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Background: Although diets rich in carotenoids are associated with reduced risks of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated., Objectives: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults., Methods: In 728 adults ≥65 y participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using HPLC. The SOMAscan assay was used to measure 1301 plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value < 0.05., Results: Plasma β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q < 0.05). No proteins were associated with α-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity., Conclusions: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provides insight into the mechanisms underlying the protective role of carotenoids on health., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: PUFA intake is associated with reduced cardiovascular and all-cause mortality in the general population; however, evidence about this association in older adults is controversial. The objective of this study was to evaluate the relationship between PUFA intake and serum concentration, and the association of these variables with all-cause and cardiovascular mortality., Methods: in this cohort study, we selected 927 community dwelling adults aged ≥65 years enrolled in the InCHIANTI study from 1998 to 2000 and followed-up for 9 years. The association between PUFA intake and serum concentration was evaluated using scatterplot and Pearson correlation test; all-cause and cardiovascular mortality was analyzed using the Kaplan-Meier method and Cox regressions adjusted for potential confounders., Results: mean age of the population was 75 years (SD 7.3), 55% were women. There was no association between overall PUFAs, linolenic and linoleic acid intake and their serum concentration. There was no association between quartiles (Q) of PUFA intake and all-cause mortality: compared to Q1 of PUFA intake, the adjusted HR (95% CI) for overall mortality were: 1.05 (0.74-1.50) in Q2, 1.10 (0.76-1.58) in Q3, and 0.98 (0.68-1.41) in Q4; this lack of association was confirmed for cardiovascular mortality. Compared to Q1, participants in the fourth quartile of PUFA serum concentration had lower risk of all-cause mortality (adjusted HR [95%CI]: Q2 1.10 [0.79-1.53], Q3 0.84 [0.60-1.19], Q4 0.66 [0.44-0.995]), no association was found for cardiovascular mortality., Conclusions: In our sample of community-dwelling older adults, PUFA intake is not associated with PUFA serum concentration. Interventions to modulate PUFA concentration based on dietary intake may not be effective in preventing mortality in this population., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

The viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) is increasingly used to induce maternal immune activation (mIA) to model neurodevelopmental disorders (NDDs). Robust and reproducible phenotypes across studies are essential for the generation of models that will enhance our understanding of NDDs and enable the development of improved therapeutic strategies. However, differences in mIA-induced phenotypes using poly(I:C) have been widely observed, and this has prompted the reporting of useful and much needed methodological guidelines. Here, we perform a detailed investigation of molecular weight and endotoxin variations in poly(I:C) procured from two of the most commonly used suppliers, Sigma and InvivoGen. We demonstrate that endotoxin contamination and molecular weight differences in poly(I:C) composition lead to considerable variability in maternal IL-6 response in rats treated on gestational day (GD)15 and impact on fetal outcomes. Specifically, both endotoxin contamination and molecular weight predicted reductions in litter size on GD21. Further, molecular weight predicted a reduction in placental weight at GD21. While fetal body weight at GD21 was not affected by poly(I:C) treatment, male fetal brain weight was significantly reduced by poly(I:C), dependent on supplier. Our data are in agreement with recent reports of the importance of poly(I:C) molecular weight, and extend this work to demonstrate a key role of endotoxin on relevant phenotypic outcomes. We recommend that the source and batch numbers of poly(I:C) used should always be stated and that molecular weight variability and endotoxin contamination should be minimised for more robust mIA modelling., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Aims: Increased uric acid levels correlate with cardiovascular disease and cardiovascular/overall mortality. To identify a uric acid threshold above which cardiovascular mortality rises, we studied the relationship between uric acid concentration and overall/cardiovascular mortality., Methods and Results: We analyzed data from the InCHIANTI study, a cohort study of Italian community-dwelling people with 9 years of follow-up. We selected a sample of 947 individuals over 64 years of age, free from cardio-cerebrovascular disease and with available uric acid measurement at baseline. The sample was divided according to plasma uric acid tertiles. The Hazard ratio (HR) for mortality was calculated by multivariate Cox proportional hazard model. Mean age of participants was 75.3 ± 7.3 years; the mean value of uric acid was 5.1 ± 1.4 mg/dl. Over 9-years of follow-up, 342 (36.1%) participants died, 143 deaths (15.1%) were due to cardiovascular disease. Subjects with higher uric acid concentrations presented a higher cardiovascular mortality [II (4.6-5.5 mg/dl) vs I (1.8-4.5 mg/dl) tertile HR: 1.98, 95%C.I. 1.22-3.23; III (≥5.6 mg/dl) vs I tertile HR: 1.87, 95%C.I. 1.13-3.09]. We found a non-linear association between uric acid concentrations and cardiovascular mortality with the lowest mortality for values of about 4.1 mg/dl and a significant risk increment for values above 4.3 mg/dl., Conclusion: In community-dwelling older individuals free from cardio-cerebrovascular events, the lowest 9-year cardiovascular mortality was observed for uric acid values far below current target values. If confirmed, these data might represent the background for investigating the efficacy of uric acid levels reduction in similar populations., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: The relation between liver fibrosis scores and health outcomes in older people has been barely investigated. We aimed to evaluate the association of four liver fibrosis scores (fibrosis-4 -FIB-4-, NAFLD fibrosis score -NFS-, BARD and aspartate aminotransferase/alanine aminotransferase ratio -AST/ALT-) with mortality and incident disability at 6 years in an older population., Methods: We studied 962 individuals aged ≥65 (mean age 74.4; female 55.5%) with a mean follow-up of 95.7 months, enrolled in the InCHIANTI study. The relationship between liver fibrosis scores and mortality and disability was assessed through Cox and log-binomial regressions., Results: NFS and FIB-4 were associated with higher overall (aHR ranging 1.38-1.78 for intermediate risk of fibrosis and 1.60-2.02 for high risk) and cardiovascular (aHR ranging 1.76-2.90 for intermediate and 2.22-2.42 for high risk) mortality. AST/ALT and BARD were only associated with overall mortality. Only NFS and FIB-4 high risk classes were associated with incident disability (aRR ranging 1.93-2.76). Despite poor sensitivity, all scores showed high specificity (ranging 0.88-0.95)., Conclusion: Higher risk of liver fibrosis is associated with higher risk of poor health outcomes. Liver fibrosis scores may help to stratify the risk and, mainly, identify elderly patients with favorable prognosis., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans., Objective: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes., Methods: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes., Results: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs., Conclusions: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies., (Copyright © American Society for Nutrition 2019.)

