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BackgroundThe effects of aging on circadian patterns of behavior are insufficiently described. To address this, we characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults both overall, and in relation, to sociodemographic characteristics.MethodsWe examined cross-sectional associations between RAR and age, sex, race, education, multimorbidity burden, financial, work, martial, health, and smoking status using assessments of older adults with wrist-worn free-living actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). RAR parameters were determined by mapping an extension to the traditional cosine curve to activity data. Functional principal component analysis determined variables accounting for variance.ResultsAge was associated with several metrics of dampened RAR; women had stronger and more robust RAR vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P

BackgroundFalls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated.MethodsIn this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy (MRS) after an acute bout of exercise (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS).ResultsAt least one fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400m walk gait speed (1.0 ± 0.2 vs. 1.1 ± 0.2, p

BACKGROUND: Aging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. We characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults, both overall, and in relation, to sociodemographic characteristics. METHODS: We analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables. RESULTS: Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (all P < 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P

Translating our knowledge of the biological aging from animal models to humans may give rise to novel approaches of targeting multiple aging-related diseases simultaneously and increasing health span. Here, for the first time, we use transcriptomic signatures of monocytes to identify biological aging pathways underlying multiple aging-related diseases in humans. The ordinal logistic regression was used to cross-sectionally investigate transcriptomics of the comorbidity index in 1264 community-based Multi-Ethnic Study of Atherosclerosis (MESA) adults, 47% Caucasian, 32% Hispanic, 21% African American, and 51% female, aged 55-94 years. The comorbidity index was defined as the number of prevalent aging-related diseases including cardiovascular disease, type-2 diabetes, hypertension, cancer, dementia, chronic kidney disease, chronic obstructive pulmonary disease, and hip fracture. We identified 708 gene transcripts associated with the comorbidity index (FDR

Treatments that target fundamental processes of aging are expected to delay several aging-related conditions simultaneously. Testing the efficacy of these treatments for potential anti-aging benefits will require clinical trials with endpoints that reflect the potential benefits of slowing processes of aging. There are several potential types of endpoints to capture the benefits of slowing a process of aging, and a consensus is needed to standardize and compare the results of these trials and to guide the analysis of observational data to support trial planning. Using biomarkers instead of clinical outcomes would substantially reduce the size and the duration of clinical trials. This requires validation of surrogate markers showing that treatment induced change in the marker reliably predicts the magnitude of change in the clinical outcome. The surrogate marker must also reflect the biological mechanism for the effect of treatment on the clinical outcome. "Biological age" is a superficially attractive marker for such trials. However, it is essential to establish that treatment induced change in biological age reliably predict the magnitude of benefits in the clinical outcome. Reaching consensus on clinical outcomes for geroscience trials and then validating potential surrogate biomarkers requires time, effort, and coordination that will be worthwhile to develop surrogate outcomes that can be trusted to efficiently test the value of many anti-aging treatments under development.

Cellular metabolism generates molecular damage affecting all levels of biological organization. Accumulation of this damage over time is thought to play a central role in the aging process, but damage manifests in diverse molecular forms complicating its assessment. Insufficient attention has been paid to date to the role of molecular damage in aging-related phenotypes, particularly in humans, in part because of the difficulty in measuring its various forms. Recently, omics approaches have been developed that begin to address this challenge, because they are able to assess a sizeable proportion of age-related damage at the level of small molecules, proteins, RNA, DNA, organelles and cells. This review describes the concept of molecular damage in aging and discusses its diverse aspects from theoretical models to experimental approaches. Measurement of multiple types of damage enables studies of the role of damage in human aging outcomes and lays a foundation for testing interventions to reduce the burden of molecular damage, opening new approaches to slowing aging and reducing its consequences.

