Dual cognitive and mobility impairments and future dementia - Setting a research agenda.

Dual cognitive and mobility impairments are associated with an increased risk of dementia. Recent studies examining temporal trajectories of mobility and cognitive function in aging found that dual decline is associated with higher dementia risk than memory decline or gait decline only. Although initial data show that individuals with dual decline or impairment have excessive cardiovascular and metabolic risk factors, the causes of dual decline or what underlies dual decline with a high risk of dementia remain largely unknown. In December 2021, the National Institute on Aging Intramural and Extramural Programs jointly organized a workshop on Biology Underlying Moving and Thinking to explore the hypothesis that older persons with dual decline may develop dementia through a specific pathophysiological pathway. The working group discussed assessment methods for dual decline and possible mechanisms connecting dual decline with dementia risk and pinpointed the most critical questions to be addressed from a translational perspective.

Protein intake, physical activity and grip strength in European and North American community-dwelling older adults: a pooled analysis of individual participant data from four longitudinal ageing cohorts.

INTRODUCTION: Higher dietary protein, alone or in combination with physical activity (PA), may slow the loss of age-related muscle strength in older adults. We investigated the longitudinal relationship between protein intake and grip strength, and the interaction between protein intake and PA, using four longitudinal ageing cohorts. METHODS: Individual participant data from 5584 older adults (52% women; median: 75, IQR: 71.6, 79.0 years) with up to 8.5 years (mean: 4.9, SD: 2.3 years) of follow-up from the Health ABC, NuAge, LASA and Newcastle 85+ cohorts were pooled. Baseline protein intake was assessed with food frequency questionnaires and 24h recalls and categorized into <0.8, 0.8-<1.0, 1.0-<1.2 and ≥1.2 g/kg adjusted body weight (aBW)/d. The prospective association between protein intake, its interaction with PA, and grip strength (sex- and cohort-specific) was determined using joint models (hierarchical linear mixed effects and a link function for Cox proportional hazards models). RESULTS: Grip strength declined on average by 0.018 SD (95%CI: -0.026, -0.006) every year. No associations were found between protein intake, measured at baseline, and grip strength, measured prospectively, or rate of decline of grip strength in models adjusted for sociodemographic, anthropometric, lifestyle and health variables (e.g., protein intake ≥1.2 vs <0.8 g/kg aBW/d: ß= -0.003, 95%CI: -0.014,0.005 SD per year). There also was no evidence of an interaction between protein intake and PA. CONCLUSIONS: We failed to find evidence in this study to support the hypothesis that higher protein intake, alone or in combination with higher PA, slowed the rate of grip strength decline in older adults.

The Vitamin D Metabolite Ratio Is Independent of Vitamin D Binding Protein Concentration.

BACKGROUND: 25-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. METHODS: We 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. RESULTS: Participants 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]. CONCLUSIONS: The 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.

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.

Serum Calcitriol Concentrations and Kidney Function Decline, Heart Failure, and Mortality in Elderly Community-Living Adults: The Health, Aging, and Body Composition Study.

RATIONALE & OBJECTIVES: Lower 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 DESIGN: Case-cohort study. SETTING & PARTICIPANTS: Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. PREDICTOR: Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. OUTCOMES: Major 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 APPROACH: Baseline 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. RESULTS: During 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. LIMITATIONS: Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. CONCLUSIONS: Lower 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.

Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.

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<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC).

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.

Association of urinary uromodulin with kidney function decline and mortality: the health ABC study
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BACKGROUND: Urine uromodulin (uUMOD) is a protein secreted by the kidney tubule. Recent studies have suggested that higher uUMOD may be associated with improved kidney and mortality outcomes. METHODS: Using a case-cohort design, we evaluated the association between baseline uUMOD levels and ≥ 30% estimated glomerular filtration rate (eGFR) decline, incident chronic kidney disease (CKD), rapid kidney function decline, and mortality using standard and modified Cox proportional hazards regression. RESULTS: The median value of uUMOD was 25.8 µg/mL, mean age of participants was 74 years, 48% were women, and 39% were black. Persons with higher uUMOD had lower prevalence of diabetes and coronary artery disease (CAD), and had lower systolic blood pressure. Persons with higher uUMOD also had higher eGFR, lower urinary albumin to creatinine ratio (ACR), and lower C-reactive protein (CRP). There was no association of uUMOD with > 30% eGFR decline. In comparison to those in the lowest quartile of uUMOD, those in the highest quartile had a significantly (53%) lower risk of incident CKD (CI 73%, 18%) and a 51% lower risk of rapid kidney function decline (CI 76%, 1%) after multivariable adjustment. Higher uUMOD was associated with lower risk of mortality in demographic adjusted models, but not after multivariable adjustment. CONCLUSION: Higher levels of uUMOD are associated with lower risk of incident CKD and rapid kidney function decline. Additional studies are needed in the general population and in persons with advanced CKD to confirm these findings.
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Self-reported Mobility in Older Patients Predicts Early Postoperative Outcomes after Elective Noncardiac Surgery.