Objectives: Frailty phenotype (FP) has low sensitivity toward the identification of older people who will lose 1 or more activities of daily living. Nevertheless, the definition of disability in terms of activities of daily living may not resemble the pattern of functional impairment occurring during aging. The aim of this study was to examine the discriminative capacity of the FP toward the identification of patterns of disabilities in an extended list of tasks, identified among community-dwelling older people., Design: Longitudinal cohort study., Setting and Participants: We included 997 persons age 65 years and older selected from the Invecchiare in Chianti (InCHIANTI) Study population., Measures: Using latent class analysis, we assessed the pattern of 3-year changes in 24 functional tasks. Then, we calculated the discriminative capacity of the FP for each pattern of disability. Analyses were stratified by sex., Results: In both men and women, we recognized 3 classes: stable function; disability in complex tasks; and global functional disability. Among women, ability of FP to identify persons in global functional disability showed sensitivity = 0.42, specificity = 0.98, positive and negative predictive values 0.75 and 0.91; the corresponding values for prediction of disability in complex tasks were 0.13, 0.98, 0.68, and 0.75. Similar results were obtained among men., Conclusions/implications: Over 3 years, older people of the InCHIANTI population remained largely functional stable, some persons developed deficiency in complex tasks, and a minority developed global functional disability. Trying to predict these 3 patterns may be useful for the care of older people in order to promote individualized interventions to reduce the burden of disabilities and their consequences. To this purpose, FP showed a fairly good capacity to identify people at risk of functional decline, but further studies are needed to identify instruments with better prognostic capacity., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: High dietary sodium intake is a risk factor for cardiovascular events and death. Recently, a J-shaped correlation between sodium intake and adverse outcomes has been shown. The evidence on the association between sodium intake and cardiovascular outcomes in the elderly is scant. The objective of this study was to evaluate the correlation between sodium intake and cardiovascular events and mortality in an elderly population, taking into account frailty status., Design: Cohort study of community dwelling older people enrolled in the InCHIANTI (Invecchiare in Chianti - Aging in the Chianti) study from 1998 to 2000 and followed-up for 9 years., Setting: Two communities in Tuscany, Italy., Participants: A total of 920 participants 65 years of age and older, with 24-hour urinary sodium excretion data., Measurements: Nine-year mortality and incident cardiovascular events were analyzed using Cox and nonlinear log-binomial models, stratified by frailty status. Sensitivity analysis in participants without hypertension and cardiovascular diseases was performed., Results: Mean age of the population was 74.5 years (standard deviation 6.99); 55.4% were women. There was a bi-modal association between sodium excretion and mortality, with risk increasing only below sodium excretion of 6.25 g/d [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.20-1.38], confirmed in the adjusted model (HR 1.12, 95% CI 1.04-1.22). These results were confirmed in participants without cardiovascular diseases. After stratification for frailty phenotype, the association was stronger in frail participants (adjusted HR 1.23, 95% CI 1.02-1.50 vs HR 1.11, 95% CI 1.01-1.22 in robust participants). There was no association between 24-hour sodium excretion and 9-year incidence of cardiovascular diseases (adjusted risk ratio 0.96, 95% CI 0.90-1.02)., Conclusions: Reduced sodium excretion is associated with increased mortality in a sample of community-dwelling older people, especially among the frail participants. High levels of sodium excretion are not associated with adverse outcomes in this population; therefore, sodium restriction might not be beneficial in older people., (Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)

Background: Older adults are more susceptible to higher inflammatory levels and depression. Moreover, diet may influence inflammation as well as depression but no previous study examined whether inflammatory dietary patterns are related to depression in an older population. To investigate the longitudinal association between inflammatory dietary patterns (using reduced rank regression (RRR)) and depressive symptoms in a population sample of Italian older adults., Methods: We included 827 participants (aged≥65years) at baseline in 1998. Follow-up measurements were collected after 3, 6 and 9years. We used RRR to identify inflammatory dietary patterns at baseline. The Centre for Epidemiologic Studies Depression (CES-D) scale was used to assess depressive symptoms by using continuous scores and depression by using a cut-off point (CES-D≥20)., Results: We identified two inflammatory dietary patterns using different sets of response variables. Dietary pattern I was related to inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor α and was characterized by high intakes of refined grains, sweet snacks, pasta and rice. After full adjustment for confounders, no longitudinal association was found when comparing extreme quartiles of this dietary pattern and depressive symptoms (Q1vs Q4, model 4: B=0.04, 95% CI: -0.06, 0.13) or depression (Q1vs Q4, model 4: OR=0.90, 95% CI: 0.55, 1.45). Dietary pattern II was related to inflammatory markers CRP, IL-18, IL-1β, IL-1 receptor antagonist and was characterized by high intakes of pasta, sugar-sweetened beverages, processed meat and chocolate and sweets. When comparing extreme quartiles, this dietary pattern was not longitudinally associated with depressive symptoms (Q1vs Q4, model 4: B=-0.04, 95% CI: -0.13, 0.05) but an inverse association was found for depression (Q1vs Q4, model 4: OR=0.56, 95% CI: 0.40, 0.94)., Conclusion: Our study does not support the hypothesis that dietary patterns linked to inflammatory markers are associated with higher depressive symptoms and higher depression incidence. However, dietary intake in our population of older adults was quite homogeneous which makes it difficult to show clear associations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log 10 (Bayes factor) ≥ 8.07] and for gondoic acid at FADS1/2 and GCKR [log 10 (Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR , where the number of variants in the 99% credible set was reduced from 16 (covering 94.8 kb) to 5 (covering 19.6 kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1 , FADS1/2 , GCKR , and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways. Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background and Objective: The fall risk assessment tool (FRAT-up) is a tool for predicting falls in community-dwelling older people based on a meta-analysis of fall risk factors. Based on the fall risk factor profile, this tool calculates the individual risk of falling over the next year. The objective of this study is to evaluate the performance of FRAT-up in predicting future falls in multiple cohorts., Methods: Information about fall risk factors in 4 European cohorts of older people [Activity and Function in the Elderly (ActiFE), Germany; English Longitudinal Study of Aging (ELSA), England; Invecchiare nel Chianti (InCHIANTI), Italy; Irish Longitudinal Study on Aging (TILDA), Ireland] was used to calculate the FRAT-up risk score in individual participants. Information about falls that occurred after the assessment of the risk factors was collected from subsequent longitudinal follow-ups. We compared the performance of FRAT-up against those of other prediction models specifically fitted in each cohort by calculation of the area under the receiver operating characteristic curve (AUC)., Results: The AUC attained by FRAT-up is 0.562 [95% confidence interval (CI) 0.530-0.594] for ActiFE, 0.699 (95% CI 0.680-0.718) for ELSA, 0.636 (95% CI 0.594-0.681) for InCHIANTI, and 0.685 (95% CI 0.660-0.709) for TILDA. Mean FRAT-up AUC as estimated from meta-analysis is 0.646 (95% CI 0.584-0.708), with substantial heterogeneity between studies. In each cohort, FRAT-up discriminant ability is surpassed, at most, by the cohort-specific risk model fitted on that same cohort., Conclusions: We conclude that FRAT-up is a valid approach to estimate risk of falls in populations of community-dwelling older people. However, further studies should be performed to better understand the reasons for the observed heterogeneity across studies and to refine a tool that performs homogeneously with higher accuracy measures across different populations., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)

