Showing papers by "Anne B. Newman published in 2021"

Genetic insights into biological mechanisms governing human ovarian ageing.

Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Remote Research and Clinical Trial Integrity During and After the Coronavirus Pandemic.

Abstract: Approximately 1 year ago, in March 2020, clinical trials were suddenly and severely disrupted by the COVID-19 pandemic. Pandemic-related restrictions that limited or prevented in-person visits resulted in unprecedented obstacles to clinical trial enrollment, data collection, and intervention delivery for many clinical trials.1 As of April 21, 2021, ClinicalTrials.gov listed 1773 suspended clinical trials, with many trials identifying the COVID-19 pandemic as the primary reason for suspension. Ongoing trials that were not suspended are likely to be experiencing challenges with enrollment and fidelity to aspects of study protocols that require in-person contact, including interventions and outcome assessment. Many clinical trial investigators replaced in-person interactions with alternative approaches conducted remotely.2 A survey of 245 clinical trial investigators reported that the proportion of participant interactions conducted remotely increased from 9% in January 2020 to 57% in May 2020.2 Remote interactions with participants implemented in response to the pandemic included mailings or drop-off of devices, such as physical activity monitors or pulse oximeters for outcome measurements, and mail delivery or drop-off of pills or devices for trial interventions.3,4 Additional activities implemented to avoid in-person visits included use of telephone, web-based or video interactions, home visits, or outdoor visits to collect outcomes or administer interventions.3-5 These remote activities facilitated clinical trial progress during the pandemic. Embedded trials build data collection for a clinical trial into essential clinical care and represent another alternative to in-person clinical trial interactions. An example is the ongoing Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults (PREVENTABLE) trial (NCT04262206), in which 20 000 participants 75 years or older are randomized to atorvastatin 40 mg daily or placebo and followed up with the electronic health record for outcomes of disability-free survival and cardiovascular events. Medications are mailed to participants’ homes. Outcomes that are not part of routine clinical care, including detailed cognitive assessments and physical performance testing, are collected at participants’ homes by trained research staff. A visit to a research laboratory is required to collect blood for a biorepository of red blood cells and DNA. An example of a fully remote trial was a randomized, double-blind, clinical trial conducted in St Louis, Missouri, that evaluated whether fluvoxamine, compared with placebo, improved outcomes in 152 outpatients newly diagnosed with COVID-19.4 Eligibility screening was conducted by email and telephone and COVID diagnosis was confirmed using electronic health record review. Informed consent was obtained remotely, typically electronically. Participants performed baseline and follow-up self-assessments at home with equipment, including a pulse oximeter, blood pressure monitor, and thermometer, delivered to their doorstep. Selfcollected baseline data were reported by telephone to study staff. After randomization, participants were instructed by telephone or email to begin the study drug, delivered to their doorstep. After randomization, participants entered outcome data twice daily via emailed RedCap surveys. Telephone-based data collection was used for individuals without internet access. The primary outcome, consisting of an oxygen saturation of less than 92% while breathing room air combined with dyspnea or hospitalization for dyspnea or pneumonia, occurred in none of 80 participants in the fluvoxamine group and in 6 of 72 (8.3%) in the placebo group (absolute difference, 8.7%; 95% CI, 1.8%-16.4%; P = .009). In summary, this preliminary clinical trial was successfully completed without any in-person contact.4 After the pandemic, these alternative clinical trial methods could remain, potentially facilitating trial participation for individuals with multiple comorbid health conditions, for whom travel to a medical center is difficult. For example, with increased availability of portable devices, some in-person assessments for trials such as with electrocardiograms (ECGs), carotid ultrasound, spirometry, polysomnography, strength testing, and walking speed could be conducted at home or in a mobile van. Video-administered neuropsychological testing was recently validated.5 However, participants with cognitive impairment must have a caregiver to assist with testing.5 Whether other tests that are usually collected in-person could be safely and accurately obtained remotely remains unclear. Could a research participant demonstrate ability to stand from a chair independently and safely, while encouraged using standardized instructions via video? How would the risk of a fall be managed? Could a cognitive test be administered over video while controlling background noise and household member interference? Could someone at home properly self-administer spirometry testing and read results off a small digital screen or transmit data via Bluetooth? Despite a do-it-yourself era of online instructional videos, this type of data collection may not provide rigorous and reproducible results. Some evidence justifies caution before abandoning or greatly reducing in-person visits for evaluation of clinical trial participants. First, the degree to which medical center visits discourage clinical trial participation is unclear. In a systematic review of 13 studies conducted before the pandemic, that evaluated barriers to clinical trial participation by older adults with cancer, VIEWPOINT

Machine Learning in Aging: An Example of Developing Prediction Models for Serious Fall Injury in Older Adults.

