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1.  Genetic Variation at NCAN Locus is Associated with Inflammation and Fibrosis in Non-alcoholic Fatty Liver Disease in Morbid Obesity 
Human heredity  2013;75(1):10.1159/000346195.
Objective
Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity.
Methods
In 1,092 bariatric patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed.
Results
We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. Rs2228603[T] was associated with lower serum LDL, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD.
Conclusion
NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.
doi:10.1159/000346195
PMCID: PMC3864002  PMID: 23594525
Obesity; dyslipidemia; steatohepatitis; cirrhosis; steatosis
2.  Trajectories of Gait Speed Predict Mortality in Well-Functioning Older Adults: The Health, Aging and Body Composition Study 
Background.
Although gait speed slows with age, the rate of slowing varies greatly. To date, little is known about the trajectories of gait speed, their correlates, and their risk for mortality in older adults.
Methods.
Gait speed during a 20-m walk was measured for a period of 8 years in initially well-functioning men and women aged 70–79 years participating in the Health, Aging and Body Composition study. We described the trajectories of gait speed and examined their correlates using a group-based mixture model. Also risk associated with different gait speed trajectories on all-cause mortality was estimated using a Cox-proportional hazard model.
Results.
Of 2,364 participants (mean age, 73.5±2.9 years; 52% women), we identified three gait speed trajectories: slow (n = 637), moderate (n = 1,209), and fast decline (n = 518). Those with fast decline slowed 0.030 m/s per year or 2.4% per year from baseline to the last follow-up visit. Women, blacks, and participants who were obese, had limited knee extensor strength, and had low physical activity were more likely to have fast decline than their counterparts. Participants with fast decline in gait speed had a 90% greater risk of mortality than those with slow decline.
Conclusion.
Despite being well-functioning at baseline, a quarter of older adults experienced fast decline in gait speed, which was associated with an increased risk of mortality.
doi:10.1093/gerona/gls197
PMCID: PMC3593620  PMID: 23051974
Gait speed; Older adults; Mortality.
3.  Reproducibility of peroneal motor nerve conduction measurement in older adults 
Objective
While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults.
Methods
We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age=82.9 ± 2.7, n=62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day.
Results
Low CVs (2.15–4.24%) and moderate to high ICCs (0.75–0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race, or study site.
Conclusion
NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender.
Significance
These data provide evidence to support use of these measures in aging research.
doi:10.1016/j.clinph.2012.07.027
PMCID: PMC3562564  PMID: 23022036
Motor nerve conduction; aging; peripheral nerve function; reproducibility; diabetes
4.  Objective measurements of daily physical activity patterns and sedentary behaviour in older adults: Age, Gene/Environment Susceptibility-Reykjavik Study 
Age and Ageing  2012;42(2):222-229.
Background: objectively measured population physical activity (PA) data from older persons is lacking. The aim of this study was to describe free-living PA patterns and sedentary behaviours in Icelandic older men and women using accelerometer.
Methods: from April 2009 to June 2010, 579 AGESII-study participants aged 73–98 years wore an accelerometer (Actigraph GT3X) at the right hip for one complete week in the free-living settings.
Results: in all subjects, sedentary time was the largest component of the total wear time, 75%, followed by low-light PA, 21%. Moderate-vigorous PA (MVPA) was <1%. Men had slightly higher average total PA (counts × day−1) than women. The women spent more time in low-light PA but less time in sedentary PA and MVPA compared with men (P < 0.001). In persons <75 years of age, 60% of men and 34% of women had at least one bout ≥10 min of MVPA, which decreased with age, with only 25% of men and 9% of women 85 years and older reaching this.
Conclusion: sedentary time is high in this Icelandic cohort, which has high life-expectancy and is living north of 60° northern latitude.
doi:10.1093/ageing/afs160
PMCID: PMC3575120  PMID: 23117467
physical activity; accelerometry; sedentary behaviour; older adults; BMI; AGES-Reykjavik; older people
5.  ACTIVITY ENERGY EXPENDITURE AND INCIDENT COGNITIVE IMPAIRMENT IN OLDER ADULTS 
Archives of internal medicine  2011;171(14):1251-1257.
Introduction
Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on subjective self-reports of physical activity, which only moderately correlate to objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment.
Methods
We calculated AEE as 90% of total energy expenditure (assessed over two weeks using doubly-labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998–2000). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination (3MS). Cognitive impairment was defined as a decline of >1.0 SD (9 points) between baseline and follow-up.