Background: Consuming fruit and vegetables (FVs) may protect against frailty, but to our knowledge no study has yet assessed their prospective dose-response relation., Objective: We sought to examine the dose-response association between FV consumption and the risk of frailty in older adults., Design: Data were taken from 3 independent cohorts of community-dwelling older adults: the Seniors-ENRICA (Study on Nutrition and Cardiovascular Risk Factors in Spain) cohort (n = 1872), Three-City (3C) Bordeaux cohort (n = 581), and integrated multidisciplinary approach cohort (n = 473). Baseline food consumption was assessed with a validated computerized diet history (Seniors-ENRICA) or with a food-frequency questionnaire (3C Bordeaux and AMI). In all cohorts, incident frailty was assessed with the use of the Fried criteria. Results across cohorts were pooled with the use of a random-effects model., Results: During a mean 2.5-y follow-up, 300 incident frailty cases occurred. Fully adjusted models showed that the pooled ORs (95% CIs) of incident frailty comparing participants who consumed 1, 2, or ≥3 portions of fruit/d to those with no consumption were, respectively, 0.59 (0.27, 0.90), 0.58 (0.29, 0.86), and 0.48 (0.20, 0.75), with a P-trend of 0.04. The corresponding values for vegetables were 0.69 (0.42, 0.97), 0.56 (0.35, 0.77), and 0.52 (0.13, 0.92), with a P-trend < 0.01. When FVs were analyzed together, the pooled ORs (95% CIs) of incident frailty were 0.41 (0.21, 0.60), 0.47 (0.25, 0.68), 0.36 (0.18, 0.53), and 0.31 (0.13, 0.48), with a P-trend < 0.01 for participants who consumed 2, 3, 4, or ≥5 portions/d, respectively, compared with those who consumed ≤1 portion/d. An inverse dose-response relation was also found between the baseline consumption of fruit and risk of exhaustion, low physical activity, and slow walking speed, whereas the consumption of vegetables was associated with a decreased risk of exhaustion and unintentional weight loss., Conclusions: Among community-dwelling older adults, FV consumption was associated with a lower short-term risk of frailty in a dose-response manner, and the strongest association was obtained with 3 portions of fruit/d and 2 portions of vegetables/d., (© 2016 American Society for Nutrition.)

Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression., Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation., Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium., Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05)., Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation., (© 2016 American Society for Nutrition.)

Background: Resveratrol may play a protective role against the frailty syndrome (FS) because of its antioxidant and anti-inflammatory properties., Objective: We prospectively evaluated the association between habitual dietary resveratrol exposure and the development of FS after 3-, 6-, and 9-y follow-up periods in a community-dwelling older population., Design: We conducted a longitudinal analysis with the use of data from 769 participants aged ≥65 y from the Invecchiare in Chianti (Aging in Chianti) study. Total dietary resveratrol (TDR) intake was estimated at baseline with the use of a validated food-frequency questionnaire, which was developed to assess participants' usual food intakes over the previous year, and an ad hoc resveratrol database. Total urinary resveratrol (TUR) was analyzed with the use of liquid chromatography-tandem mass spectrometry with a previous solid-phase extraction at baseline. The combination of both measures [total dietary resveratrol plus total urinary resveratrol (TDR+TUR)] was computed with the use of the Howe's method. FS was assessed at baseline and at 3-, 6-, and 9-y of follow-up and was defined as the presence of ≥3 of the following 5 criteria: shrinking, exhaustion, sedentariness, slowness, and weakness., Results: TDR+TUR concentrations were inversely associated with FS risk over 3-y of follow-up (OR for comparison of extreme tertiles: 0.11; 95% CI: 0.03, 0.45; P-trend = 0.002) but not after 6- and 9-y of follow-up in multinomial logistic regression models adjusted for baseline frailty status and potential confounders. These results did not differ when analyses were further adjusted for inflammatory markers., Conclusion: Higher habitual dietary resveratrol exposure was associated with lower risk of older community dwellers developing FS during the first 3 y of follow-up but not after longer follow-up periods., (© 2015 American Society for Nutrition.)

Background: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake., Objectives: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations., Design: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium., Results: We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake., Conclusions: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile., (© 2015 American Society for Nutrition.)