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH)2 D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D-binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR)

BackgroundDietary recommendations may underestimate the protein older adults need for optimal bone health. This study sought to determine associations of protein intake with bone mineral density (BMD) and fracture among community-dwelling White and Black older adults.MethodProtein as a percentage of total energy intake (TEI) was assessed with a Food Frequency Questionnaire in 2160 older adults (73.5 ± 2.8 years; 51.5% women; 35.8% Black) in the Health, Aging, and Body Composition prospective cohort. Hip, femoral neck, and whole body BMD was assessed by dual-energy x-ray absorptiometry at baseline and 4 years, and lumbar trabecular, cortical, and integral BMD was assessed by computed tomography at baseline and 5 years. Fragility fractures over 5 years were adjudicated from self-report data collected every 6 months. Associations with tertiles of protein intake were assessed using analysis of covariance for BMD and multivariate Cox regression for fracture, adjusting for confounders.ResultsParticipants in the upper protein tertile (≥15% TEI) had 1.8%-6.0% higher mean hip and lumbar spine BMD compared to the lower protein tertile (

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

ObjectiveLow 25-hydroxyvitamin D (25[OH]D) levels and metabolic syndrome (MetS) are prevalent among older adults; however, longitudinal studies examining 25(OH)D status and MetS are lacking. We explore the association of 25(OH)D levels with prevalent and incident MetS in white and black older adults. Research Design and Methods. A total of 1620 white and 1016 black participants aged 70-79 years from the Health ABC cohort with measured 25(OH)D levels and data on MetS and covariates of interest were examined. The association between 25(OH)D levels and prevalent MetS at baseline and incident MetS at 6-year follow-up was examined in whites and blacks separately using logistic regression adjusting for demographics, lifestyle factors, and renal function.ResultsAt baseline, 635 (39%) white and 363 (36%) black participants had prevalent MetS. In whites, low 25(OH)D levels were associated with prevalent MetS (adjusted OR (95% CI), 1.85 (1.47, 2.34)) and 1.96 (1.46, 2.63) for 25(OH)D of 20-

Background25-Hydroxyvitamin D [25(OH)D] may be a poor marker of vitamin D status as it reflects differences in vitamin D binding protein (VDBP) between individuals. The vitamin D metabolite ratio [VMR, ratio of 24,25(OH)2D3 to 25(OH)D3] is a marker of vitamin D status that has been hypothesized to be independent of variability in VDBP. This hypothesis has not been directly evaluated.MethodsWe measured 25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and VDBP in 377 community-dwelling older adults that participated in the Health Aging and Body Composition Study. 24,25(OH)2D3 and 25(OH)D3 were used to calculate the VMR. We used linear regression to assess the relationship between VDBP with the VMR, 24,25(OH)2D3, 25(OH)D3, and 1,25(OH)2D3.ResultsParticipants had mean age 75 ± 3 years, 52% were female, 40% were black, and 24% had chronic kidney disease. VDBP concentrations were associated with sex, serum albumin, and VDBP phenotype in multivariable models. In fully adjusted models, each 1% higher VDBP was associated with a 0.92%[95% CI(0.37,1.49%)], 0.76% (0.39, 1.13%), and 0.57% (0.29, 0.85%), higher 24,25(OH)2D3, 25(OH)D3, and 1,25(OH)2D3. The VMR was independent of VDBP concentration, [0.16%(-0.11, 0.44) higher VMR per 1% higher VDBP, P = .25].ConclusionsThe VMR was independent of VDBP concentration, whereas VDBP was strongly directly associated with the individual vitamin D metabolite concentrations. Prior studies evaluating only 25(OH)D3 may have been confounded by absence of data on VDBP status. The VMR may serve as an important biomarker of vitamin D status and clinical outcomes that can be utilized in populations with a large spectrum of VDBP concentrations.

IntroductionMild parkinsonian signs (MPS) are associated with morbidity. Identification of MPS progression markers may be vital for preventive management, yet has not been pursued. This study aimed to ascertain clinical/neuroimaging features predictive of MPS progression.Methods205 participants in the Health ABC Study were included. MPS was defined using published guidelines. MPS progression was evaluated by determining UPDRS-III change between baseline and follow-up ≥2 years later. Standard brain MRI and DTI were obtained at baseline. Correlation coefficients between demographics, vascular risk factors, imaging markers, and UPDRS-III change were adjusted for follow-up time. Linear regression was used to adjust for possible confounders in the relationship between imaging markers and MPS progression.Results30% of participants had baseline MPS. Demographics and risk factors did not differ significantly between participants with MPS (MPS+) and without MPS (MPS-). Mean follow-up time was 3.8±0.8 years. Older age, male gender, diabetes were associated with faster rate of UPDRS-III change in MPS- but not MPS+ participants. Among MPS- participants, the only imaging marker associated with faster UPDRS-III progression was higher gray matter mean diffusivity (MD), widespread in various cortico-subcortical bihemispheric regions, independent of age, gender, diabetes. No imaging features were associated with UPDRS-III change among MPS+ participants.ConclusionsLower gray matter integrity predicted MPS progression in those who did not have baseline MPS. Microstructural imaging may capture early changes related to MPS development, prior to macrostructural change. Any future management promoting gray matter preservation may inhibit MPS development.