Abstract: Background Advances in computational algorithms and the availability of large datasets with clinically relevant characteristics provide an opportunity to develop machine learning prediction models to aid in diagnosis, prognosis, and treatment of older adults. Some studies have employed machine learning methods for prediction modeling, but skepticism of these methods remains due to lack of reproducibility and difficulty in understanding the complex algorithms that underlie models. We aim to provide an overview of two common machine learning methods: decision tree and random forest. We focus on these methods because they provide a high degree of interpretability. Method We discuss the underlying algorithms of decision tree and random forest methods and present a tutorial for developing prediction models for serious fall injury using data from the Lifestyle Interventions and Independence for Elders (LIFE) study. Results Decision tree is a machine learning method that produces a model resembling a flow chart. Random forest consists of a collection of many decision trees whose results are aggregated. In the tutorial example, we discuss evaluation metrics and interpretation for these models. Illustrated using data from the LIFE study, prediction models for serious fall injury were moderate at best (area under the receiver operating curve of 0.54 for decision tree and 0.66 for random forest). Conclusions Machine learning methods offer an alternative to traditional approaches for modeling outcomes in aging, but their use should be justified and output should be carefully described. Models should be assessed by clinical experts to ensure compatibility with clinical practice.

Older molecular brain age in severe mental illness

Abstract: Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular, and structural changes that are robust on the group level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20–90 years. Individual estimates of “molecular age” were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as “delta age”. Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRScis-eQTL and PRSGWAS), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r = 0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer’s disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.

Relationships Between Level and Change in Sarcopenia and Other Body Composition Components and Adverse Health Outcomes: Findings from the Health, Aging, and Body Composition Study

Abstract: We investigated how baseline values and rates of decline in components of sarcopenia and other body composition parameters relate to adverse clinical outcomes using the Health, Aging, and Body Composition Study. 2689 participants aged 70–79 years were studied. Appendicular lean mass, whole body fat mass, and total hip BMD were ascertained using DXA; muscle strength by grip dynamometry; and muscle function by gait speed. Baseline values and 2–3 year conditional changes (independent of baseline) in each characteristic were examined as predictors of mortality, hospital admission, low trauma fracture, and recurrent falls in the subsequent 10–14 years using Cox regression (generalized estimating equations used for recurrent falls) with adjustment for sex, ethnicity, age, and potential confounders. Lower levels and greater declines in all parameters (excluding hip BMD level) were associated (p < 0.05) with increased rates of mortality; fully-adjusted hazard ratios per SD lower gait speed and grip strength were 1.27 (95% CI 1.19, 1.36) and 1.14 (1.07, 1.21), respectively. Risk factors of hospital admission included lower levels and greater declines in gait speed and grip strength, and greater declines in hip BMD. Lower levels and greater declines in fat mass and hip BMD were associated with low trauma fracture. Lower gait speed, higher fat mass, and both lower levels and greater declines in grip strength were related to recurrent falls. Lower baseline levels and greater declines in musculoskeletal parameters were related to adverse outcomes. Interventions to maximize peak levels in earlier life and reduce rates of age-related decline may reduce the burden of disease in this age group.

Validation of a deficit-accumulation Frailty Index in the ASPREE study and its predictive capacity for disability-free survival

Abstract: Frailty is a state of heightened vulnerability and susceptibility to physiologic stressors that increases with age. It has shown increasing utility in predicting a range of adverse health outcomes. Here, we characterise a 67-item deficit-accumulation frailty index (FI) in 19,110 community-dwelling individuals in the ASPREE clinical trial. Participants aged 65 to 98 years were recruited from the U.S. and Australia, and were without diagnosed dementia and cardiovascular disease, and without major physical disability. The median FI score was 0.10 (IQR: 0.07; 0.14) at baseline, and the prevalence of frailty (FI> 0.21) increased from 8.1% to 17.4% after six years. FI was positively associated with age, and women had significantly higher scores than men at all ages. The FI was negatively correlated with gait speed (r =-0.31) and grip strength (r = -0.46), and strongly associated with a modified Fried frailty phenotype (p<0.0001, for all comparisons). Frailty was associated with the primary composite outcome capturing independent life lived free of major disability and dementia, and increased the rate of persistent physical disability (HR:21.3, 95% CI:15.6-28.9). It added significantly to the predictive capacity of these outcomes above age, sex and ethnicity alone. The FI is thus a useful biomarker of aging even among relatively healthy older individuals, and provides important information about an individual's vulnerability to and risk of disease.

