The relationship between plasma carotenoids and depressive symptoms in older persons.

OBJECTIVE: We examined the cross-sectional and longitudinal relationship between plasma carotenoids and depressive symptoms over a 6-year follow-up in older persons. METHODS: This research is part of the InCHIANTI Study, a prospective population-based study of older persons in Tuscany, Italy. The sample for this analysis included 958 women and men aged 65 years and older. Plasma total carotenoids were assessed at baseline. Depressive symptoms were assessed at baseline and at the 3- and 6-year follow-up using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D ≥ 20. RESULTS: At baseline, higher total carotenoids level were associated with lower probability of depressed mood (OR = 0.82, 95%CI = 0.68-0.99, P = 0.04) after adjustment for sociodemographic, health and inflammation. After the exclusion of participants with baseline depressed mood and use of antidepressants, higher total carotenoids level were associated with lower risk of incident depressed mood (OR = 0.72, 95%CI = 0.52-0.99, P = 0.04) at 6-year follow-up, after adjustment for confounders plus baseline CES-D. Inflammatory marker Interleukin-1 receptor antagonist partially mediated this association. CONCLUSIONS: Low plasma concentrations of carotenoids are associated with depressive symptoms and predict the development of new depressive symptoms in older persons. Understanding the mechanism of this association may reveal potential targets for prevention and treatment.

Bisphenol A exposure is associated with in vivo estrogenic gene expression in adults.

BACKGROUND: Bisphenol A (BPA) is a synthetic estrogen commonly used in polycarbonate plastic and resin-lined food and beverage containers. Exposure of animal and cell models to doses of BPA below the recommended tolerable daily intake (TDI) of 50 µg/kg/day have been shown to alter specific estrogen-responsive gene expression, but this has not previously been shown in humans. OBJECTIVE: We investigated associations between BPA exposure and in vivo estrogenic gene expression in humans. METHODS: We studied 96 adult men from the InCHIANTI population study and examined in vivo expression of six estrogen receptor, estrogen-related receptor, and androgen receptor genes in peripheral blood leukocytes. RESULTS: The geometric mean urinary BPA concentration was 3.65 ng/mL [95% confidence interval (CI): 3.13, 4.28], giving an estimated mean excretion of 5.84 µg/day (95% CI: 5.00, 6.85), significantly below the current TDI. In age-adjusted models, there were positive associations between higher BPA concentrations and higher ESR2 [estrogen receptor 2 (ER beta)] expression (unstandardized linear regression coefficient = 0.1804; 95% CI: 0.0388, 0.3221; p = 0.013) and ESRRA (estrogen related receptor alpha) expression (coefficient = 0.1718; 95% CI: 0.0213, 0.3223; p = 0.026): These associations were little changed after adjusting for potential confounders, including obesity, serum lipid concentrations, and white cell subtype percentages. Upper-tertile BPA excretors (urinary BPA > 4.6 ng/mL) had 65% higher mean ESR2 expression than did lower-tertile BPA excretors (0-2.4 ng/mL). CONCLUSIONS: Because activation of nuclear-receptor-mediated pathways by BPA is consistently found in laboratory studies, such activation in humans provides evidence that BPA is likely to function as a xenoestrogen in this sample of adults.

Endogenous secretory receptor for advanced glycation end products is associated with low serum interleukin-1 receptor antagonist and elevated IL-6 in older community-dwelling adults.