Results
After adjustment for baseline 3MS, demographics, fat free mass, sleep duration, self-reported health, and diabetes, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (OR, 95% CI 0.09, 0.01–0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (p-for-trend over tertiles=0.05).
Conclusions
These findings indicate that greater activity energy expenditure may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined.
doi:10.1001/archinternmed.2011.277
PMCID: PMC3923462  PMID: 21771893
6.  Low 25-Hydroxyvitamin D Predicts the Onset of Mobility Limitation and Disability in Community-Dwelling Older Adults: The Health ABC Study 
Background.
Although low 25-hydroxyvitamin D (25(OH)D) is prevalent among older adults and is associated with poor physical function, longitudinal studies examining vitamin D status and physical function are lacking. We examined the association between 25(OH)D, parathyroid hormone (PTH), and the onset of mobility limitation and disability over 6 years of follow-up in community-dwelling, initially well-functioning older adults participating in the Health, Aging and Body Composition study (n = 2,099).
Methods.
Serum 25(OH)D and PTH were measured at the 12-month follow-up visit (1998–1999). Mobility limitation and disability (any/severe difficulty walking 1/4 mile or climbing 10 steps) was assessed semiannually over 6 years of follow-up. The association between 25(OH)D, PTH, and mobility limitation and disability was examined using Cox proportional hazard regression models adjusted for demographics, season, behavioral characteristics, and chronic conditions.
Results.
At baseline, 28.9% of the participants had 25(OH)D <50 nmol/L and 36.1% had 25(OH)D of 50 to <75 nmol/L. Participants with 25(OH)D <50 and 50 to <75 nmol/L were at greater risk of developing mobility limitation (HR (95% CI): 1.29 (1.04–1.61) and 1.27 (1.05–1.53), respectively) and mobility disability (HR (95% CI): 1.93 (1.32–2.81) and 1.30 (0.92–1.83), respectively) over 6 years of follow-up compared with participants with 25(OH)D ≥75 nmol/L. Elevated PTH, however, was not significantly associated with developing mobility limitation or disability.
Conclusions.
Low 25(OH)D was associated with an increased risk of mobility limitation and disability in community-dwelling, initially well-functioning black and white older adults. Prevention or treatment of low 25(OH)D may provide a pathway for reducing the burden of mobility disability in older adults.
doi:10.1093/gerona/gls136
PMCID: PMC3598356  PMID: 22573914
25-hydroxyvitamin D; Mobility limitation; Vitamin D; Parathyroid hormone
7.  AORTIC PULSE WAVE VELOCITY PREDICTS FOCAL WHITE MATTER HYPERINTENSITIES IN A BIRACIAL COHORT OF OLDER ADULTS 
Hypertension  2012;61(1):160-165.
While the cross-sectional relationship of arterial stiffness with cerebral small vessel disease is consistently shown in middle-aged and young-old adults, its less clear if these associations remain significant over time in very old adults. We hypothesize that arterial stiffness is longitudinally associated with white matter characteristics and associations are stronger within watershed areas.
Neuroimaging was obtained in 2006–08 from 303 elderly (mean age 82.9 years, 59% women, 41% black) with pulse wave velocity measures in 1997–98. Multivariable regression models estimated the coefficients for pulse wave velocity (cm/sec) in relationship to presence, severity and spatial distribution of white matter hyperintensities, gray matter volume and fractional anisotropy from diffusion tensor, adjusting for demographic, cardiovascular risk factors and diseases from 1997–98 to 2006–08.
Higher pulse wave velocity in 1997–98 was associated with greater white matter hyperintensities volume in 2006–08 within the left superior longitudinal fasciculus (age and total brain white matter hyperintensities-adjusted p=0.023), but not with white matter hyperintensities in other tracts, or with fractional anisotropy or gray matter volume from total brain (p>0.2). Associations were stronger in blacks than in whites remaining significant in fully adjusted models.
Elderly with white matter hyperintensities in tracts related to processing speed and memory are more likely to have had higher pulse wave velocity values ten years prior, before neuroimaging data being available. Future studies should address whether arterial stiffness can serve as an early biomarker of covert brain structural abnormalities and whether early arterial stiffness control can promote successful brain aging, especially in black elderly.
doi:10.1161/HYPERTENSIONAHA.112.198069
PMCID: PMC3521843  PMID: 23172923
pulse wave velocity; small vessel disease; longitudinal; fractional anisotropy; community-dwelling elderly
8.  Educational Attainment and Late Life Telomere Length in the Health, Aging and Body Composition Study 
Brain, behavior, and immunity  2012;27(1):15-21.
Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2,599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806 basepairs) than those with post-high school education (4926 basepairs; B=125, SE= 47.6, p = .009). A significant interaction of race and education (B = 207.8, SE = 98.7, p = .035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B = 119.7, SE = 47.6, p = .012). While higher income was associated with longer LTL, the effect was not significant (p > .10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.
doi:10.1016/j.bbi.2012.08.014
PMCID: PMC3543785  PMID: 22981835
Socioeconomic status; education; telomere length; race; health disparities
9.  Pulmonary Function Impairment May be An Early Risk Factor for Late-Life Cognitive Impairment 
Background
Low pulmonary function (PF) is associated with poor cognitive function and dementia. There are few studies of change in PF in mid-life and late-life cognitive status.
Design and Participants
We studied this is 3,665 subjects from AGES-Reykjavik Study who had at least one measure of forced expiratory volume/ 1 sec (FEV1) and were cognitively tested on average 23 years later. A subset of 1,281 subjects had two or three measures of FEV1 acquired over a 7.8 year period. PF was estimated as FEV1/Height2. Rate of PF decline was estimated as the slope of decline over time. Cognitive status was measured with continuous scores of memory, speed of processing, and executive function, and as the dichotomous outcomes of mild cognitive impairment (MCI) and dementia.
Results
Lower PF measured in mid-life predicted lower memory, speed of processing, executive function, and higher likelihood of MCI and dementia 23 years later. Decrease of PF over a 7.8-year period in mid-life was not associated with lower cognitive function or dementia.
Conclusion
Reduced PF measured in mid-life may be an early marker of later cognitive problems. Additional studies characterizing early and late PF changes are needed.
doi:10.1111/jgs.12069
PMCID: PMC3545414  PMID: 23311554
Cognition; Dementia; Forced Expiratory Volume; Longitudinal Cohort Studies
10.  Hyperleptinemia, Adiposity, and Risk of Metabolic Syndrome in Older Adults 
Background. Abdominal adiposity and serum leptin increase with age as does risk of metabolic syndrome. This study investigates the prospective association between leptin and metabolic syndrome risk in relation to adiposity and cytokines. Methods. The Health, Aging, and Body Composition study is a prospective cohort of older adults aged 70 to 79 years. Baseline measurements included leptin, cytokines, BMI, total percent fat, and visceral and subcutaneous fat. Multivariate logistic regression was used to determine the association between leptin and metabolic syndrome (defined per NCEP ATP III) incidence after 6 years of follow-up among 1,120 men and women. Results. Leptin predicted metabolic syndrome in men (P for trend = 0.0002) and women (P for trend = 0.0001). In women, risk of metabolic syndrome increased with higher levels of leptin (compared with quintile 1, quintile 2 RR = 3.29, CI = 1.36, 7.95; quintile 3 RR = 3.25, CI = 1.33, 7.93; quintile 4 RR = 5.21, CI = 2.16, 12.56; and quintile 5 RR = 7.97, CI = 3.30, 19.24) after adjusting for potential confounders. Leptin remained independently associated with metabolic syndrome risk after additional adjustment for adiposity, cytokines, and CRP. Among men, this association was no longer significant after controlling for adiposity. Conclusion. Among older women, elevated concentrations of leptin may increase the risk of metabolic syndrome independent of adiposity and cytokines.
doi:10.1155/2013/327079
PMCID: PMC3888758  PMID: 24455217
11.  Hearing Loss and Cognitive Decline Among Older Adults 
JAMA internal medicine  2013;173(4):10.1001/jamainternmed.2013.1868.
Background
Whether hearing loss is independently associated with accelerated cognitive decline in older adults is unknown.
Methods
We studied 1984 older adults (mean age 77.4 years) enrolled in the HealthABC study, a prospective observational study begun in 1997–98. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State [3MS] scores ≥ 80) who underwent audiometric testing in Year 5. Participants were followed for 6 years. Hearing was defined at baseline using a pure-tone average (PTA) of thresholds at 0.5 – 4 kHz in the better-hearing ear. Cognitive testing was performed in Years 5, 8, 10, and 11 and consisted of the 3MS (measuring global function) and the Digit Symbol Substitution test (DSS, measuring executive function). Incident cognitive impairment was defined as a 3MS score < 80 or a decline in 3MS > 5 points from baseline. Mixed-effects regression and Cox models were adjusted for demographic and cardiovascular risk factors.