The Relationship Between Intermuscular Fat and Physical Performance Is Moderated by Muscle Area in Older Adults

Abstract: BACKGROUND Age-related deposition of fat in skeletal muscle is associated with functional limitations. Skeletal muscle fat may be present in people with preserved muscle mass or accompanied by muscle wasting. However, it is not clear if the association between muscle fat deposition and physical performance is moderated by muscle mass. OBJECTIVE To determine whether the association between midthigh intermuscular fat and physical performance is moderated by muscle area. METHODS We performed a cross-sectional analysis of the Health, Aging, and, Body Composition (ABC) study data collected in 2002-2003 (n = 1897, women: 52.2%). Midthigh muscle cross-sectional area (by computed tomography) and physical performance measures were compared across quartiles of intermuscular fat absolute area. Moderation analysis was performed to determine the conditional effect of intermuscular fat on physical performance as a function of muscle area. Conditional effects were evaluated at three levels of muscle area (mean and ± 1 standard deviation [SD]; 213.2 ± 53.2 cm2). RESULTS Simple slope analysis showed that the negative association between intermuscular fat area (cm2) and leg strength (N·m) was of greater magnitude (beta coefficient [b], 95% confidence interval [CI] = -0.288 [-0.427, -0.148]) in participants with greater muscle area (ie, 1 SD above the mean) compared to those with lower muscle area (ie, at mean [b = -0.12 {-0.248, 0.008}] or 1 SD below the mean [b = 0.048 {-0.122, 0.217}]). Similarly, the negative association of intermuscular fat with 400-m walk speed (m/s) and chair stand (seconds) was greater in those with higher muscle areas (p < .001) compared to those with lower muscle areas. CONCLUSIONS The association between higher intermuscular fat area and impaired physical function in aging is moderated by muscle area.

Effect of Aspirin on Activities of Daily Living Disability in Community-Dwelling Older Adults.

Abstract: Background: Cerebrovascular events, dementia and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults. Methods: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100mg aspirin versus placebo recruited 19,114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the U.S. Six basic ADLs were assessed every six months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after six months. Proportional hazards modelling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk. Results: Over a median 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 versus 5.3 events/1000py; HR=0.81, 95% CI:0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability there were more deaths in the aspirin group (24 versus 12). Discussion: Low-dose aspirin in initially healthy older people did not reduce risk of incident ADL disability, although there was evidence of reduced persistent ADL disability.

NIA Long Life Family Study: Objectives, Design, and Heritability of Cross Sectional and Longitudinal Phenotypes.

Abstract: The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multi-national, population-based multi-generational family study of the genetic and non-genetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006-2009) recruited 4,953 individuals from 539 two-generation families, selected from the upper 1% tail of the Family Longevity Selection Score (FLoSS, which quantifies the degree of familial clustering of longevity). Demographic, anthropometric, cognitive, activities of daily living, ankle-brachial index, blood pressure, physical performancea and pulmonary function, along serum, plasma, lymphocytes, red cells, and DNA were collected. A GWAS (Ilumina Omni 2.5M chip) followed by imputation was conducted. Visit 2 (2014-2017) repeated all Visit 1 protocols and added carotid ultrasonography of atherosclerotic plaque and wall thickness, additional cognitive testing, and perceived fatigability. On average, LLFS families show healthier aging profiles than reference populations, such as the Framingham Heart Study, at all age/sex groups, for many critical healthy aging phenotypes. However, participants are not uniformly protected. There is considerable heterogeneity among the pedigrees, with some showing exceptional cognition, others showing exceptional grip strength, others exceptional pulmonary function, etc. with little overlap in these families. There is strong heritability for key healthy aging phenotypes, both cross sectionally and longitudinally, suggesting that at least some of this protection may be genetic. Little of the variance in these heritable phenotypes is explained by the common genome (GWAS + Imputation), which may indicate that rare protective variants for specific phenotypes may be running in selected families.

Association of Non-Steroidal Anti-Inflammatory Drugs with Kidney Health in Ambulatory Older Adults.