BACKGROUND: Specific geriatric assessment tools may complement traditional perioperative risk stratification. The aim of this study was to evaluate whether self-reported mobility is predictive of postoperative outcomes in older patients undergoing elective noncardiac surgery. METHODS: Patients aged 69 yr or older (n = 197) underwent (1) traditional risk assessments (American Society of Anesthesiologists physical status classification and Revised Cardiac Risk Index), (2) five-point frailty evaluation, (3) self-reported mobility assessment using the Mobility Assessment Tool-short form (range, 30.21 [poor] to 69.76 [excellent]), and (4) measurements of high-sensitivity C-reactive protein. Outcomes were postoperative complications, time to discharge, and nursing home placement (NHP). RESULTS: In the sample of this study (mean age, 75 ± 5 yr; 51% women), 72% had intermediate- or high-risk surgery. Median time to discharge was 3 days (interquartile range, 1 to 4 days). Thirty patients (15%) developed postoperative complications, and 27 (13%) required NHP. After controlling for age, sex, body mass index, pain score, Revised Cardiac Risk Index, American Society of Anesthesiologist physical status, surgical risk, and high-sensitivity C-reactive protein, worse self-reported mobility (per 10-point decrease in Mobility Assessment Tool, which is equivalent to 1 SD) was associated with more postoperative complications (odds ratio [OR], 1.69; 95% CI, 1.05 to 2.73), later time to discharge (hazards ratio, 0.81; 95% CI, 0.68 to 0.96), and increased NHP (OR, 2.01; 95% CI, 1.13 to 3.56). By using the same model, intermediate frailty or frailty increased NHP (OR, 3.11; 95% CI, 1.02 to 9.54) but was not related to either postoperative complications or time to discharge. CONCLUSIONS: Preoperative self-reported mobility using a novel and brief assessment may help identify elderly patients at risk for adverse postoperative events.

Sensorimotor Peripheral Nerve Function and the Longitudinal Relationship With Endurance Walking in the Health, Aging and Body Composition Study.

OBJECTIVES: To determine whether lower extremity sensorimotor peripheral nerve deficits are associated with reduced walking endurance in older adults. DESIGN: Prospective cohort study with 6 years of follow-up. SETTING: Two university research clinics. PARTICIPANTS: Community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from the 2000-2001 annual clinical examination (N=2393; mean age ± SD, 76.5±2.9y; 48.2% men; 38.2% black) and a subset with longitudinal data (n=1178). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants underwent peripheral nerve function examination in 2000-2001, including peroneal motor nerve conduction amplitude and velocity, vibration perception threshold, and monofilament testing. Symptoms of lower extremity peripheral neuropathy included numbness or tingling and sudden stabbing, burning, pain, or aches in the feet or legs. The Long Distance Corridor Walk (LDCW) (400 m) was administered in 2000-2001 and every 2 years afterward for 6 years to assess endurance walking performance over time. RESULTS: In separate, fully adjusted linear mixed models, poor vibration threshold (>130 µm), 10-g and 1.4-g monofilament insensitivity were each associated with a slower 400-m walk completion time (16.0 s, 14.4s, and 6.9 s slower, respectively; P<.05 for each). Poor motor amplitude (<1 mV), poor vibration perception threshold, and 10-g monofilament insensitivity were related to greater slowing per year (4.7, 4.2, and 3.8 additional seconds per year, respectively; P<.05), although poor motor amplitude was not associated with initial completion time. CONCLUSIONS: Poorer sensorimotor peripheral nerve function is related to slower endurance walking and greater slowing longitudinally. Interventions to reduce the burden of sensorimotor peripheral nerve function impairments should be considered to help older adults maintain walking endurance-a critical component for remaining independent in the community.

Genome-wide association of body fat distribution in African ancestry populations suggests new loci.

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

Transcriptomic profiles of aging in purified human immune cells.

BACKGROUND: Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret. RESULTS: Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55-94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age. Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types. CONCLUSIONS: An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.

Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia.