Results
Individuals with baseline hearing loss (PTA > 25 dB, n = 1162) had rates of decline in 3MS and DSS scores that were 41% and 32% greater, respectively, than those in normal hearing individuals (3MS: −0.65 points/year [95% CI: −0.73 – −0.56] vs. −0.46 points/year [95% CI: −0.55 – −0.36], p=.004; DSS: −0.83 points/year [95% CI: −0.94 – −0.73] vs. −0.63 points/year [95% CI: −0.75 – −0.51], p=.015). Compared to those with normal hearing, individuals with hearing loss had a 24% (Hazard ratio: 1.24 [95% CI: 1.05 – 1.48]) increased risk of incident cognitive impairment. Rates of cognitive decline and the risk of incident cognitive impairment were linearly associated with the severity of an individual’s baseline hearing loss.
Conclusion
Hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults. Further studies investigating the mechanistic basis of this association and whether hearing rehabilitative interventions could affect cognitive decline are needed.
doi:10.1001/jamainternmed.2013.1868
PMCID: PMC3869227  PMID: 23337978
12.  Association of a Modified Physiologic Index With Mortality and Incident Disability: The Health, Aging, and Body Composition Study 
Background.
Indexes constructed from components may identify individuals who age well across systems. We studied the associations of a Modified Physiologic Index (systolic blood pressure, forced vital capacity, Digit Symbol Substitution Test score, serum cystatin-C, serum fasting glucose) with mortality and incident disability.
Methods.
Data are from the Health, Aging, and Body Composition study on 2,737 persons (51.2% women, 40.3% black) aged 70–79 years at baseline and followed on average 9.3 (2.9) years. Components were graded 0 (healthiest), 1 (middle), or 2 (unhealthiest) by tertile or clinical cutpoints and summed to calculate a continuous index score (range 0–10). We used multivariate Cox proportional hazards regression to calculate risk of death or disability and determined accuracy predicting death using the area under the curve.
Results.
Mortality was 19% greater per index unit (p < .05). Those with highest index scores (scores 7–10) had 3.53-fold greater mortality than those with lowest scores (scores 0–2). The unadjusted index (c-statistic = 0.656, 95% CI 0.636–0.677, p < .0001) predicted death better than age (c-statistic = 0.591, 95% CI 0.568–0.613, p < .0001; for comparison, p < .0001). The index attenuated the age association with mortality by 33%. A model including age and the index did not predict death better than the index alone (c-statistic = 0.671). Prediction was improved with the addition of other markers of health (c-statistic = 0.710, 95% CI 0.689–0.730). The index was associated with incident disability (adjusted hazard ratio per index unit = 1.04, 95% CI 1.01–1.07).
Conclusions.
A simple index of available physiologic measurements was associated with mortality and incident disability and may prove useful for identifying persons who age well across systems.
doi:10.1093/gerona/gls123
PMCID: PMC3636673  PMID: 22546961
Aging; Index; Mortality; Disability; Longevity
13.  25-Hydroxyvitamin D Status and Change in Physical Performance and Strength in Older Adults 
American Journal of Epidemiology  2012;176(11):1025-1034.
Low 25-hydroxyvitamin D (25(OH)D) concentrations are common among older adults and are associated with poorer physical performance and strength, but results from longitudinal studies have been inconsistent. The 25(OH)D threshold for physical performance and strength was determined, and both cross-sectional and longitudinal associations between 25(OH)D and physical performance and strength were examined, in men and women aged 71–80 years from the Health, Aging, and Body Composition Study (n = 2,641). Baseline serum 25(OH)D was measured in 1998–1999, and physical performance and strength were measured at baseline and at 2- and 4-year follow-up. Piecewise regression models were used to determine 25(OH)D thresholds. Linear regression and mixed models were used to examine cross-sectional and longitudinal associations. The 25(OH)D thresholds were 70–80 nmol/L for physical performance and 55–70 nmol/L for strength. Participants with 25(OH)D <50 nmol/L had poorer physical performance at baseline and at 2- and 4-year follow-up than participants with 25(OH)D ≥75 nmol/L (P < 0.01). Although physical performance and strength declined over 4 years of follow-up (P < 0.0001), in general, the rate of decline was not associated with baseline 25(OH)D. Older adults with low 25(OH)D concentrations had poorer physical performance over 4 years of follow-up, but low 25(OH)D concentrations were not associated with a faster rate of decline in physical performance or strength.
doi:10.1093/aje/kws147
PMCID: PMC3571245  PMID: 23118104
aged; 25-hydroxyvitamin D; muscle strength; physical performance
14.  Cerebral microbleeds and age-related macular degeneration: The AGES-Reykjavik Study 
Neurobiology of aging  2012;33(12):2935-2937.