Abstract: Background/objectives Non-steroidal anti-inflammatory drugs (NSAIDs) can cause kidney injury, especially in older adults. However, previously reported associations between NSAID use and kidney health outcomes are inconsistent and limited by reliance on serum creatinine-based GFR estimates. This analysis investigated the association of NSAID use with kidney damage in older adults using multiple kidney health measures. Design Cross-sectional and longitudinal analyses. Setting Multicenter, community-based cohort. Participants Two thousand nine hundred and ninty nine older adults in the Health ABC Study. A subcohort (n = 500) was randomly selected for additional biomarker measurements. Exposure Prescription and over-the-counter NSAID use ascertained by self-report. Measurements Baseline estimated glomerular filtration rate (eGFR) by cystatin C (cysC), urine albumin-to-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) were measured in 2,999 participants; alpha-1 microglobulin (α1m), neutrophil gelatinase-associated lipocalin (NGAL), propeptide type III procollagen (PIIINP), and uromodulin (UMOD) were measured in 500 participants. GFR was estimated three times over 10 years and expressed as percent change per year. Results Participants had a mean age of 74 years, 51% were female, and 41% African-American. No eGFR differences were detected between NSAID users (n = 655) and non-users (n = 2,344) at baseline (72 ml/min/1.73 m2 in both groups). Compared to non-users, NSAID users had lower adjusted odds of having ACR greater than 30 mg/g (0.67; 95% confidence interval (CI) = 0.51-0.89) and lower mean urine IL-18 concentration at baseline (-11%; 95% CI = -4% to -18%), but similar mean KIM-1 (5%; 95% CI = -5% to 14%). No significant differences in baseline concentrations of the remaining urine biomarkers were detected. NSAID users and non-users did not differ significantly in the rate of eGFR decline (-2.2% vs -2.3% per year). Conclusion Self-reported NSAID use was not associated with kidney dysfunction or injury based on multiple measures, raising the possibility of NSAID use without kidney harm in ambulatory older adults. More research is needed to define safe patterns of NSAID consumption.

Association of fatigue, inflammation, and physical activity on gait speed: the Long Life Family Study

Abstract: Fatigue, inflammation, and physical activity (PA) are all independently associated with gait speed, but their directionality is not fully elucidated. Evaluate the bidirectional associations amongst fatigue, inflammation, and PA on gait speed. This cross sectional study included probands (n = 1280, aged 49–105) and offspring (n = 2772, aged 24–88) in the Long Life Family Study. We assessed gait speed, fatigue with the question “I could not get going”, inflammation using fasting interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP), and self-reported PA as walking frequency in the past two weeks. The two generations were examined separately using linear mixed modeling. Lower fatigue, lower IL-6, and greater PA were all associated with faster gait speed in both generations (all p < 0.05); lower CRP was only associated with faster gait speed in the offspring. PA explained the association of fatigue and gait speed via a 16.1% (95% CI 9.7%, 26.7%) attenuation of the direct associations for the probands and 9.9% (95% CI 6.3%, 18.8%) in the offspring. In addition, IL-6 explained more of the association of fatigue and gait speed than the association between PA and gait speed, via a 14.9% (95% CI 9.2%, 23.4%) attenuation of the direct association in the offspring only. Results revealed a potential directionality from fatigue to IL-6 to PA that may lead to faster gait speed. Future work should examine these relationships longitudinally to establish temporality and causality. Our findings support a signal that lowering fatigue and inflammation and increasing physical activity may delay functional decline.

What Cut-Point in Gait Speed Best Discriminates Community-Dwelling Older Adults With Mobility Complaints From Those Without? A Pooled Analysis From the Sarcopenia Definitions and Outcomes Consortium.

Abstract: Author(s): Cawthon, Peggy M; Patel, Sheena M; Kritchevsky, Stephen B; Newman, Anne B; Santanasto, Adam; Kiel, Douglas P; Travison, Thomas G; Lane, Nancy; Cummings, Steven R; Orwoll, Eric S; Duchowny, Kate A; Kwok, Timothy; Hirani, Vasant; Schousboe, John; Karlsson, Magnus K; Mellstrom, Dan; Ohlsson, Claes; Ljunggren, Osten; Xue, Qian-Li; Shardell, Michelle; Jordan, Joanne M; Pencina, Karol M; Fielding, Roger A; Magaziner, Jay; Correa-de-Araujo, Rosaly; Bhasin, Shalender; Manini, Todd M | Abstract: BackgroundCut-points to define slow walking speed have largely been derived from expert opinion.MethodsStudy participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4-6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.ResultsAmong 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but l0.75 m/s); and 421 (8.3%) as "slow" (walking speed l0.62 m/s). Among 13 589 men, CART analysis identified 3 cut-points, classifying 10 001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2901 (21.3%) as "fast" (walking speed ≥0.74 m/s but l1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but l0.74 m/s); and 190 (1.4%) as "slow" (walking speed l0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the 2 slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.ConclusionsCut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

Elevated IL-6 and CRP Levels Are Associated With Incident Self-Reported Major Mobility Disability: A Pooled Analysis of Older Adults With Slow Gait Speed.