Background: Although metabolic syndrome (MS) is a typical condition of middle-aged/older person, the association between MS and mortality risk has not been confirmed in people over 65 years. We hypothesized that while in the elderly MS phenotype might lose its value in predicting mortality risk, the two core factors of MS, i.e. insulin resistance (IR) and low grade systemic inflammation (LGSI) would not., Methods: 1011 community-dwelling older individuals (InCHIANTI study) were included. MS phenotype was defined by NCEP-ATP-III criteria. IR was calculated by HOMA; high-sensitivity C reactive protein was measured by ELISA. Subjects were divided into four groups based on presence/absence of IR (HOMA ≥ 2.27) and LGSI (hs-CRP ≥ 3 g/L): Group 1: no IR/LGSI (reference); Group 2: LGSI only; Group 3: IR only; Group 4: IR + LGSI. Hazard Ratios (HR) for 9-years cardiovascular (CVD) and total mortality, according to IR/LGSI groups, were estimated in subjects with (n.311) and without MS by Cox model., Results: 31.8% of subjects with MS phenotype had no IR, 45.3% had no LGSI; moreover, 51% of subjects with both IR and LGSI didn't display the MS phenotype. MS phenotype was not associated with CVD (HR: 1.29; 95%C.I.:0.92-1.81) or total (HR: 1.07; 95%C.I.:0.86-1.34) mortality risk, whereas the presence of IR plus LGSI was associated with increased CVD (no MS: HR 2.07, 95%CI: 1.12-3.72; MS: HR 9.88, 95%CI: 2.18-4), and overall (no MS: HR 1.72, 95%CI: 1.001-3.17; MS: HR 1.51, 95%CI: 1.02-2.28) mortality risk. The presence of IR (HR: 6.90, 95%CI: 1.45-32) or LGSI (HR 7.56, 95%CI: 1.63-35) was associated with CVD mortality, only among individuals with MS phenotype., Conclusions: Among community-dwelling older individuals, IR and LGSI, but not MS phenotype, was associated with 9-years overall and CVD mortality risk. Since a reduced "overlap" between MS phenotype and its physiopathological core (IR and LGSI) might be present with aging, we suggest that the definition of MS might be more holistic in advanced age, and probably comprise the measurement of IR and LGSI., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background & Aims: Metabolic syndrome (MetS) is associated with incident disability in middle-aged subjects. We evaluated the association of MetS with functional ability in an older population., Methods: We enrolled 1155 participants aged 65+, derived from the InCHIANTI study, and followed for 3 years. MetS was diagnosed according to the National Cholesterol Education Program's ATP-III criteria. Functional ability was estimated using the Katz's activities of daily living (ADLs), and the Lawton and Brody for the instrumental activities of daily living (IADLs) scales. The association between disability and MetS at baseline and after follow-up was assessed by logistic regression., Results: At baseline, MetS was associated with reduced probability of ADLs disability among participants aged 74+ (OR = .33, 95% CI = .14-.77; p = .010), but not in younger (5.08, 95% CI = .88-29.24; p = .069). Also, MetS was associated with reduced probability of incident ADLs disability (OR = .61, 95% CI .41-.91; p = .016), but neither with prevalent, nor incident IADLs disability., Conclusions: In older persons, MetS is associated with reduced probability of prevalent and incident ADLs disability. Whether older persons with MetS should receive treatment and whether the current diagnostic criteria for MetS apply to older individuals need further investigation., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD., Objective: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD., Design: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls., Results: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49)., Conclusions: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Polyphenols might have a role in the prevention of several chronic diseases, but evaluating total dietary polyphenol (TDP) intake from self-reported questionnaires is inaccurate and unreliable. A promising alternative is to use total urinary polyphenol (TUP) concentration as a proxy measure of intake. The current study evaluated the relationship between TUPs and TDPs and all-cause mortality during a 12-y period among older adult participants. The study population included 807 men and women aged 65 y and older from the Invecchiare in Chianti study, a population-based cohort study of older adults living in the Chianti region of Tuscany, Italy. TUP concentrations were measured at enrolment (1998-2000) using the Folin-Ciocalteau assay after a solid-phase extraction. TDPs were also estimated at baseline throughout a validated food frequency questionnaire and using our database based on USDA and Phenol-Explorer databases. We modeled associations using Kaplan-Meier survival and Cox proportional hazards models, with adjustment for potential confounders. During the 12-y follow-up, 274 participants (34%) died. At enrollment, TUP excretion adjusted for age and sex tended to be greater in participants who survived [163 ± 62 mg gallic acid equivalents (GAE)/d)] than in those who died (143 ± 63 mg GAE/d) (P = 0.07). However, no significant differences were observed for TDPs. In the multivariable Cox model, participants in the highest tertile of TUP at enrolment had a lower mortality rate than those in the lowest tertile [HR = 0.70 (95% CI: 0.49-0.99); P-trend = 0.045], whereas no significant associations were found between TDP and overall mortality. TUP is an independent risk factor for mortality among community-dwelling older adults, suggesting that high dietary intake of polyphenols may be associated with longevity.

Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants., Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake., Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data., Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7))., Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms., Methods: In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p<1×10(-5)) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies., Results: The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05×10(-7)). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19×10(-3)). This 5q21 region reached genome-wide significance (p = 4.78×10(-8)) in the overall meta-analysis combining discovery and replication studies (n = 51,258)., Conclusions: The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms., (Copyright © 2013 Society of Biological Psychiatry. All rights reserved.)

Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.

Oxidized LDLs (ox.LDLs) uptake by macrophages inside the arterial wall is a crucial step in atherosclerotic disease, and some studies suggest that high ox.LDLs plasma levels might be associated with cardiovascular disease (CVD). However, whether high ox.LDLs continue to be a CVD risk factors in older persons is unknown. We investigated the clinical correlates of plasma ox.LDLs, and their role in predicting long-term CVD/cardiac mortality in 1025 older community dwelling individuals (mean age: 75.5 ± 7.4 years; females: 55%) from the InCHIANTI study. Kaplan-Meier curves were fitted to explore the relationship between tertiles of ox.LDLs (ox.LDL/LDL-C ratio) and time to CVD/cardiac death. Hazard Ratios (HR) were estimated by Cox regression analysis. At multivariate analysis, ox.LDLs were independently associated with LDL-C, triglycerides, and HDL-C (adjusted r(2): 0.42; P = 0.001). The ox.LDL/LDL-C ratio (the extent of LDLs oxidation) was independently correlated with HDL-C, triglycerides, and beta-carotene (adjusted r(2): 0.15, P = 0.001). Among 1025 individuals, 392 died after 9 years, 166 from CVD. The HR for CVD/cardiac mortality was not significantly different across tertiles of ox.LDLs or ox.LDL/LDL-C ratio, both in the whole sample and in individuals with prevalent CVD. We conclude that in an elderly population LDL-C, triglycerides, and HDL-C are the most important determinants of ox.LDLs levels, indirectly suggesting an association between small dense LDLs and LDLs oxidation. No association emerged between higher ox.LDLs levels and 9 years CVD/cardiac mortality, suggesting that in advanced age the prognostic information added by ox.LDLs on CVD/cardiac mortality might be negligible., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: The prevalence of peripheral artery disease (PAD) increases with aging and is higher in persons with metabolic syndrome and diabetes. PAD is associated with adverse outcomes, including frailty and disability. The protective effect of testosterone and sex hormone binding globulin (SHBG) for diabetes in men suggests that the biological activity of sex hormones may affect PAD, especially in older populations., Methods: Nine hundred and twenty-one elderly subjects with data on SHBG, testosterone (T), estradiol (E2) were selected from InCHIANTI study. PAD was defined as an Ankle-Brachial Index (ABI) < 0.90. Logistic regression models adjusted for age (Model 1), age, BMI, insulin, interleukin-6, physical activity, smoking, chronic diseases including metabolic syndrome (Model 2), and a final model including also sex hormones (Model 3) were performed to test the relationship between SHBG, sex hormones and PAD., Results: The mean age (±SD) of the 419 men and 502 women was 75.0 ± 6.8 years. Sixty two participants (41 men, 21 women) had ABI < 0.90. Men with PAD had SHBG levels lower than men without PAD (p = 0.03). SHBG was negatively and independently associated with PAD in men (p = 0.028) but not in women. The relationship was however attenuated after adjusting for sex hormones (p = 0.07). The E2 was not significantly associated with PAD in both men and women. In women, but not in men, T was positively associated with PAD, even after adjusting for multiple confounders, including E2 (p = 0.01)., Conclusions: Low SHBG and high T levels are significantly and independently associated with the presence of PAD in older men and women, respectively., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Adherence to a Mediterranean-style diet is associated with a lower risk for mortality, cognitive decline, and dementia. Whether adherence to a Mediterranean-style diet protects against age-related frailty is unclear. Therefore, our objective was to examine the association between a Mediterranean-style diet with the risk of frailty in community-dwelling older persons. We conducted longitudinal analyses using data from 690 community-living persons (≥65 y) who were randomly selected from a population registry in Tuscany, Italy. Participants of the Invecchiare in Chianti study of aging completed the baseline examination in 1998-2000 and were re-examined at least once over 6 y. Adherence to a Mediterranean-style diet (scored 0-9, modeled categorically as ≤3, 4-5, and ≥6) was computed from the European Prospective Investigation into Cancer and nutrition FFQ previously validated in this cohort. Frailty was defined as having at least 2 of the following criteria: poor muscle strength, feeling of exhaustion, low walking speed, and low physical activity. After a 6-y follow-up, higher adherence (score ≥6) to a Mediterranean-style diet was associated with lower odds of developing frailty [OR = 0.30 (95% CI: 0.14, 0.66)] compared with those with lower adherence (score ≤3). A higher adherence to a Mediterranean-style diet at baseline was also associated with a lower risk of low physical activity (OR = 0.62; 95% CI: 0.40, 0.96) and low walking speed [OR = 0.48 (95% CI: 0.27, 0.86)] but not with feelings of exhaustion and poor muscle strength. In community-dwelling older adults, higher adherence to a Mediterranean-style diet was inversely associated with the development of frailty.