We test the hypothesis that cerebral microbleeds (CMB) and age-related macular degeneration (AMD), both linked to amyloid-β deposition, are correlated. This study includes 4205 participants (mean age 76.2; 57.8% women) in the AGES-Reykjavik Study (2002–2006). CMB were assessed from magnetic resonance images and AMD from digital retinal images. Data were analyzed with multinomial logistic models controlling for major confounders. Evidence of CMB was detected in 476 persons (272 with strict lobar CMB and 204 with non-lobar CMB). AMD was detected in 1098 persons (869 with early AMD, 140 with exudative AMD, and 89 with pure geographic atrophy). Early and exudative AMD were not associated with CMB. The adjusted odds ratio of pure geographic atrophy was 1.62 (95% confidence interval 0.93–2.82, P=0.089) for having any CMB, 1.43 (0.66–3.06, P=0.363) for strict lobar CMB, and 1.85 (0.89–3.87, P=0.100) for non-lobar CMB. This study provides no evidence that amyloid deposits in the brain and AMD are correlated. However, the suggestive association of geographic atrophy with CMB warrants further investigation.
doi:10.1016/j.neurobiolaging.2012.01.012
PMCID: PMC3368038  PMID: 22382405
Age-related macular degeneration; Cerebral microbleeds; Amyloid-β; The AGES-Reykjavik Study
15.  The Electrocardiographic PR Interval and Adverse Outcomes in Older Adults: the Health, Aging and Body Composition Study 
Background
The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults.
Methods and results
The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We employed multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per standard deviation (SD) increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (age 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. Following multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval [CI], 1.02 to 1.25) and a 13% increased risk of incident AF (95% CI, 1.04 to 1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% CI, 1.11 to 1.93). PR interval was not associated with increased all-cause mortality.
Conclusions
We identified significant relations of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.
doi:10.1161/CIRCEP.112.975342
PMCID: PMC3613778  PMID: 23243193
PR interval; epidemiology; heart failure; atrial fibrillation; mortality; aging
16.  Beyond Breast Cancer: Mammographic Features and Mortality Risk in a Population of Healthy Women 
PLoS ONE  2013;8(10):e78722.
Background
Breast fibroglandular (dense) tissue is a risk factor for breast cancer. Beyond breast cancer, little is known regarding the prognostic significance of mammographic features.
Methods
We evaluated relationships between nondense (fatty) breast area and dense area with all-cause mortality in 4,245 initially healthy women from the Breast Cancer Detection Demonstration Project; 1,361 died during a mean follow-up of 28.2 years. Dense area and total breast area were assessed using planimeter measurements from screening mammograms. Percent density reflects dense area relative to breast area and nondense area was calculated as the difference between total breast area and dense area. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression.
Results
In age-adjusted models, greater nondense and total breast area were associated with increased risk of death (HR 1.17, 95% CI 1.10-1.24 and HR 1.13, 95% CI 1.06-1.19, per SD difference) while greater dense area and percent density were associated with lower risk of death (HR 0.91, 95% CI 0.86-0.95 and HR 0.87, 95% CI 0.83-0.92, per SD difference). Associations were not attenuated with adjustment for race, education, mammogram type (x-ray or xerogram), smoking status, diabetes and heart disease. With additional adjustment for body mass index, associations were diminished for all features but remained statistically significant for dense area (HR 0.94, 95% CI 0.89-0.99, per SD difference) and percent density (HR 0.93, 95% CI 0.87-0.98, per SD difference).
Conclusions
These data indicate that dense area and percent density may relate to survival in healthy women and suggest the potential utility of mammograms beyond prediction of breast cancer risk.
doi:10.1371/journal.pone.0078722
PMCID: PMC3808289  PMID: 24205300
17.  Genetic Associations with Valvular Calcification and Aortic Stenosis 
The New England journal of medicine  2013;368(6):503-512.
BACKGROUND
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
METHODS
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
RESULTS
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
CONCLUSIONS
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
doi:10.1056/NEJMoa1109034
PMCID: PMC3766627  PMID: 23388002
18.  Mitochondrial DNA sequence variation is associated with free-living activity energy expenditure in the elderly 
Biochimica et Biophysica Acta  2012;1817(9):1691-1700.