Abstract: Background Elevated Interleukine-6 (IL-6) and C-reactive protein (CRP) are associated with aging-related reductions in physical function, but little is known about their independent and combined relationships with major mobility disability (MMD), defined as the self-reported inability to walk a quarter-mile. Methods We estimated the absolute and relative effect of elevated baseline IL-6, CRP, and their combination on self-reported MMD risk among older adults (≥68 years; 59% female) with slow gait speed ( Results We found higher MMD risk per unit increase in log IL-6 [HR=1.26 (95% CI 1.13 to 1.41)]. IL-6 meeting pre-determined threshold considered to be high (>2.5 pg/mL) was similarly associated with higher risk of MMD [HR=1.31 (95% CI: 1.12 to 1.54)]. Elevated CRP (CRP >3.0 mg/L) was also associated with increased MMD risk [HR=1.38 (95% CI: 1.10 to 1.74)]. The CRP effect was more pronounced among participants with elevated IL-6 [HR=1.62 (95% CI: 1.12 to 2.33)] compared to lower IL-6 levels [HR=1.19 (95% CI: 0.85 to 1.66)]. Conclusions High baseline IL-6 and CRP were associated with increased risk of MMD among older adults with slow gait speed. A combined biomarker model suggests CRP was associated with MMD when IL-6 was elevated.

A Metabolite Composite Score Attenuated a Substantial Portion of the Higher Mortality Risk Associated With Frailty Among Community-Dwelling Older Adults.

Abstract: BACKGROUND Frailty is more prevalent among black versus white older Americans. We previously identified 37 metabolites associated with the vigor to frailty spectrum using the Scale of Aging Vigor in Epidemiology (SAVE) among older black men from the Health, Aging, and Body Composition (Health ABC) study. Here, we sought to develop a metabolite composite score based on the 37 SAVE-associated metabolites and determine whether the composite score predicts mortality and whether it attenuates the association between frailty and mortality among older black men. METHODS Plasma metabolites were measured using liquid chromatography-mass spectrometry. Most of the 37 metabolites were organic acids/derivatives or lipids. Metabolites were ranked into tertiles: tertiles associated with more vigorous SAVE scores were scored 0, mid-tertiles were scored 1, and tertiles associated with frailer SAVE scores were scored 2. Composite scores were the sum of metabolite tertile scores. We examined mortality associations using Cox regression. Percent attenuation estimated the extent to which metabolites attenuated the association between frailty and mortality. RESULTS One standard deviation frailer SAVE was associated with 30% higher mortality, adjusting for age and site (p = .0002); this association was attenuated by 56% after additionally adjusting for the metabolite composite score. In this model, one standard deviation higher metabolite composite score was associated with 46% higher mortality (p < .0001). Metabolite composite scores also predicted mortality (p = .045) in a validation sample of 120 older adults (40% men, 90% white). CONCLUSION These metabolites may provide a deeper characterization of the higher mortality that is associated with frailty among older adults.

Body Composition by Computed Tomography vs Dual-Energy X-ray Absorptiometry: Long-Term Prediction of All-Cause Mortality in the Health ABC Cohort.