Background: Several formulas are available to estimate glomerular filtration rate (GFR) at the bedside. A decrease in GFR has been associated with poorer performance. We hypothesized that it is related to worsening disability as well. The aim of this study was to evaluate whether the Modification of Diet in Renal Disease formulas can predict worsening disability better than the classic Cockcroft-Gault formula or the measured creatinine clearance., Methods: We studied 666 participants in the InCHIANTI study with 6 years of follow-up data. We evaluated whether directly measured creatinine clearance and GFR estimated using the Modification of Diet in Renal Disease and Cockcroft-Gault formulas predict new disability defined as the loss of ≥ 1 ADL over the 6-year follow-up., Results: The mean age was 73.1 years (SD: 6.1), 57.7% were women. Fewer than 5% of participants were disabled at baseline. Eighty-one (12.2%) participants experienced a decline in activities of daily life score at follow-up. Declining GFR was associated with increasing risk of worsening disability (Mantel-Haenszel P < .001), with an increased steepness in the curve at GFR below 60 mL/min. The relative risks for worsening disability in people with GFR less than 60 mL/min/m were 3.19 (95% CI: 2.12-4.79) and 4.40 (95% CI: 2.80-6.94) using the Modification of Diet in Renal Disease and the Cockcroft-Gault equations, respectively. The corresponding figures obtained with measured creatinine clearance was 3.95 (95% CI: 2.60-6.01). After adjustment for potential confounders, however, these estimates were substantially reduced., Conclusion: Estimation of renal function with the Cockcroft-Gault or Modification of Diet in Renal Disease formulas can help to identify elderly at risk of worsening disability. The mechanism by which reduced kidney function predicts disability should be further investigated., Competing Interests: The authors report no conflicts of interest., (Copyright © 2012 American Medical Directors Association. All rights reserved.)