BACKGROUND: Advanced glycation end products (AGEs) are thought to cause inflammation through interaction with the receptor for AGEs (RAGE), therefore contributing to adverse aging-related processes. The relationship between AGEs, RAGE, and inflammation has not been well characterized. METHODS: We examined the relationship of plasma endogenous secretory RAGE (esRAGE); carboxymethyl-lysine (CML), a circulating AGE; and inflammatory mediators in 1,298 adults, 20-97 years, who participated in the InCHIANTI study in Tuscany, Italy. Blood levels of esRAGE, CML, interleukin-1 receptor antagonist (IL-1RA), IL-1ß, tumor necrosis factor-α (TNF-α), IL-6, IL-6 receptor (IL-6R), IL-18, C-reactive protein (CRP), transforming growth factor-ß (TGF-ß), and fibrinogen were measured. RESULTS: Log plasma esRAGE was associated with log IL-1RA (ß = -0.069, SE = 0.036, p = .05) and log IL-6 (ß = 0.077, SE = 0.035, p = .03), respectively, in separate multivariable linear regression models, adjusting for potential confounders. Log plasma esRAGE was also negatively associated with log TGF-ß but did not reach statistical significance (ß = -0.091, SE = 0.053, p = .09). Log plasma esRAGE was not significantly associated with log IL-1ß, log TNF-α, IL-6R, log IL-18, or CRP. Log plasma CML was not associated with any of the inflammatory mediators except for IL-6R (ß = -14.10, SE = 5.94, p = .02) and fibrinogen (ß = 13.95, SE = 7.21, p = .05) in separate multivariable models, adjusting for potential confounders. CONCLUSIONS: Plasma esRAGE is correlated with higher IL-6 and lower IL-1RA. These findings suggest that plasma esRAGE plays a role in modulating inflammation, although the exact mechanisms remain to be elucidated.

SHBG, sex hormones, and inflammatory markers in older women.

CONTEXT: In premenopausal and older women, high testosterone and estradiol (E2) and low SHBG levels are associated with insulin resistance and diabetes, conditions characterized by low-grade inflammation. OBJECTIVE: The aim of the study was to examine the relationship between SHBG, total testosterone, total E2, and inflammatory markers in older women. DESIGN AND PATIENTS: We conducted a retrospective cross-sectional study of 433 women at least 65 yr old from the InCHIANTI Study, Italy, who were not on hormone replacement therapy or recently hospitalized and who had complete data on SHBG, testosterone, E2, C-reactive protein (CRP), IL-6, soluble IL-6 receptor (sIL-6r), and TNF-α. Relationships between sex hormones and inflammatory markers were examined by multivariate linear regression analyses adjusted for age, body mass index, smoking, insulin, physical activity, and chronic disease. RESULTS: In fully adjusted analyses, SHBG was negatively associated with CRP (P = 0.007), IL-6 (P = 0.008), and sIL-6r (P = 0.02). In addition, testosterone was positively associated with CRP (P = 0.006), IL-6 (P = 0.001), and TNF-α (P = 0.0002). The negative relationship between testosterone and sIL-6r in an age-adjusted model (P = 0.02) was no longer significant in a fully adjusted model (P = 0.12). E2 was positively associated with CRP (P = 0.002) but not with IL-6 in fully adjusted models. In a final model including E2, testosterone, and SHBG, and all the confounders previously considered, SHBG (0.23 ± 0.08; P = 0.006) and E2 (0.21 ± 0.08; P = 0.007), but not testosterone (P = 0.21), were still significantly associated with CRP. CONCLUSION: In late postmenopausal women not on hormone replacement therapy, SHBG and E2 are, respectively, negative and positive, independent and significant correlates of a proinflammatory state.

Mediterranean diet and mobility decline in older persons.

We examined whether adherence to a Mediterranean-style diet has positive effects on mobility assessed over a 9-year follow-up in a representative sample of older adults. This research is part of the InCHIANTI Study, a prospective population-based study of older persons in Tuscany, Italy. The sample for this analysis included 935 women and men aged 65 years and older. Adherence to the Mediterranean diet was assessed at baseline by the standard 10-unit Mediterranean diet score (MDS). Lower extremity function was measured at baseline, and at the 3-, 6- and 9-year follow-up visits using the short physical performance battery (SPPB). At baseline, higher adherence to Mediterranean diet was associated with better lower body performance. Participants with higher adherence experienced less decline in SPPB score, which was of 0.9 points higher (p<.0001) at the 3-year-follow, 1.1 points higher (p=0.0004) at the 6-year follow-up and 0.9 points higher (p=0.04) at the 9-year follow-up compared to those with lower adherence. Among participants free of mobility disability at baseline, those with higher adherence had a lower risk (HR=0.71, 95% CI=0.51-0.98, p=0.04) of developing new mobility disability. High adherence to a Mediterranean-style diet is associated with a slower decline of mobility over time in community-dwelling older persons. If replicated, this observation is highly relevant in terms of public health.