Abstract: BACKGROUND Body composition assessment by computed tomography (CT) predicts health outcomes in diverse populations However, its performance in predicting mortality has not been directly compared to dual-energy X-ray absorptiometry (DXA) Additionally, the association between different body compartments and mortality, acknowledging the compositional nature of the human body, is not well studied Compositional data analysis, which is applied to multivariate proportion-type data set, may help to account for the interrelationships of body compartments by constructing log ratios of components Here, we determined the associations of baseline CT-based measures of mid-thigh cross-sectional areas versus DXA measures of body composition with all-cause mortality in the Health ABC cohort, using both traditional (individual body compartments) and compositional data analysis (using ratios of body compartments) approaches METHODS The Health ABC study assessed body composition in 2911 older adults in 1996-1997 We investigated the individual and ratios of (by compositional analysis) body compartments assessed by DXA (lean, fat, and bone masses) and CT (muscle, subcutaneous fat area, intermuscular fat, and bone) on mortality, using Cox proportional hazard models RESULTS Lower baseline muscle area by CT (hazard ratio [HR]men = 056; 95% confidence interval [95% CI]: 048-067, HRwomen = 060; 95% CI: 048-074) and fat mass by DXA (HRmen = 048; 95% CI: 024-095) were predictors of mortality in traditional Cox regression analysis Consistently, compositional data analysis revealed that lower muscle area versus IMF, muscle area versus bone area, and lower fat mass versus lean mass were associated with higher mortality in both sexes CONCLUSION Both CT measure of muscle area and DXA fat mass (either individually or relative to other body compartments) were strong predictors of mortality in both sexes in a community research setting

Association Between Myocardial Strain and Frailty in CHS

Abstract: Background: Myocardial strain, measured by speckle-tracking echocardiography, is a novel measure of subclinical cardiovascular disease and may reflect myocardial aging. We evaluated the association...

Weight Loss through Lifestyle Intervention Improves Mobility in Older Adults.

Abstract: BACKGROUND AND OBJECTIVES The high prevalence of overweight or obesity in older adults is a public health concern because obesity affects health, including risk of mobility disability. RESEARCH DESIGN AND METHODS The Mobility and Vitality Lifestyle Program (MOVE UP), delivered by community health workers (CHW), enrolled 303 community-dwelling adults to assess the impact of a 32-session behavioral weight management intervention. Participants completed the program at 26 sites led by 22 CHWs. Participation was limited to people aged 60-75 who had a BMI 27-45 kg/m 2. The primary outcome was performance on the Short Physical Performance Battery (SPPB) over 12 months. RESULTS Participants were age (sd) 67.7 (4.1) and mostly female (87%); 22.7% were racial minorities. The mean (sd) BMI at baseline was 34.7 (4.7). Participants attended a median of 24 of 32 sessions; 240 (80.3%) completed the 9- or 13-month outcome assessment. Median weight loss in the sample was 5% of baseline body weight. SPPB total scores improved by +0.31 units (p < .006), gait speed by +0.04 m/sec (p < .0001), and time to complete chair stands by -0.95 sec (p < .0001). Weight loss ≥ 5% was associated with a gain of +0.73 in SPPB score. Increases in activity (by self-report or device) were not independently associated with SPPB outcomes but did reduce the effect of weight loss. DISCUSSION AND IMPLICATIONS Promoting weight management in a community group setting may be an effective strategy for reducing risk of disability in older adults.

Genetic insights into the biological mechanisms governing human ovarian ageing

Abstract: Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Heterogeneity of the Predictive Polygenic Risk Scores for Coronary Heart Disease Age-at-Onset in Three Different Coronary Heart Disease Family-Based Ascertainments

Abstract: Background: Polygenic risk scores (PRS) for coronary heart disease (CHD) may contribute to assess the overall risk of CHD. We evaluated how PRS may influence CHD risk when the distribution of age-a...

Association of Retail Environment and Neighborhood Socioeconomic Status With Mortality Among Community-Dwelling Older Adults in the United States: Cardiovascular Health Study

Abstract: BACKGROUND Few studies have examined the association of neighborhood environment and mortality among community-dwelling older populations. Geographic Information Systems (GIS)-based measures of neighborhood physical environment may provide new insights on the health effects of the social and built environment. METHODS We studied 4,379 community-dwelling older adults in the US aged ≥65 years from the Cardiovascular Health Study. Principal component analysis was used to identify neighborhood components from 48 variables assessing facilities and establishments, demographic composition, socio-economic status, and economic prosperity. We used a Cox model to evaluate the association of neighborhood components with five-year mortality. Age, sex, race, education, income, marital status, body mass index, smoking status, disability, coronary heart disease, and diabetes were included as covariates. We also examined the interactions between neighborhood components and sex and race (Black vs. white or other). RESULTS We identified five neighborhood components, representing facilities and resources, immigrant communities, community-level economic deprivation, resident-level socio-economic status and residents' age. Communities' economic deprivation and residents' socio-economic status were significantly associated with five-year mortality. We did not find interactions between sex or race and any of the five neighborhood components. The results were similar in a sensitivity analysis where we used ten-year mortality as the outcome. CONCLUSIONS We found that communities' economic status but not facilities in communities was associated with mortality among older adults. These findings revealed the importance and benefits living in a socio-economically advantaged neighborhood could have on health among older residents with different demographic backgrounds.