Human longevity and healthy aging show moderate heritability (20%-50%). We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10(-8)). We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p < 10(-5)). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Polyphenols have beneficial effects on several chronic diseases but assessing polyphenols intake from self-reported dietary questionnaires tends to be inaccurate and not very reliable. A promising alternative is to use urinary excretion of polyphenols as a proxy measure of intake. The best method to assess urinary excretion is to collect 24-h urine. However, since collecting 24-h urine method is expensive, time consuming and may be difficult to implement in large population-based studies, measures obtained from spot urine normalized by creatinine are commonly used. The purpose of the study was to evaluate the correlation between polyphenols dietary intake and total urinary polyphenol excretion (TPE), expressed by both 24-h volume and urinary creatinine normalization in 928 participants from the InCHIANTI study. Dietary intake data were collected using a validated food frequency questionnaire. Urinary TPE was analyzed by Folin-Ciocalteau assay. Both urinary TPE expression models were statistically correlated (r=0.580), and the partial correlation coefficient improved (pr=0.722) after adjusting for the variables that modify the urinary creatinine excretion (i.e. gender, age, BMI, physical activity and renal function). In crude models, polyphenol intake was associated with TPE corrected by 24-h volume (r=0.211; P<0.001), but not with creatinine normalization (r=0.014; P=0.692). However, urinary TPE expressed by creatinine correction was significantly correlated with dietary polyphenols after adjusting for covariates (pr=0.113; P=0.002). We conclude that urinary TPE expressed by 24-h volume is a better biomarker of polyphenol dietary intake than by urinary creatinine normalization. After covariate adjustment, both can be used for studying the relationships between polyphenol intake and health in large-scale epidemiological studies., Competing Interests: The authors are not aware of any conflict of interest., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Aim: Previous studies have shown that increased levels of C-reactive protein (CRP) predict cardiovascular events, including stroke, myocardial infarction and death from cardiovascular causes. Previous studies have also shown that increased levels of CRP are strong predictors of the progression of pre-existing carotid artery plaques. However, whether CRP is involved in the development of new plaques, that may or may not be associated with clinical events, in subjects with clean carotid arteries has been scarcely investigated., Methods and Results: 486 "InCHIANTI" Study participants (200 men and 286 women, 72% aged 65 years and over) free from carotid artery plaques at baseline, also underwent carotid artery scan three years later. We tested the association of baseline characteristics, cardiovascular risk factors and inflammatory markers with the development of new carotid artery plaques. Older participants were significantly more likely to develop new plaques. Independent of age, the relative risks of developing new plaques associated with heavy smoking and family history of atherosclerosis were 1.7 (95%CI 1.5-1.9) and 1.9 (95%CI 1.2-3.1), respectively. Participants with high (>3 μg/mL) and moderate (≥1 and ≤3 μg/mL) CRP levels had a relative risk of 2.2 (95%CI 1.9-2.6) and 1.9 (95%CI 1.6-2.3) respectively, when compared with subjects with low (<1 μg/mL) CRP levels. Surprisingly, risk factors such as hypertension, diabetes, dyslipidemia and overweight/obesity were not significant predictors of the development of new carotid artery plaques., Conclusions: High CRP levels independently predict the development of new plaques in older persons with carotid arteries free from atherosclerotic lesions., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women., Methods: Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up., Results: In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p=0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N=321), (lowest versus highest quartile: HR 3.1; 95% CI 1.5-6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest., Conclusions: In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: Increased interleukin-6 plasma levels have been reported in metabolic syndrome (MS); nevertheless, it is unclear whether interleukin-6 activity is exerted through direct signalling only or also through the "trans-signalling". This issue is important to clarify since signalling and "trans-signalling" affect different tissues. We investigated the relationship between MS and the interleukin-6 system in an older population., Methods: Data from 997 older community dwelling individuals (age ≥ 65 years; females: 56.2%) enrolled the InChianti study were analysed. Interleukin-6, soluble interleukin-6 receptor (sIL-6r), and soluble glycoprotein 130 (sgp130) were measured on plasma by ELISA. MS was defined by the NCEP ATP III criteria; 309 individuals (31%) resulted affected by MS., Results: Subjects with MS had higher interleukin-6 and sgp130 levels compared to controls; a trend toward higher levels of sIL-6R was also observed. The risk of having MS was increased in individuals with high sIL-6r or/and sgp130 levels, independent of age, gender, and interleukin-6 levels. Elevated sgp130 levels were associated with higher plasma glucose, HOMA, triglycerides, and with diabetes both in subjects with and without MS. Although the risk of high sgp130 levels was generally associated with MS (O.R.: 1.77, 95%C.I.: 1.39-2.25), this excess of risk was not present in MS phenotypes excluding the criteria "elevated glucose" or "elevated triglycerides". Furthermore, the association between sgp130 and MS disappeared after adjustment for HOMA., Conclusions: We found that older individuals with MS have increased sgp130 plasma levels compared with controls; nevertheless, our data suggest that this association might be mediated by insulin resistance., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background & Aims: Insulin-like growth factor (IGF-1) stimulates cell proliferation and inhibits cell apoptosis. Recent studies underline its importance as anabolic hormone and nutritional marker in older individuals. IGF-1 synthesis and bioactivity are modulated by nutritional factors including selenium intake. However, whether circulating IGF-1 levels are positively influenced by plasma selenium, one of the most important human antioxidants, is still unknown., Methods: Selenium and total IGF-1 were measured in 951 men and women ≥ 65 years from the InCHIANTI study, Tuscany, Italy., Results: Means (SD) of plasma selenium and total IGF-1 were 0.95 (0.15) μmol/L and 113.4 (31.2)ng/mL, respectively. After adjustment for age and sex, selenium levels were positively associated with total IGF-1 (β±SE: 43.76±11.2, p=0.0001). After further adjustment for total energy and alcohol intake, serum alanine aminotransferase (ALT), congestive heart failure, selenium remained significantly associated with IGF-1 (β±SE: 36.7±12.2, p=0.003). The association was still significant when IL-6 was introduced in the model (β±SE: 40.1±12.0, p=0.0008)., Conclusions: We found an independent, positive and significant association between selenium and IGF-1 serum levels in community dwelling older adults., (Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

In patients with overt inflammatory diseases, up-regulated hepcidin impairs iron absorption and macrophage release, causing anemia. Whether the mild proinflammatory state of aging is associated with increased hepcidin is unknown. We characterized the relationships between urinary hepcidin, iron status, anemia, and inflammation in 582 patients 65 years or older participating in the InCHIANTI (Invecchiare in Chianti, "Aging in the Chianti Area") study, a population-based study of aging in Tuscany, Italy. Compared with nonanemic persons, urinary hepcidin (nanograms/milligram of urinary creatinine) was significantly lower in iron deficiency and inflammation anemia compared with no anemia or other anemia types. Urinary hepcidin was positively correlated with log(ferritin) and negatively correlated with the soluble transferrin receptor/log(ferritin) ratio but not correlated with markers of inflammation: interleukin-6 (IL-6), IL-1beta, tumor necrosis factor-alpha, and C-reactive protein (CRP). Lower iron was significantly correlated with higher IL-6 and CRP. Adjusting for confounders, IL-6 and CRP remained significantly associated with serum iron, with no evidence that such a relationship was accounted for by variability in urinary hepcidin. In conclusion, elevated proinflammatory markers were associated with anemia and low iron status, but not with higher urinary hepcidin. Future studies should test whether hepcidin production becomes up-regulated only in situations of overt inflammation.

Objective: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women., Methods: We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 x 10(-4) for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin., Results: The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3 x 10(-24)) as well as in both women- and men-specific analyses (p=8.7 x 10(-17) and p=2.5 x 10(-11), respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01)., Conclusions: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

To investigate genetic variants that affect iron concentrations in persons not affected by overt genetic disorders of iron metabolism, a genome-wide association study was conducted in the InCHIANTI Study (N = 1206) and the Baltimore Longitudinal Study of Aging (N = 713). The top 2 single-nucleotide polymorphisms were examined for replication in the Women's Health and Aging Study (WHAS) I and II (N = 569). The single-nucleotide polymorphism most strongly associated with lower serum iron concentration was rs4820268 (P = 5.12 x 10(-9)), located in exon 13 of the transmembrane protease serine 6 (TMPRSS6) gene, an enzyme that promotes iron absorption and recycling by inhibiting hepcidin antimicrobial peptide transcription. The allele associated with lower iron concentrations was also associated with lower hemoglobin levels, smaller red cells, and more variability in red cell size (high red blood cell distribution width). Our results confirm the association of TMPRSS6 variants with iron level and provide further evidence of association with other anemia-related phenotypes.