The purpose of this study is to explore the impact of body weight change following intentional weight loss on incident fracture and bone mineral density (BMD) in overweight and obese adults with diabetes. A total of 1885 individuals with type 2 diabetes (baseline age: 58.5 ± 6.7 years, 58% women, body mass index: 35.7 ± 6.0 kg/m2) who participated in the Look AHEAD study and lost any weight 1 year after being randomized to an intensive lifestyle intervention were assessed. Body weight was measured annually and participants were categorized as weight regainers, weight cyclers, or continued losers/maintainers based on a ±3% annual change in weight from year 1 to year 4. Adjudicated overall fracture incidence was captured from years 4 through 13 (median follow-up duration 11.5 years). Hip and spine BMD was assessed in a subset of participants at baseline, year 4 (n = 468), and year 8 (n = 354), using dual-energy X-ray absorptiometry. Cox proportional hazards and linear regression models, adjusted for relevant covariates, were performed for fracture and BMD outcomes, respectively. Fifty-eight percent, 22%, and 20% of participants were classified as weight regainers, weight cyclers, and continued losers/maintainers, respectively; and 217 fractures (men n = 63; women n = 154) were recorded during the follow-up period. There were no statistically significant differences in total incident fracture rates for weight regainers (HR [95% CI]: 1.01 [95% CI, 0.71 to 1.44]) or weight cyclers (HR [95% CI]: 1.02 [95% CI, 0.68 to 1.53]) when compared to continued losers/maintainers (p = 0.99). Similarly, follow-up BMD estimates did not significantly vary by weight pattern group, although consistent trends for lowered BMD in the hip region were noted for continued losers/maintainers and weight cyclers compared with weight regainers. Patterns of weight change in the 3 years following 1 year of intentional weight loss were not associated with subsequent fracture or significantly reduced BMD in this cohort of overweight and obese adults with type 2 diabetes. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

BackgroundA goal of gerontology is discovering aging phenotypes that reflect biological aging distinct from disease pathogenesis. Biomarkers that strongly and independently associated with mortality and that statistically attenuated chronologic age could be used to define such a phenotype. We determined the association of a Biomarker Index (BI) with mortality and compared it with a validated Physiologic Index (PI) in older adults.MethodsThe indices were constructed in the Cardiovascular Health Study, mean (SD) age 74.5 (5.1) years. The BI incorporated circulating levels of new biomarkers, including insulin-like growth factor-1, insulin-like growth factor-binding protein 3, amino-terminal pro-B-type natriuretic peptide, dehydroepiandrosterone sulfate, and interleukin-6, and was built in test (N = 2,197) and validation (N = 1,124) samples. The PI included carotid intima-media thickness, pulmonary capacity, brain white matter grade, cystatin-C, and fasting glucose. Multivariable Cox proportional hazards models predicting death were calculated with 10 years of follow-up.ResultsIn separate age-adjusted models, the hazard ratio for mortality per point of the BI was 1.30 (95% confidence interval 1.25, 1.34) and the BI attenuated age by 25%. The hazard ratio for the PI was 1.28 (1.24, 1.33; 29% age attenuation). In the same model, the hazard ratio for the BI was 1.23 (1.18, 1.28) and for the PI was 1.22 (1.17, 1.26), and age was attenuated 42.5%. Associations persisted after further adjustment.ConclusionsThe BI and PI were significantly and independently associated with mortality. Both attenuated the age effect on mortality substantially. The indices may be feasible phenotypes for developing interventions hoping to alter the trajectory of aging.