Reply to: Say What?! Ableist Logic Used in Misguided Attempt to Combat Ageism During COVID-19.

Abstract: To the Editor: Cruise and Lashewicz present an interesting perspective to our editorial, “COVID-19 Pandemic and ageism: a call for comment humanitarian care.” They point out how our editorial used “ableism” logic, e.g., discrimination and prejudicial reasoning and language towards individuals that have or are perceived to have disabilities, when we used characteristics of resilience and wisdom of older adults as justification to receive care. And in so doing we “succumbed to the neoliberal ideas that humanitarian care is something to be earned” as opposed to being universally afforded to all people regardless of their ability. The authors critique was unexpected, and suggests that best intentions may reveal implicit biases. We do not feel the need to apologize, but offer appreciation for their insightful comments. We have spent our professional careers advancing the understanding of the biopsychosocial and cultural determinants of aging, the diagnosis and management of diseases and disabilities of late life, and pushing healthcare systems to broaden care management practices for older adults. We never made the assumption that older persons with cognitive or physical impairments would or could not have wisdom or resilience. To the contrary, we are reminded of these personal characteristics every day. The timeframe of when the editorial was written is important—in mid-March and early April, 2020. This was early in the pandemic when rapid community spread of COVID-19 was plaguing major cities in the United States; much was unknown about the illness; treatment protocols for the severely ill were not well worked out, and healthcare resources were being over whelmed with critically ill patients. In this crisis the implicit bias of “ageism” was on the rise as allocation of limited resources and triage decisions were being made for who got what treatments, when and where. We were keenly focused on mitigating the implicit bias of ageism, and to provide a voice for those at risk of losing personal agency to make decisions and rationing healthcare based on age alone. We appreciate the authors point about humanistic ideals and challenging any form of healthcare rationing based on wellness or ability. We chose to highlight resilience and wisdom as a means to help humanize older patients and to remind clinicians, healthcare administrators and policy makers that age, in and of itself, should not be the sole determinant of who gets treated during this ongoing pandemic. It is interesting that our attempts to combat “ageism” by promoting humanistic considerations was perceived to de-humanize through the act of trying to humanize. We think that Cruise and Lashewicz have spotted a general problem with all -isms.

Using lipid profiling to better characterize metabolic differences in apolipoprotein E (APOE) genotype among community-dwelling older Black men.

Abstract: Apolipoprotein E (APOE) allelic variation is associated with differences in overall circulating lipids and risks of major health outcomes. Lipid profiling provides the opportunity for a more detailed description of lipids that differ by APOE, to potentially inform therapeutic targets for mitigating higher morbidity and mortality associated with certain APOE genotypes. Here, we sought to identify lipids, lipid-like molecules, and important mediators of fatty acid metabolism that differ by APOE among 278 Black men ages 70–81. Using liquid chromatography-mass spectrometry methods, 222 plasma metabolites classified as lipids, lipid-like molecules, or essential in fatty acid metabolism were detected. We applied principal factor analyses to calculate a factor score for each main lipid category. APOE was categorized as e4 carriers (n = 83; e3e4 or e4e4), e2 carriers (n = 58; e2e3 or e2e2), or e3 homozygotes (n = 137; e3e3). Using analysis of variance, the monoacylglycerol factor, cholesterol ester factor, the factor for triacylglycerols that consist mostly of polyunsaturated fatty acids, sphingosine, and free carnitine significantly differed by APOE (p < 0.05, false discovery rate < 0.30). The monoacylglycerol factor, cholesterol ester factor, and sphingosine were lower, whereas the factor for triacylglycerols that consisted mostly of polyunsaturated fatty acids was higher among e2 carriers than remaining participants. Free carnitine was lower among e4 carriers than e3 homozygotes. Lower monoacylglycerols and cholesteryl esters and higher triacylglycerols that consist mostly of polyunsaturated fatty acids may be protective metabolic characteristics of APOE e2 carriers, whereas lower carnitine may reflect altered mitochondrial functioning among e4 carriers in this cohort of older Black men.

Level and Change in N-Terminal Pro-B-Type Natriuretic Peptide and Kidney Function and Survival to Age 90.