Background: We test the hypothesis that in older persons higher plasma levels of inflammatory markers predict the development of depressive symptoms during a 6-year follow-up., Method: This study is part of the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study, a prospective population-based study of older persons. The sample consisted of 991 participants, ages 65 years and older. Serum levels of C-reactive protein, interleukin (IL)-1beta, IL-1 receptor antagonist (ra), tumor necrosis factor-alpha, IL-6, IL-6 receptor, and IL-18 were measured. Depressive symptoms were assessed at baseline and at the 3- and 6-year follow-ups with the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D > 20. Potential confounders were baseline variables related to sociodemographic, somatic health, and functional status., Results: At baseline, IL-1ra levels were significantly higher (p = .004) in depressed compared with nondepressed participants. After adjustment for confounders, among subjects free of depression at baseline, those in the third and fourth IL-1ra quartiles compared with those in the lowest quartile had, respectively, a 2.32-fold (95% confidence interval: 1.21-4.42, p = .01) and 2.78-fold (95% confidence interval: 1.47-5.26, p = .002) higher risk of developing depressed mood during a 6-year follow-up., Conclusions: In old age, persons with high plasma levels of IL1-ra had a higher risk of developing depressive symptoms over time. These findings suggest a potential causal role for inflammation in the development of depressive symptoms in older persons.

Metabolic syndrome (MS) and "low grade" systemic inflammation (LGSI) are very common findings in the older population. Although MS and LGSI have been associated in adults, it is not known what is the real contribution of MS, and its single components, to LGSI in older persons, due to the potential confounding effect of comorbidity and aging. We investigated the relationship between increased C-reactive protein (CRP) plasma levels, a marker of LGSI, and MS in 1044 older (> or =65 years) community dwelling Italian individuals enrolled the InChianti study. Metabolic syndrome was defined by the NCEP-ATP III-AHA/NHLBI criteria. High sensitivity CRP (hs.CRP) levels were measured by enzyme-linked immunosorbent assay, and defined as high when >3mg/L. The overall prevalence of MS was 31%. The prevalence of high hs.CRP was 54.5% in subjects with, and 41.3% in those without MS (p<0.001). MS was associated with high hs.CRP levels after adjustment for age, gender, and comorbidity (OR: 1.93, 95% CI: 1.46-2.55). Compared to subjects with MS and no LGSI, individuals with MS and LGSI were characterized by higher waist circumference, BMI, and HOMA score. Multivariate logistic regression analysis confirmed the association between waist circumference and high hs.CRP levels in subjects with MS (waist circumference III vs. I tertile OR: 2.60, 95% CI: 1.79-3.77) independent of age, gender, and important confounding variables including comorbidity. Additional analyses, conducted with and without dichotomization of hs.CRP levels, confirmed the central role of waist circumference in the LGSI phenomenon, independent of gender and diagnosis of MS. We conclude that in older individuals, MS is associated with LGSI, but the association is mainly supported by a strong independent correlation between waist circumference and high hs.CRP levels. In the absence of this specific MS component, it seems that the contribution of MS to LGSI would be modest at best.

Background: Although selenium plays an important role in muscle function, the relation between circulating selenium and muscle strength in elderly adults has not been characterized., Objective: The objective was to examine the hypothesis that low plasma selenium is associated with poor muscle strength in older adults., Design: We measured plasma selenium and hip, grip, and knee strength in a cross-sectional study of 891 men and women aged >or=65 y from the Invecchiare in Chianti (InCHIANTI) Study, a population-based cohort study in Tuscany (Italy). Poor muscle strength was defined as the lowest quartile of hip flexion, grip, and knee extension strength., Results: Overall, mean (+/-SD) plasma selenium was 0.95 +/- 0.15 mumol/L. After adjustment for age, sex, education, total energy intake, body mass index, and chronic disease, participants in the lowest versus the highest quartile of plasma selenium were at higher risk of poor hip strength [odds ratio (OR): 1.69; 95% CI: 1.02, 2.83; P = 0.04, P for linear trend = 0.04], knee strength (OR: 1.94; 95% CI: 1.18, 3.19; P = 0.009, P for linear trend = 0.01), and grip strength (OR: 1.94; 95% CI: 1.19, 3.16; P = 0.008, P for linear trend = 0.08)., Conclusions: Low plasma selenium is independently associated with poor skeletal muscle strength in community-dwelling older adults in Tuscany.

Objective: Although depression has been associated with hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis, recent studies among depressed elderly have found decreased cortisol levels, which may be due to underlying physical frailty associated with HPA-axis hypoactivity. The authors examined the relationship between urinary cortisol level and late-life depressive symptoms. The authors also explored whether hypo- and hypercortisolemic depressive symptoms are qualitatively different., Methods: Data are from 881 community-dwelling participants, average age 74.2 years, of the Aging in the Chianti Area Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) scale and cortisol levels were determined in 24-hour urine samples., Results: Mean urinary cortisol level was 98.9 microg/24 hours (SD=47.8), and 31% of the sample had significant depressive symptoms (CES-D > or =16). There was no linear association between urinary cortisol level and depressive symptoms; however, there was a nonlinear association between urinary cortisol level and depressive symptoms. Older persons in the lowest and highest urinary cortisol deciles were 2.2 and 1.9 times more likely to have significant depressive symptoms than older persons in all other deciles. Depressed persons with low cortisol presented more physical frailty than depressed persons with high cortisol., Conclusion: Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the HPA axis, which suggests distinct mechanisms for these associations.

Background: Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased incidence of coronary heart disease (CHD). A better understanding of the mechanisms leading to low HDL-C and CHD is essential for planning treatment strategies. Clinical studies have demonstrated that cytokines might affect both concentration and composition of plasma lipoproteins, including HDLs., Methods: We investigated the possible association between low HDL-C levels, defined as < or =10th gender specific percentile, and circulating markers of inflammation (IL-1beta, TNF-alpha, IL-6, IL-10, IL-18, and CRP) in a population of 1044 community dwelling older Italian subjects from the InChianti study., Results: Using logistic regression analysis we demonstrated that IL-6 levels (III versus I tertile, OR: 2.10; 1.10-3.75), TG (III versus I tertile OR: 27.45; 8.47-88.93), fasting insulin (III versus I tertile OR: 2.84; 1.50-5.42), and age (OR: 1.038; 1.002-1.075) were associated with low HDL-C independent of smoking, BMI, waist circumference, hypertension, diabetes, physical activity, alcohol intake, oral hypoglycaemics, CRP, IL-18, and TNF-alpha levels. The adjusted attributable risk of low HDL-C in the exposed group (III tertile of IL-6) was 54%., Conclusions: The present study provides the epidemiological evidence that besides triglycerides, fasting insulin, and age, IL-6 is one of the main correlates of low HDL-C levels in older individuals.