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P

Rationale & objectivesLower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored.Study designCase-cohort study.Setting & participantsWell-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study.PredictorSerum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry.OutcomesMajor kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up.Analytic approachBaseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression.ResultsDuring 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations.LimitationsObservational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race.ConclusionsLower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function.

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

Using data from the Health, Aging, and Body Composition study, we examined whether low 25-hydroxyvitamin D (25[OH]D) concentrations were associated with prevalent or incident cognitive impairment. Serum 25(OH)D concentrations were measured in 2,786 older adults and categorized as 1.5 standard deviations below race and education specific means on either digit symbol substitution test or modified mini-mental state test. Logistic regression determined the odds of cognitive impairment at baseline and year 5 by 25(OH)D category. 25(OH)D concentrations were

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

ObjectiveTo characterize change in physical performance and differential prevalence of low skeletal muscle mass and strength (sarcopenia) and lower 25-hydroxyvitamin D concentrations among older women who developed urinary incontinence (UI) symptoms.MethodsThis is a secondary analysis of the Health, Aging, and Body Composition Study. Urinary incontinence symptoms were assessed using validated questions. The Short Physical Performance Battery measured physical performance. Sarcopenia, defined by low muscle mass and strength, was determined using validated cutoffs for gait speed, grip strength, and appendicular skeletal muscle mass. All parameters were evaluated at baseline and year 4. Serum 25-hydroxyvitamin D concentrations were assessed at year 2. The primary outcome was change in Short Physical Performance Battery total scores. Sarcopenia and lower serum 25-hydroxyvitamin D concentrations have been independently associated with poor physical performance and UI and were therefore included as secondary outcomes. Univariate and multivariate analyses were used to characterize the associations of change in physical performance from baseline to year 4, incidence of sarcopenia, and lower serum 25-hydroxyvitamin D on the development of UI symptoms.ResultsOf the 1,583 women enrolled, 910 were excluded (730 had baseline UI; 180 with missing data). Six hundred seventy-three women were continent at baseline; 223 (33%) developed UI symptoms at year 4. SPPB total scores significantly declined in women with UI versus continent women (mean difference continent-incident UI 0.32, 95% CI 0.04-0.60, P=.02). Of subscale measures, standing balance showed the greatest decline at 0.20 (0.05-0.36; continent-incident UI, respectively; P=.009). Sarcopenia developed at a higher rate with incident UI (adjusted odds ratio [OR] 1.7, 95% CI 1.0-2.9). Low 25-hydroxyvitamin D was not associated with incident UI (adjusted OR 1.1, 95% CI 0.7-1.6 and 1.1, 95% CI 0.7-1.6 for deficient or insufficient versus sufficient status, respectively).ConclusionWe observed a significant decline in standing balance among older women who developed UI symptoms. This decline may be associated with coinciding development of sarcopenia.

Background/objectivesPoor appetite in older adults leads to sub-optimal food intake and increases the risk of undernutrition. The impact of poor appetite on food intake in older adults is unknown. The aim of this study was to examine the differences in food intake among older community-dwelling adults with different reported appetite levels.DesignCross-sectional analysis of data from a longitudinal prospective study.SettingHealth, aging, and body composition study performed in the USA.Participants2,597 community-dwelling adults aged 70-79.MeasurementsA semi-quantitative, interviewer-administered, 108-item food frequency questionnaire designed to estimate dietary intake. Poor appetite was defined as the report of a moderate, poor, or very poor appetite in the past month and was compared with good or very good appetite.ResultsThe mean age of the study sample was 74.5 ± 2.8 years; 48.2% were men, 37.7% were black, and 21.8% reported a poor appetite. After adjustment for total energy intake and potential confounders (including biting/chewing problems), participants with a poor appetite had a significantly lower consumption of protein and dietary fiber, solid foods, protein rich foods, whole grains, fruits, and vegetables, but a higher consumption of dairy foods, fats, oils, sweets, and sodas compared to participants with very good appetite. In addition, they were less likely to report consumption of significant larger portion sizes.ConclusionOlder adults reporting a poor appetite showed a different dietary intake pattern compared to those with (very) good appetite. Better understanding of the specific dietary intake pattern related to a poor appetite in older adults can be used for nutrition interventions to enhance food intake, diet variety, and diet quality.