral hygiene is a modifiable risk factor for healthcare-associated pneumonia, but its role in community-acquired pneumonia is unclear.
To identify novel modifiable risk factors, focusing on oral hygiene, for pneumonia requiring hospitalization among community-dwelling older adults.
Prospective observational cohort study
Memphis, Tennessee and Pittsburgh, Pennsylvania
Of 3075 well-functioning community-dwelling adults aged 70–79 years enrolled in the Health, Aging, and Body Composition Study from 1997–1998, 1441 had complete data, dental exam within six months of baseline, and were eligible for this study.
The primary outcome was pneumonia requiring hospitalization through 2008.
Of 1441 participants, 193 were hospitalized for pneumonia. In a multivariable model, male gender (HR 2.07, 95%CI 1.51–2.83), white race (HR 1.44, 95%CI 1.03–2.01), history of pneumonia (HR 3.09, 95%CI 1.86–5.14), pack-years of smoking (HR 1.006, 95%CI 1.001–1.011), and percent predicted FEV1 (moderate vs. mild/normal lung function [HR 1.78, 95%CI 1.28–2.48], severe vs. mild/normal lung function [HR 2.90, 95%CI 1.51–5.57]) were non-modifiable risk factors for pneumonia. Incident mobility limitation (HR 1.77, 95%CI 1.32–2.38) and higher mean oral plaque score (HR 1.29, 95%CI 1.02–1.64) were modifiable risk factors for pneumonia. Average Attributable Fractions revealed that 11.5% of pneumonias were attributed to incident mobility limitation and 10.3% to mean oral plaque score ≥1.
Incident mobility limitation and higher mean oral plaque score were two modifiable risk factors attributable for 22% of pneumonias requiring hospitalization. These data suggest innovative opportunities for pneumonia prevention among community-dwelling older adults.
PMCID: PMC3714374  PMID: 23772872
pneumonia; community-dwelling; risk factors
Obesity is associated with increased risk of many types of cancer. Less is known regarding associations between adipose depots and cancer risk. We aimed to explore relationships between adipose depots, risk of cancer and obesity-related cancer (per NCI definition) in participants initially aged 70–79 without prevalent cancer (1,179 men, 1,340 women), and followed for incident cancer for 13 years. Measures included body mass index (BMI), total adipose tissue from dual-energy X-ray absorptiometry and computed tomography measures: visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), thigh intermuscular adipose tissue and thigh muscle attenuation (Hounsfield Unit, HU), low HU indicates fatty infiltration. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression adjusted for demographics, lifestyle variables and medical conditions. During follow-up 617 participants developed cancer of which 224 were obesity-related cancers. Total adipose tissue and VAT were positively associated with cancer risk among women (HR 1.14, 95% CI 1.01–1.30 per SD increase, HR 1.15, 95% CI 1.02–1.30 per SD increase). There were no associations with cancer risk among men. Total adipose tissue was positively associated with obesity-related cancer risk among women (HR 1.23, 95% CI 1.03–1.46 per SD increase). VAT was positively associated with obesity-related cancer risk among men (HR 1.30, 95% CI 1.06–1.60 per SD increase) and remained associated even with adjustment for BMI (HR 1.40, 95% CI 1.08–1.82 per SD increase). These findings provide insight into relationships between specific adipose depots and cancer risk and suggest differential relationships among men and women.
PMCID: PMC4071344  PMID: 24869972
Obesity; weight; adipose; body fat; cancer incidence; cancer risk; aging
Frontiers in Genetics  2014;5:159.
The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.
PMCID: PMC4042684  PMID: 24917880
NALP1; lipids; genomewide association study; aging; familial longevity; family-based study
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
PMCID: PMC3696959  PMID: 23583979
Most genome-wide association studies are confined to middle-aged populations. It is unclear whether associations between single nucleotide polymorphisms (SNPs) and obesity persist in old age. We aimed to relate 10 body mass index (BMI)–associated SNPs to weight, BMI, % fat, visceral and subcutaneous adipose tissue in Health ABC and AGES-Reykjavik comprising 4,846 individuals of European Ancestry, and 1,139 African Americans over age 65. SNPs were scaled using effect estimates from candidate SNPs. In Health ABC, a SNP near GNPDA2 was modestly associated with weight and SAT area (p = .008, p = .001). Risk score (sum of scaled SNPs) was associated with weight, BMI, and SAT area (p < .0001 for all), but neither GNPDA2 nor risk score was associated with weight, BMI, visceral adippose tissue, subcutaneous adipose tissue, or % fat in AGES-Reykjavik. In African Americans, a SNP near SEC16B was weakly associated with weight (p = .04). In this sample of older adults, no BMI-associated SNPs were associated with weight or adiposity.
PMCID: PMC3660116  PMID: 23160366
Obesity; Aging; Genetics; SNPs.
Neurobiology of aging  2013;35(2):442.e1-442.e8.
Mitochondrial dysfunction occurs early in the course of several neurodegenerative diseases, and is potentially related to increased oxidative damage and amyloid-β (Aβ) formation in Alzheimer’s disease. The goals of this study were to assess mtDNA sequence associations with dementia risk, 10-year cognitive change, and markers of oxidative stress and Aβ among 1089 African-Americans in the population-based Health, Aging, and Body Composition Study. Participants were free of dementia at baseline, and incidence was determined in 187 (18%) cases over 10 to 12 follow-up years. Haplogroup L1 participants were at increased risk for developing dementia (odds ratio = 1.88, 95% confidence interval = 1.23–2.88, p = 0.004), lower plasma Aβ42 levels (p = 0.03), and greater 10-year decline on the Digit Symbol Substitution Test (p = 0.04) when compared with common haplogroup L3. The p.V193I, ND2 substitution was associated with significantly higher Aβ42 levels (p = 0.0012), and this association was present in haplogroup L3 (p = 0.018) but not L1 (p = 0.90) participants. All associations were independent of potential confounders, including APOEε4 status and nuclear genetic ancestry. Identification of mtDNA sequence variation associated with dementia risk and cognitive decline may contribute to the development of new treatment targets and diagnostic tests that identify responders to interventions targeting mitochondria.
PMCID: PMC4019378  PMID: 24140124
Dementia; Mitochondria; mtDNA; Amyloid-β; Oxidative stress
In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle-aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction.
To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events.
Design, Setting, and Participants
A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997–1998 and 2006–2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events.
Main Outcome Measure
Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization).
At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02–1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20–1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%–19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32%–2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33–3.02; and HR, 1.66; 95% CI, 1.18–2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, −0.4% to 11.8%).
Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors.
PMCID: PMC4006989  PMID: 22496264

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