Using data from InCHIANTI, a prospective population-based survey of older persons, we examined the relationship of peroneal nerve conduction velocity (NCV, a measure of nerve myelination) and compound muscle action potential (CMAP, a measure of axonal degeneration) with calf muscle mass and density, two complementary measures of sarcopenia. NCV and CMAP were assessed by surface electroneurography of the right peroneal nerve conducted in 1162 participants, 515 men and 647 women, age 21-96 years, free of major neurological diseases. Cross-sectional muscle area and calf muscle density were measured using peripheral quantitative computerized tomography (pQCT). Both nerve and muscle parameters declined with age although in most cases the decline was not linear. In both sexes, CMAP, but not NCV, was independently and significantly associated with calf muscle density. These findings suggest that intrinsic changes in the muscle tissue are partially caused by a reduction in the number of motor axons.

Background: The role of magnesium in maintaining muscle integrity and function in older adults is largely unknown., Objective: We aimed to investigate the relation between serum magnesium concentrations and muscle performance in older subjects., Design: Data are from the baseline examination conducted between September 1998 and March 2000 of the InCHIANTI (aging in the Chianti area) study, a prospective epidemiologic survey of risk factors for late-life disability. From among 1453 randomly selected community residents completing a home interview, 1138 men (46%) and women (aged 66.7 +/- 15.2 y; x +/- SD) with complete data on muscle performance and serum magnesium who were not severely cognitively compromised and had no evidence of kidney disease or hypercalcemia were included in the analysis. Muscle performance was evaluated by grip strength, lower-leg muscle power, knee extension torque, and ankle extension isometric strength and was normalized for age and body mass index (BMI) within each sex., Results: After adjustment for age, sex, BMI, laboratory variables, presence of chronic diseases, muscle area, muscle density, and physical activity level, serum magnesium concentrations were significantly associated with indexes of muscle performance, including grip strength (beta = 2.0 +/- 0.5, P = 0.0002), lower-leg muscle power (beta = 8.8 +/- 2.7, P = 0.001), knee extension torque (beta = 31.2 +/- 7.9, P < 0.0001), and ankle extension strength (beta = 3.8 +/- 0.5, P < 0.0001)., Conclusions: The serum magnesium concentration is an independent correlate of muscle performance in older persons. Whether magnesium supplementation improves muscle function remains to be shown.

Background: Frailty is a common condition in elders and identifies a state of vulnerability for adverse health outcomes., Objective: Our objective was to provide a biological face validity to the well-established definition of frailty proposed by Fried et al., Design: Data are from the baseline evaluation of 923 participants aged > or =65 y enrolled in the Invecchiare in Chianti study. Frailty was defined by the presence of > or =3 of the following criteria: weight loss, exhaustion, low walking speed, low hand grip strength, and physical inactivity. Muscle density and the ratios of muscle area and fat area to total calf area were measured by using a peripheral quantitative computerized tomography (pQCT) scan. Analyses of covariance and logistic regressions were performed to evaluate the relations between frailty and pQCT measures., Results: The mean age (+/-SD) of the study sample was 74.8 +/- 6.8 y, and 81 participants (8.8%) had > or =3 frailty criteria. Participants with no frailty criteria had significantly higher muscle density (71.1 mg/cm(3), SE = 0.2) and muscle area (71.2%, SE = 0.4) than did frail participants (69.8 mg/cm(3), SE = 0.4; and 68.7%, SE = 1.1, respectively). Fat area was significantly higher in frail participants (22.0%, SE = 0.9) than in participants with no frailty criteria (20.3%, SE = 0.4). Physical inactivity and low walking speed were the frailty criteria that showed the strongest associations with pQCT measures., Conclusion: Frail subjects, identified by an easy and inexpensive frailty score, have lower muscle density and muscle mass and higher fat mass than do nonfrail persons.

Background: Little is known about the relationship between dietary patterns and peripheral arterial disease (PAD). Our aim was to estimate the association between nutrient intake and diagnosis of PAD., Methods and Results: We assessed the nutrient intake of 1251 home-dwelling subjects enrolled in the InCHIANTI study, mean age 68 years (S.D.: 15). We explored the relationship between nutrient intake, obtained through the European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaire, and PAD, defined as an ankle-brachial index (ABI)<0.90. After adjustment for potential confounders, we found a reduction of the risk of having an ABI<0.90 associated with vegetable lipid intake>or=34.4 g/day (OR: 0.39; 95% CI: 0.16-0.97), Vitamin E intake>or=7.726 mg/day (OR: 0.37; 95% CI 0.16-0.84) and higher serum HDL cholesterol concentration (OR: 0.76; 95% CI: 0.63-0.92 for 10mg/dl increase). Age (OR: 1.11; 95% CI 1.07-1.14 for 1 year increase), smoking (OR: 1.03; 95% CI: 1.01-1.04 for 10 packs/year increase) and pulse pressure (OR: 1.11; 95% CI: 1.03-1.19 for 5 mmHg increase) were associated with an increased risk of PAD., Conclusions: A higher intake of vegetable lipids, Vitamin E and higher concentrations of serum HDL cholesterol characterize subjects free from PAD. Prospective studies are needed to verify whether this dietary pattern and/or interventions aimed at increasing HDL cholesterol exert some protective effect against PAD.

Background: The mechanism by which high circulating homocysteine concentrations are a risk factor for atherothrombosis is incompletely understood. A proinflammatory state is related to atherosclerosis, and recent studies suggest that acute phase reactants correlate with circulating concentrations of homocysteine., Objective: We determined whether high concentrations of inflammatory markers are associated with hyperhomocysteinemia independently of dietary vitamin intakes, vitamin concentrations, and cardiovascular disease risk factors in a large, representative sample of the general population., Design: Five hundred eighty-six men and 734 women were randomly selected from the inhabitants of 2 small towns near Florence, Italy., Results: After adjustment for multiple potential confounders, interleukin 1 receptor antagonist (IL-1ra) and interleukin 6 (IL-6) concentrations were significantly (P < 0.001) associated with plasma homocysteine concentrations in older (>65 y) populations. Compared with participants in the lowest IL-6 tertile, those in the highest tertile had a higher risk of having homocysteine concentrations that were high (>30 micromol/L; odds ratio: 2.6; 95% CI: 1.1, 5.6; P = 0.024) or in the intermediate range 15-30 micromol/L (odds ratio: 1.6; 95% CI: 1.2, 2.2; P = 0.0014). Sedentary state, intakes of vitamin B-6 and folic acid, and serum folate, vitamin B-12, vitamin B-6, and alpha-tocopherol concentrations were significant independent correlates of homocysteine., Conclusions: High circulating concentrations of IL-1ra and IL-6 are independent correlates of hyperhomocysteinemia and may explain, at least in part, the association between homocysteine and atherosclerosis.