LRP5 gene polymorphism and cortical bone.

BACKGROUND AND AIMS: There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women. METHODS: We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21-94 yrs). Trabecular vBMD (vBMDt, mg/cm3), cortical vBMD (vBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. CONCLUSION: These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women.

Plasma soluble gp130 levels are increased in older subjects with metabolic syndrome. The role of insulin resistance.

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.

Daily bisphenol A excretion and associations with sex hormone concentrations: results from the InCHIANTI adult population study.

BACKGROUND: Bisphenol A (BPA) is a high production volume chemical widely used in packaging for food and beverages. Numerous studies have demonstrated that BPA can alter endocrine function in animals, yet human studies remain limited. OBJECTIVE: We estimated daily excretion of BPA among adults and examined hypothesized associations with serum estrogen and testosterone concentrations. METHODS: We conducted cross-sectional analyses using data from the InCHIANTI Study, a prospective population-based study of Italian adults. Our study included 715 adults between 20 and 74 years old. BPA concentrations were measured by liquid chromatography-mass spectrometry in 24-hr urine samples. The main outcome measures were serum concentrations of total testosterone and 17beta-estradiol. RESULTS: Geometric mean urinary BPA concentration was 3.59 ng/mL [95% confidence interval (CI), 3.42-3.77 ng/mL], and mean excretion was 5.63 microg/day (5th population percentile, 2.1 microg/day; 95th percentile, 16.4 microg/day). We found higher excretion rates among men, younger respondents, and those with increasing waist circumference (p = 0.013) and weight (p = 0.003). Higher daily BPA excretion was associated with higher total testosterone concentrations in men, in models adjusted for age and study site (p = 0.044), and in models additionally adjusted for smoking, measures of obesity, and urinary creatinine concentrations (beta = 0.046; 95% CI, 0.015-0.076; p = 0.004). We found no associations with the other serum measures. We also found no associations with the primary outcomes among women, but we did find an association between BPA and SHBG concentrations in the 60 premenopausal women. CONCLUSION: Higher BPA exposure may be associated with endocrine changes in men. The mechanisms involved in the observed cross-sectional association with total testosterone concentrations need to be clarified.

Frailty and the homeostatic network.

Trajectories of health and functioning with age show extreme variability among different individuals. In frail, older persons the decline in functional reserve is accelerated and compensatory mechanisms start failing, with high risk of homeostasis disruption and consequent negative health outcomes. Frailty is currently conceptualized as an age-related alteration in physiology and pathology that results into a typical constellation of signs and symptoms. Although current attempts to identify frail, older individuals for clinical purposes is based on measures of mobility and motor performance, candidate biological markers that may be specific of the frailty syndrome start to emerge in the literature. Different theories have been drawn to describe the interaction of aging process and loss of ability in performance. One of these hypothesis is based on the progressive dysregulation that occur with age in the homeostatic network and the less efficiency and efficacy in its vital mechanism that allows at all levels integration, from mitochondrial function to societal and community adaptations.

Serum 25-hydroxyvitamin D and depressive symptoms in older women and men.

CONTEXT: Hypovitaminosis D and depressive symptoms are common conditions in older adults. OBJECTIVE: We examined the relationship between 25-hydroxyvitamin D [25(OH)D] and depressive symptoms over a 6-yr follow-up in a sample of older adults. DESIGN AND SETTING: This research is part of a population-based cohort study (InCHIANTI Study) in Tuscany, Italy. PARTICIPANTS: A total of 531 women and 423 men aged 65 yr and older participated. MAIN OUTCOME MEASURE: Serum 25(OH)D was measured at baseline. Depressive symptoms were assessed at baseline and at 3- and 6-yr follow-ups using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D of 16 or higher. Analyses were stratified by sex and adjusted for relevant biomarkers and variables related to sociodemographics, somatic health, and functional status. RESULTS: Women with 25(OH)D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 2.1 (P = 0.02) and 2.2 (P = 0.04) points higher at, respectively, 3- and 6-yr follow-up. Women with low vitamin D (Vit-D) had also significantly higher risk of developing depressive mood over the follow-up (hazard ratio = 2.0; 95% confidence interval = 1.2-3.2; P = 0.005). In parallel models, men with 25(OH)D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 1.9 (P = 0.01) and 1.1 (P = 0.20) points higher at 3- and 6-yr follow-up. Men with low Vit- D tended to have higher risk of developing depressed mood (hazard ratio = 1.6; 95% confidence interval = 0.9-2.8; P = 0.1). CONCLUSION: Our findings suggest that hypovitaminosis D is a risk factor for the development of depressive symptoms in older persons. The strength of the prospective association is higher in women than in men. Understanding the potential causal pathway between Vit- D deficiency and depression requires further research.