We investigated the predictive value of geriatric assessment (GA) on overall survival (OS) for older adults with acute myelogenous leukemia (AML). Consecutive patients ≥ 60 years with newly diagnosed AML and planned intensive chemotherapy were enrolled at a single institution. Pretreatment GA included evaluation of cognition, depression, distress, physical function (PF) (self-reported and objectively measured), and comorbidity. Objective PF was assessed using the Short Physical Performance Battery (SPPB, timed 4-m walk, chair stands, standing balance) and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS. Among 74 patients, the mean age was 70 years, and 78.4% had an Eastern Cooperative Oncology Group (ECOG) score ≤ 1. OS was significantly shorter for participants who screened positive for impairment in cognition and objectively measured PF. Adjusting for age, gender, ECOG score, cytogenetic risk group, myelodysplastic syndrome, and hemoglobin, impaired cognition (Modified Mini-Mental State Exam < 77) and impaired objective PF (SPPB < 9) were associated with worse OS. GA methods, with a focus on cognitive and PF, improve risk stratification and may inform interventions to improve outcomes for older AML patients.

Genetic and environmental factors are associated with serum 25-hydroxyvitamin D concentrations in older African Americans.

BACKGROUND: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. OBJECTIVE: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. METHODS: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-µg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. CONCLUSIONS: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.

Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Pathways linking regional hyperintensities in the brain and slower gait.

IMPORTANCE: Cerebral white matter hyperintensities (WMHs) are involved in the evolution of impaired mobility and executive functions. Executive functions and mobility are also associated. Thus, WMHs may impair mobility directly, by disrupting mobility-related circuits, or indirectly, by disrupting circuits responsible for executive functions. Understanding the mechanisms underlying impaired mobility in late life will increase our capacity to develop effective interventions. OBJECTIVE: To identify regional WMHs most related to slower gait and to examine whether these regional WMHs directly impact mobility, or indirectly by executive functions. DESIGN: Cross-sectional study. Twenty-one WMH variables (i.e., total WMH volume and WMHs in 20 tracts), gait speed, global cognition (Modified Mini-Mental State Examination; 3MS), and executive functions and processing speed (Digit-Symbol Substitution Test; DSST) were assessed. An L1-L2 regularized regression (i.e., Elastic Net model) identified the WMH variables most related to slower gait. Multivariable linear regression models quantified the association between these WMH variables and gait speed. Formal tests of mediation were also conducted. SETTING: Community-based sample. PARTICIPANTS: Two hundred fifty-three adults (mean age: 83years, 58% women, 41% black). MAIN OUTCOME MEASURE: Gait speed. RESULTS: In older adults with an average gait speed of 0.91m/sec, total WMH volume, WMHs located in the right anterior thalamic radiation (ATRR) and frontal corpuscallosum (CCF) were most associated with slower gait. There was a >10% slower gait for each standard deviation of WMH in CCF, ATRR or total brain (standardized beta in m/sec [p value]: -0.11 [p=0.046], -0.15 [p=0.007] and -0.14 [p=0.010], respectively). These associations were substantially and significantly attenuated after adjustment for DSST. This effect was stronger for WMH in CCF than for ATRR or total WMH (standardized beta in m/sec [p value]: -0.07 [p=0.190], -0.12 [p=0.024] and -0.10 [p=0.049], respectively). Adjustment for 3MS did not change these associations. The mediation analyses also found that DSST significantly mediated the associations between WMHs and gait speed. Our models were adjusted for age, sex, BMI, quadriceps strength, years of education, standing height, and prevalent hypertension. CONCLUSION: The impact, direct or indirect, of WMHs on gait speed depended on their location and was mediated by executive function. Thus, multi-faceted interventions targeting executive control functions as well as motor functions, such as balance and strength training, are candidates to the maintenance of mobility across the lifespan.

Urinary kidney injury molecule 1 (KIM-1) and interleukin 18 (IL-18) as risk markers for heart failure in older adults: the Health, Aging, and Body Composition (Health ABC) Study.

BACKGROUND: Kidney damage and reduced kidney function are potent risk factors for heart failure, but existing studies are limited to assessing albuminuria or estimated glomerular filtration rate (eGFR). We evaluated the associations of levels of urinary biomarkers of kidney tubular injury (interleukin 18 [IL-18] and kidney injury molecule 1 [KIM-1]) with future risk of heart failure. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 2,917 participants without heart failure in the Health, Aging, and Body Composition (Health ABC) cohort. PREDICTORS: Ratios of urine KIM-1, IL-18, and albumin to creatinine (KIM-1:Cr, IL-18:Cr, and ACR, respectively). OUTCOMES: Incident heart failure over a median follow-up of 12 years. RESULTS: Median values of each marker at baseline were 812 (IQR, 497-1,235)pg/mg for KIM-1:Cr, 31 (IQR, 19-56)pg/mg for IL-18:Cr, and 8 (IQR, 5-19) mg/g for ACR. 596 persons developed heart failure during follow-up. The top quartile of KIM-1:Cr was associated with risk of incident heart failure after adjustment for baseline eGFR, heart failure risk factors, and ACR (HR, 1.32; 95% CI, 1.02-1.70) in adjusted multivariate proportional hazards models. The top quartile of IL-18:Cr also was associated with heart failure in a model adjusted for risk factors and eGFR (HR, 1.35; 95% CI, 1.05-1.73), but was attenuated by adjustment for ACR (HR, 1.15; 95% CI, 0.89-1.48). The top quartile of ACR had a stronger adjusted association with heart failure (HR, 1.96; 95% CI, 1.53-2.51). LIMITATIONS: Generalizability to other populations is uncertain. CONCLUSIONS: Higher urine KIM-1 concentrations were associated independently with incident heart failure risk, although the associations of higher ACR were of stronger magnitude.