Abstract: Background Many traditional cardiovascular risk factors do not predict survival to very old age. Studies have shown associations of estimated glomerular filtration rate (eGFR) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) with cardiovascular disease and mortality in older populations. This study aimed to evaluate the associations of the level and change in eGFR and NT-pro-BNP with longevity to age 90 years. Method The population included participants (n = 3,645) in the Cardiovascular Health Study, aged between 67 and 75 at baseline. The main exposures were eGFR, calculated with the Berlin Initiative Study (BIS) 2 equation, and NT-pro-BNP, and the main outcome was survival to age 90. Mixed models were used to estimate level and change of the main exposures. Results There was an association between baseline level and change of both eGFR and NT-pro-BNP and survival to 90, and this association persisted after adjustment for covariates. Each 10 mL/min/1.73 m2 higher eGFR level was associated with an adjusted odds ratio (OR) of 1.23 (95% CI: 1.13, 1.34) of survival to 90, and a 0.5 mL/min/1.73 m2 slower decline in eGFR was associated with an OR of 1.51 (95% CI: 1.31, 1.74). A twofold higher level of NT-pro-BNP level had an adjusted OR of 0.67 (95% CI: 0.61, 0.73), and a 1.05-fold increase per year in NT-pro-BNP had an OR of 0.53 (95% CI: 0.43, 0.65) for survival to age 90. Conclusion eGFR and NT-pro-BNP appear to be important risk factors for longevity to age 90.

Pleiotropic effects between cardiovascular disease risk factors and measures of cognitive and physical function in long-lived adults.

Abstract: Cardiovacular disease (CVD) is the leading cause of death among older adults and is often accompanied by functional decline. It is unclear what is driving this co-occurrence, but it may be behavioral, environmental and/or genetic. We used a family-based study to estimate the phenotypic and shared genetic correlation between CVD risk factors and physical and cognitive functional measures. Participants (n = 1,881) were from the Long Life Family Study, which enrolled families based on their exceptional longevity (sample mean age = 69.4 years, 44% female). Cardiovascular disease risk factors included carotid vessel measures [intima-media thickness and inter-adventitial diameter], obesity [body mass index (BMI) and waist circumference], and hypertension [systolic and diastolic blood pressures]. Function was measured in the physical [gait speed, grip strength, chair stand] and cognitive [digital symbol substitution test, retained and working memory, semantic fluency, and trail making tests] domains. We used SOLAR to estimate the genetic, environmental, and phenotypic correlation between each pair adjusting for age, age2, sex, field center, smoking, height, and weight. There were significant phenotypic correlations (range |0.05–0.22|) between CVD risk factors and physical and cognitive function (all P < 0.05). Most significant genetic correlations (range |0.21–0.62|) were between CVD risk factorsand cognitive function, although BMI and waist circumference had significant genetic correlation with gait speed and chair stand time (range |0.29–0.53|; all P < 0.05). These results suggest that CVD risk factors may share a common genetic-and thus, biologic-basis with both cognitive and physical function. This is particularly informative for research into the genetic determinants of chronic disease.

Metabolic Markers Demonstrate the Heterogeneity of Myosteatosis in Community-Dwelling Older Black Men from the Health ABC Study

Abstract: Myosteatosis is a complex condition, associated with aging and diverse pathological conditions (e.g., diabetes), that contributes to mobility disability. Improved characterization of myosteatosis is required to develop targeted interventions to maintain muscle health in aging. We first determined the associations between plasma metabolites and intermuscular fat (IMF) in a cross-sectional analysis of 313 older Black men from Health ABC Study. Using partial correlation analysis, 34/350 metabolites were associated with IMF, the majority of which were lipids and organic acids. Next, we used Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), as an indicator of metabolic health to delineate the anthropometric, functional, and metabolic heterogeneity of myosteatosis in a case-control matching analysis. We categorized participants based on their IMF and HOMA-IR levels into: Low-IMF with Low- versus High-HOMA, as well as High-IMF with Low- versus High-HOMA. Among participants with similar levels of IMF, those who were metabolically unhealthy, i.e., with High HOMA-IR, had higher fat and lean mass, muscle strength, and had hyperglycemia, hypertriglyceridemia, hyperinsulinemia, and higher levels of plasma metabolites belonging to diacylglycerols, triacylglycerols, fatty acid and aminoacyl-tRNA biosynthesis pathways versus those with Low HOMA-IR. In summary, HOMA-IR delineates the heterogeneity of myosteatosis by distinguishing metabolically healthy versus unhealthy individuals.