Trail Making Test predicts physical impairment and mortality in older persons.

OBJECTIVES: To examine whether performance in the Trail Making Test (TMT) predicts mobility impairment and mortality in older persons. DESIGN: Prospective cohort study. SETTING: Community-dwelling older persons enrolled in the Invecchiare in Chianti (InCHIANTI) Study. PARTICIPANTS: Five hundred eighty-three participants aged 65 and older and free of major cognitive impairment (Mini-Mental State Examination score >21) with baseline data on TMT performance. Of these, 427 performed the Short Physical Performance Battery (SPPB) for the assessment of lower extremity function at baseline and after 6 years. Of the initial 583 participants, 106 died during a 9-year follow-up. MEASUREMENTS: The TMT Parts A and B (TMT-A and TMT-B) and SPPB were administered at baseline and 6-year follow-up. Impaired mobility was defined as an SPPB score less than 10. Vital status was ascertained over a 9-year follow-up. RESULTS: InCHIANTI participants in the fourth quartile of the time to complete TMT-B minus time to complete TMT-A (TMT (B-A)) were significantly more likely to develop an SPPB score less than 10 during the 6-year follow-up than those in the first quartile (relative risk (RR)=2.4, 95% confidence interval (CI)=1.4-3.9, P=.001). After adjusting for potential confounders, these findings were substantially unchanged (RR=2.2, 95% CI=1.4-3.6, P=.001). Worse performance on the TMT was associated with significantly greater decline in SPPB score over the 6-year follow-up, after adjusting for age, sex, and baseline SPPB scores (beta=-0.01, standard error=0.003, P=.004). During the 9-year follow-up, 18.2% of the participants died. After adjustment for age and sex, the proportion of participants who died was higher in participants in the worst than the best performance quartile of TMT (B-A) scores (hazard ratio (HR)=1.7, 95% CI=1.0-2.9, P=.048). Results were similar in a parsimonious adjusted model (HR=1.8, 95% CI=1.0-3.2, P=.04). CONCLUSION: Performance on the TMT is a strong, independent predictor of mobility impairment, accelerated decline in lower extremity function, and death in older adults living in the community. The TMT could be a useful addition to geriatric assessment.

Personal mastery and lower body mobility in community-dwelling older persons: the Invecchiare in Chianti study.

OBJECTIVES: To test the hypothesis that, in older persons, sense of personal mastery, defined as the extent to which one regards one's life chance as being under one's own control, predicts change in lower extremity performance during a 6-year follow-up. DESIGN: Prospective cohort study. SETTING: Community based. PARTICIPANTS: Six hundred twenty-six participants aged 65 and older. MEASUREMENTS: Personal mastery was assessed at baseline using Pearlin's mastery scale. Lower extremity performance was measured at baseline and at 6-year follow-up using the Short Physical Performance Battery (SPPB) of lower extremity function. RESULTS: Higher sense of mastery was associated with a significantly less-steep decline in lower extremity performance. Participants in the two lowest quartiles of personal mastery had, respectively, a 2.6 (95% confidence interval (CI)=1.4-5.1, P=.01) and 3.2 (95% CI=1.6-6.6, P=.002) higher risk of experiencing a substantial decline (> or =3 points) in SPPB scores after 6 years as those in the highest quartile. CONCLUSIONS: Older individuals with poor sense of personal mastery are at high risk of accelerated lower extremity physical function decline. Whether interventions aimed at improving personal mastery may prevent disability remains unknown.