Serum bicarbonate concentrations and kidney disease progression in community-living elders: the Health, Aging, and Body Composition (Health ABC) Study.

BACKGROUND: In populations with prevalent chronic kidney disease (CKD), lower serum bicarbonate levels are associated with more rapid CKD progression, but whether lower bicarbonate levels also are associated with risk of incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) and CKD progression among community-living persons with predominantly preserved kidney function is unknown. STUDY DESIGN: Longitudinal observational cohort study. SETTING & PARTICIPANTS: Well-functioning community-living elders aged 70-79 years at inception. PREDICTOR: Serum bicarbonate level measured at the time of collection by arterialized venous blood sample using an arterial blood gas analyzer. OUTCOMES: Change in eGFR over 7 years, and new eGFR < 60 mL/min/1.73 m(2) with a rate of loss of at least 1 mL/min/1.73 m(2) per year. MEASUREMENTS: Linear and logistic regressions were used to evaluate associations of baseline serum bicarbonate level with change in eGFR and incident eGFR < 60 mL/min/1.73 m(2). RESULTS: At baseline, mean eGFR was 84 ± 16 (SD)mL/min/1.73 m(2), and serum bicarbonate level was 25.2 ± 1.9 mmol/L. Compared with participants with higher bicarbonate concentrations (23.0-28.0 mmol/L), those with bicarbonate concentrations < 23 mmol/L (n = 85 [8%]) lost eGFR0.55 (95% CI, 0.13-0.97) mL/min/1.73 m(2) per year faster in models adjusted for demographics, CKD risk factors, baseline eGFR, and urine albumin-creatinine ratio. Among the 989 (92%) participants with baseline eGFRs > 60 mL/min/1.73 m(2), 252 (25%) developed incident eGFRs < 60 mL/min/1.73 m(2) at follow-up. Adjusting for the same covariates, participants with bicarbonate concentrations < 23 mmol/L had nearly 2-fold greater odds of incident eGFRs < 60 mL/min/1.73 m(2) (OR, 1.72; 95% CI, 0.97-3.07) compared with those with higher bicarbonate concentrations. LIMITATIONS: Only 2 measurements of kidney function separated by 7 years and loss to follow-up due to intervening mortality in this elderly population. CONCLUSIONS: Lower serum bicarbonate concentrations are associated independently with decline in eGFR and incident eGFR < 60 mL/min/1.73 m(2) in community-living older persons. If confirmed, serum bicarbonate levels may give insight into kidney tubule health in persons with preserved eGFRs and suggest a possible new target for intervention to prevent CKD development.

Macular pigment optical density is related to cognitive function in older people.

BACKGROUND: the xanthophylls lutein (L) and zeaxanthin (Z) exist in relatively high concentration in multiple central nervous tissues (e.g. cortex and neural retina). L + Z in macula (i.e. macular pigment, MP) are thought to serve multiple functions, including protection and improvement of visual performance. Also, L + Z in the macula are related to L + Z in the cortex. OBJECTIVE: to determine whether macular pigment optical density (MPOD, L + Z in the macula) is related to cognitive function in older adults. METHODS: participants were older adults (n = 108, 77.6 ± 2.7 years) sampled from the age-related maculopathy ancillary study of the Health Aging and Body Composition Study (Memphis, TN, USA). Serum carotenoids were measured using high performance liquid chromatography. MPOD was assessed using heterochromatic flicker photometry. Eight cognitive tests designed to evaluate several cognitive domains including memory and processing speed were administered. Partial correlation coefficients were computed to determine whether cognitive measures were related to serum L + Z and MPOD. RESULTS: MPOD levels were significantly associated with better global cognition, verbal learning and fluency, recall, processing speed and perceptual speed, whereas serum L + Z was significantly related to only verbal fluency. CONCLUSION: MPOD is related to cognitive function in older people. Its role as a potential biomarker of cognitive function deserves further study.