The decline in activity energy expenditure underlies a range of age-associated pathological conditions, neuromuscular and neurological impairments, disability, and mortality. The majority (90%) of the energy needs of the human body are met by mitochondrial oxidative phosphorylation (OXPHOS). OXPHOS is dependent on the coordinated expression and interaction of genes encoded in the nuclear and mitochondrial genomes. We examined the role of mitochondrial genomic variation in free-living activity energy expenditure (AEE) and physical activity levels (PAL) by sequencing the entire (~16.5 kilobases) mtDNA from 138 Health, Aging, and Body Composition Study participants. Among the common mtDNA variants, the hypervariable region 2 m.185G>A variant was significantly associated with AEE (p=0.001) and PAL (p=0.0005) after adjustment for multiple comparisons. Several unique nonsynonymous variants were identified in the extremes of AEE with some occurring at highly conserved sites predicted to affect protein structure and function. Of interest is the p.T194M, CytB substitution in the lower extreme of AEE occurring at a residue in the Qi site of complex III. Among participants with low activity levels, the burden of singleton variants was 30% higher across the entire mtDNA and OXPHOS complex I when compared to those having moderate to high activity levels. A significant pooled variant association across the hypervariable 2 region was observed for AEE and PAL. These results suggest that mtDNA variation is associated with free-living AEE in older persons and may generate new hypotheses by which specific mtDNA complexes, genes, and variants may contribute to the maintenance of activity levels in late life.
doi:10.1016/j.bbabio.2012.05.012
PMCID: PMC3389152  PMID: 22659402
metabolic rate; energy expenditure; mitochondria; mtDNA; oxidative phosphorylation; DNA sequencing
19.  Shorter telomeres are associated with obesity and weight gain in the elderly 
Objective
Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study.
Design
Levels of adiposity were assessed in 6 ways (obesity status, body mass index or BMI, the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2,721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline and 3 of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up.
Results
At baseline, TL was negatively associated with % body fat (β = −0.35 ± 0.09, p = 0.001) and subcutaneous fat (β = −2.66 ± 1.07, p = 0.01), and positively associated with leptin after adjusting for % body fat (β = 0.32 ± 0.14, p = 0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (β = 0.48 ± 0.20, p = 0.01) and % body fat (β = 0.42 ± 0.23, p = 0.05).
Conclusion
Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and warrant more prospective studies.
doi:10.1038/ijo.2011.196
PMCID: PMC3408817  PMID: 22005719
Obesity; telomere length; adiposity; telomeres
20.  Dietary and supplemental calcium intakes in relation to mortality from cardiovascular diseases in the NIH-AARP Diet and Health Study 
JAMA internal medicine  2013;173(8):639-646.
Background
Calcium intake has been promoted due to its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health.
Methods
Dietary and supplemental calcium intakes were assessed at baseline (1995–96) in 388,229 men and women aged 50–71 years in the National Institutes of Health (NIH)–AARP Diet and Health Study. Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease (CVD) deaths were ascertained using the National Death Index. Multivariate Cox Proportional hazard models adjusted for demographic, lifestyle and dietary variables were used to estimate relative risks (RRs) and 95% confidence intervals (CIs).
Results
During an average of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men supplemental calcium intake was associated with an elevated risk of CVD death (RR>1000 vs. 0 mg/day =1.20, 95% CI: 1.05–1.36), more specifically with heart disease death (RR=1.19, 95% CI: 1.03–1.37), but not significantly with cerebrovascular disease death (RR=1.14, 95% CI: 0.81–1.61). In women, supplemental calcium intake was not associated with CVD death (RR= 1.06, 95% CI: 0.96, 1.18), heart disease death (RR=1.05, 95% CI: 0.93–1.18) or cerebrovascular disease death (RR=1.08, 95% CI: 0.87–1.33). Dietary calcium intake was not related to CVD death in either men or women.
Conclusion
Our finding suggests that high intake of supplemental calcium is associated with an excess risk of CVD death in men, but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health.
doi:10.1001/jamainternmed.2013.3283
PMCID: PMC3756477  PMID: 23381719
21.  Cigarette Smoking Exposure and Heart Failure Risk in Older Adults: The Health, Aging, and Body Composition Study 
American heart journal  2012;164(2):236-242.
Background
Although there is evidence linking smoking and heart failure (HF), the association between lifetime smoking exposure and HF in older adults and the strength of this association among current and past smokers is not well known.
Methods
We examined the association between smoking status, pack-years of exposure and incident HF risk in 2, 125 participants of the Health, Aging, and Body Composition Study (age 73. 6±2. 9 years; 69. 7% females; 54. 2% whites)using proportional hazard models.
Results
At inception, 54. 8% of participants were non-smokers, 34. 8% were past smokers, and 10. 4% were current smokers. During follow-up (median, 9. 4 years), HF incidence was 11. 4 per 1000 person-years in non-smokers, 15. 2 in past smokers (hazard ratio [HR] vs. non-smokers 1. 33; 95% confidence interval [CI] 1. 01, 1. 76; p=0. 045), and 21. 9 in current smokers (HR 1. 93; 95% CI 1. 30, 2. 84; p=0. 001). After adjusting for HF risk factors, incident coronary events, and competing risk for death, a dose-effect association between pack-years of exposure and HF risk was observed (HR 1. 09; 95% CI 1. 05, 1. 14; p<0. 001 per 10 pack-years). HF risk was not modulated by pack-years of exposure in current smokers. In past smokers, HR for HF was 1. 05 (95% CI, 0. 64, 1. 72) for 1–11 pack-years; 1. 23 (95% CI, 0. 82, 1. 83) for 12–35 pack-years; and 1. 64 (95% CI, 1. 11, 2. 42) for >35 pack-years of exposure in fully adjusted models (p<0. 001 for trend) compared to non-smokers.
Conclusions
In older adults, both current and past cigarette smoking increase HF risk. In current smokers, this risk is high irrespective of pack-years of exposure, whereas in past smokers there was a dose-effect association.
doi:10.1016/j.ahj.2012.05.013
PMCID: PMC3417038  PMID: 22877810
22.  Data Mining Identifies Digit Symbol Substitution Test Score and Serum Cystatin C as Dominant Predictors of Mortality in Older Men and Women 
Rejuvenation Research  2012;15(4):405-413.
Abstract
Background
Characterization of long-term health trajectory in older individuals is important for proactive health management. However, the relative prognostic value of information contained in clinical profiles of nonfrail older adults is often unclear.
Methods
We screened 825 phenotypic and genetic measures evaluated during the Health, Aging, and Body Composition Study (Health ABC) baseline visit (3,067 men and women aged 70–79). Variables that best predicted mortality over 13 years of follow-up were identified using 10-fold cross-validation.
Results
Mortality was most strongly associated with low Digit Symbol Substitution Test (DSST) score (DSST<25; 21.9% of cohort; hazard ratio [HR]=1.87±0.06) and elevated serum cystatin C (≥1.30 mg/mL; 12.1% of cohort; HR=2.25±0.07). These variables predicted mortality better than 823 other measures, including baseline age and a 45-variable health deficit index. Given elevated cystatin C (≥1.30 mg/mL), mortality risk was further increased by high serum creatinine, high abdominal visceral fat density, and smoking history (2.52≤HR ≤3.73). Given a low DSST score (<25) combined with low-to-moderate cystatin C (<1.30 mg/mL), mortality risk was highest among those with elevated plasma resistin and smoking history (1.90≤HR≤2.02).
Conclusions
DSST score and serum cystatin C warrant priority consideration for the evaluation of mortality risk in older individuals. Both variables, taken individually, predict mortality better than chronological age or a health deficit index in well-functioning older adults (ages 70–79). DSST score and serum cystatin C can thus provide evidence-based tools for geriatric assessment.
doi:10.1089/rej.2011.1297
PMCID: PMC3419847  PMID: 22607624
23.  Body mass index, occupational activity, and leisure-time physical activity: an exploration of risk factors and modifiers for knee osteoarthritis in the 1946 British birth cohort 
Background
Knee osteoarthritis (kOA) risk is increased by obesity and physical activities (PA) which mechanically stress the joint. We examined the associations of midlife kOA with body mass index (BMI) and activity exposure across adult life and their interaction.
Methods
Data are from a UK birth cohort of 2597 participants with a clinical assessment for kOA at age 53. At ages 36, 43 and 53 BMI (kg/m2), self-reported leisure-time PA, and occupational activity (kneeling/squatting; lifting; climbing; sitting; assigned using a job-exposure matrix) were ascertained. Associations were explored using the multiplicative logistic model.
Results
BMI was strongly and positively associated with kOA in men and women. Men and women in manual occupations also had greater odds of kOA; there was a weak suggestion that kOA risk was higher among men exposed to lifting or kneeling at work. For men, the only evidence of a multiplicative interaction between BMI and activities was for lifting (p = 0.01) at age 43; BMI conferred higher kOA risk among those most-likely to lift at work (OR per increase in BMI z-score: 3.55, 95% CI: 1.72-7.33). For women, the only evidence of an interaction was between BMI and leisure-time PA (p = 0.005) at age 43; BMI conferred higher kOA risk among those at higher PA levels (OR per increase in BMI z-score: 1.59, 95% CI: 1.26-2.00 in inactive; 1.70, 95% CI: 1.14-2.55 (less-active); and 4.44; 95% CI: 2.26-8.36 (most-active).
Conclusions
At the very least, our study suggests that more active individuals (at work and in leisure) may see a greater reduction in risk of kOA from avoiding a high BMI than those less active.
doi:10.1186/1471-2474-14-219
PMCID: PMC3726290  PMID: 23883324
Knee osteoarthritis; Body mass index; Physical activity; Occupational activity
24.  Dietary Patterns and Survival of Older Adults 
Background
Recent research has linked overall dietary patterns to survival in older adults.
Objectives
The objective of this study was to determine the dietary patterns of a cohort of older adults, and to explore associations of these dietary patterns with survival over a 10-year period. A secondary goal was to evaluate participants’ quality of life and nutritional status according to their dietary patterns.
Design
The Health, Aging, and Body Composition Study is a prospective cohort study of 3,075 older adults. In this study, all-cause mortality was assessed from baseline through Year 10. Food intake was estimated with a modified Block food frequency questionnaire, and dietary patterns of 2,582 participants with complete data were derived by cluster analysis.
Results
Six dietary pattern clusters were identified, including a Healthy Foods cluster, characterized by higher intake of low-fat dairy products, fruit, whole grains, poultry, fish, and vegetables. Both the High-Fat Dairy Products and Sweets and Desserts clusters had a 1.4-fold higher risk of mortality than the Healthy Foods cluster after adjusting for potential confounders. The Healthy Foods cluster also had significantly more years of healthy life and more favorable levels of selected nutritional biomarkers than the other clusters.
Conclusions
A dietary pattern consistent with current guidelines to consume relatively high amounts of vegetables, fruit, whole grains, poultry, fish, and low-fat dairy products may be associated with superior nutritional status, quality of life and survival in older adults.
doi:10.1016/j.jada.2010.10.012
PMCID: PMC3699861  PMID: 21185969
25.  Oxidative Damage, Platelet Activation, and Inflammation to Predict Mobility Disability and Mortality in Older Persons: Results From the Health Aging and Body Composition Study 
Background.
Inflammation, oxidative damage, and platelet activation are hypothesized biological mechanisms driving the disablement process. The aim of the present study is to assess whether biomarkers representing these mechanisms predicted major adverse health-related events in older persons.
Methods.
Data are from 2,234 community-dwelling nondisabled older persons enrolled in the Health Aging and Body Composition study. Biomarkers of lipid peroxidation (ie, urinary levels of 8-iso-prostaglandin F2α), platelet activation (ie, urinary levels of 11-dehydro-thromboxane B2), and inflammation (serum concentrations of interleukin-6) were considered as independent variables of interest and tested in Cox proportional hazard models as predictors of (severe) mobility disability and overall mortality.
Results.
The sample’s (women 48.0%, whites 64.3%) mean age was 74.6 (SD 2.9) years. During the follow-up (median 11.4 years), 792 (35.5%), 269 (12.0%), and 942 (42.2%) events of mobility disability, severe mobility disability, and mortality occurred, respectively. Only interleukin-6 showed significant independent associations with the onset of all the study outcomes. Higher levels of urinary 8-iso-prostaglandin F2α and 11-dehydro-thromboxane B2 independently predicted increased risk of death (hazard ratio 1.10, 95% confidence interval 1.03–1.19 and hazard ratio 1.14, 95% confidence interval 1.06–1.23, respectively). No significant interactions of gender, race, cardiovascular disease, diabetes, and antiplatelet drugs were detected on the studied relationships.
Conclusions.
The inflammatory marker interleukin-6 is confirmed to be a robust predictor for the onset of negative health-related events. Participants with higher urinary levels of 8-iso-prostaglandin F2α and 11-dehydro-thromboxane B2 presented a higher mortality risk.
doi:10.1093/gerona/glr246
PMCID: PMC3348494  PMID: 22389462
Oxidative damage; Platelet activation; Inflammation; Disability; Mortality

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