The paraoxonase (PON1) Q192R polymorphism is not associated with poor health status or depression in the ELSA or INCHIANTI studies.

BACKGROUND: The human paraoxonase (PON1) protein detoxifies certain organophosphates, and the PON1 Q192R polymorphism (rs662) affects PON1 activity. Groups with higher dose exposure to organophosphate sheep dips or first Gulf War nerve toxins reported poorer health if they had 192R, and these associations have been used to exemplify Mendelian randomization analysis. However, a reported association of 192R with depression in a population-based study of older women recently cast doubt on the specificity of the higher dose findings. We aimed to examine associations between the PON1 Q192R polymorphism and self-reported poor health and depression in two independent population-based studies. METHODS: We used logistic regression models to examine the associations in men and women aged 60-79 years from the English Longitudinal Study of Ageing (ELSA, n = 3158) and InCHIANTI (n = 761) population studies. Outcomes included the Center for Epidemiologic Studies Depression (CES-D) scale, self-rated general health status and (in ELSA only) diagnoses of depression. RESULTS: The PON1 Q192R polymorphism was not associated with self-reported poor health {meta-analysis: odds ratio (OR) = 1.01 [confidence interval (CI) 0.91-1.13], P = 0.80} or depressive symptoms in either study or in meta-analyses [CES-D: OR = 1.01 (CI 0.87-1.17), P = 0.90]. There was also no association with histories of diagnosed depression in ELSA [OR = 1.03 (CI 0.82-1.30), P = 0.80]. CONCLUSIONS: We found no evidence of an association between the PON1 Q192R polymorphism and poor general or mental health in two independent population-based studies. Neither the claimed Q192R association with depression in the general population nor its theoretical implications were supported.

Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people.

AIMS: There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population. METHODS AND RESULTS: In the InCHIANTI Study of Aging (age >or=65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4-14, n = 594), reduced HDL (5-16, n = 635), and increased triglycerides (7-16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained <2.1% of the variance in their respective lipid concentrations, with the exception of the CETP SNP rs1800775 and HDL levels (4.76%). Combined risk allele counts outperformed the largest single-SNP effects for LDL (explaining 7.1% of variance) and triglycerides (4.8%), but not HDL (3.4%). Risk alleles were divided as near as possible into quartiles. The 31% of respondents with 10 or more LDL increasing alleles were more likely to have LDL levels above the intervention threshold (OR 3.00, 95% CI 1.67-5.39, P = 2.5 x 10(-4)), compared with the 21% with 7 or less risk alleles. Similarly, the 35% with 13 or more triglyceride risk alleles were more likely to exceed NCEP intervention thresholds (OR 2.98, 95% CI 1.43-6.22, P = 0.004) compared with the 24% with 10 or less alleles. The number of individuals reporting an MI event was small (n = 67), but an event was more common in the 36% of respondents who had the highest combined risk allele score for all three lipids (OR 3.68, 95% CI 1.21-11.2, P = 0.021) compared with the lowest risk 22%. CONCLUSION: In a representative older population, the cumulative effects of proven LDL- and triglyceride-altering genetic variants increased the odds of crossing the lipid-level threshold for therapeutic intervention by approximately three-fold.

Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations.

The B vitamins are components of one-carbon metabolism (OCM) that contribute to DNA synthesis and methylation. Homocysteine, a by-product of OCM, has been associated with coronary heart disease, stroke and neurological disease. To investigate genetic factors that affect circulating vitamin B6, vitamin B12, folate and homocysteine, a genome-wide association analysis was conducted in the InCHIANTI (N = 1175), SardiNIA (N = 1115), and BLSA (N = 640) studies. The top loci were replicated in an independent sample of 687 participants in the Progetto Nutrizione study. Polymorphisms in the ALPL gene (rs4654748, p = 8.30 x 10(-18)) were associated with vitamin B6 and FUT2 (rs602662, [corrected] p = 2.83 x 10(-20)) with vitamin B12 serum levels. The association of MTHFR, a gene consistently associated with homocysteine, was confirmed in this meta-analysis. The ALPL gene likely influences the catabolism of vitamin B6 while FUT2 interferes with absorption of vitamin B12. These findings highlight mechanisms that affect vitamin B6, vitamin B12 and homocysteine serum levels.

Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.

Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.

Predictivity of survival according to different equations for estimating renal function in community-dwelling elderly subjects.

BACKGROUND: Detection of subjects with early chronic kidney disease (CKD) is important because some will progress up to stage 5 CKD, and most are at high risk of cardiovascular morbidity and mortality. While validity and precision of estimated glomerular filtration rate (eGFR) equations in tracking true GFR have been repeatedly investigated, their prognostic performance for mortality has not been hitherto compared. This is especially relevant in an elderly population in whom the risk of death is far more common than progression. METHODS: We analysed data of participants in the InCHIANTI study, a community-based cohort study of older adults. Twenty-four-hour creatinine clearance (Ccr), Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD)-derived equations (six and four input variables) were calculated at enrolment (1998-2000), and all-cause mortality and cardiovascular mortality were prospectively ascertained by Cox regression over a 6-year follow-up. RESULTS: Of the 1270 participants, 942 (mean age 75 years) had complete data for this study. The mean renal function ranged from 77 ml/min/1.73 m(2) by Ccr to 64 ml/min/1.73 m(2) by C-G. Comparisons among equations using K/DOQI staging highlight relevant mismatches, with a prevalence of CKD ranging from 22% (MDRD-4) to 40% (C-G). Reduced renal function was a strong independent predictor of death. In a Cox model--adjusted for demographics, physical activity, comorbidities, proteinuria and inflammatory parameters-participants with Ccr 60-90 ml/min/1.73 m(2) and Ccr <60 ml/min/1.73 m(2) were, respectively, 1.70 (95% CI: 1.02-2.83) and 1.91 (95% CI: 1.11-3.29) times more likely to die over the follow-up compared to those with Ccr >90 ml/min/1.73 m(2). For the C-G, the group with values <60 ml/min/1.73 m(2) had a significant higher all-cause mortality compared to those with values >90 ml/min/1.73 m(2) (HR 2.59, 95% CI: 1.13-5.91). The classification based on the MDRD formulae did not provide any significant prognostic information. The adjusted risk of all-cause mortality followed a similar pattern when Ccr and estimating equations were introduced as continuous variables or dichotomized as higher or lower than 60 ml/min. C-G was the best prognostic indicator of cardiovascular mortality. Possibly, Ccr and C-G are better prognostic indicators than MDRD-derived equations because they incorporate a stronger effect of age. CONCLUSIONS: In a South-European elderly population, the prevalence of CKD is high and varies widely according to the method adopted to estimate GFR. Researchers and clinicians who want to capture the prognostic information on mortality related to kidney function should use the Ccr or C-G formula and not MDRD equations. These results highlight the importance of strategies for early detection and clinical management of CKD in elderly subjects.

Interleukin-1 receptor antagonist and incident depressive symptoms over 6 years in older persons: the InCHIANTI study.

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.

Elevated C-reactive protein levels and metabolic syndrome in the elderly: The role of central obesity data from the InChianti study.

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.

Low total plasma carotenoids are independent predictors of mortality among older persons: the InCHIANTI study.

BACKGROUND: Plasma carotenoids are considered a valid biological marker for fruit and vegetable dietary intake. Recent studies show that low carotenoid levels are associated with a high risk of inflammation, cancer, and cardiovascular disease. AIM OF THE STUDY: To determine whether low plasma carotenoids are associated with increased mortality among older adults. METHODS: Longitudinal study among 1,043 adults, 65 years and older, in the InCHIANTI study, a population-based cohort of adults living in the community in the Tuscany region, Italy. RESULTS: Mean total carotenoid concentration was 1.80 micromol/l. During eight years of follow-up, 310 (29.7%) of participants died. Eight-year survival was lower in the lowest compared with the highest tertile of total serum carotenoids (P < 0.0001 by Mantel-Haenszel chi-square). In a multivariate Cox proportional hazards model adjusted for age, education, smoking, body mass index, energy intake, and chronic diseases, adults in the highest tertile of plasma carotenoids at enrollment had lower mortality compared to those in the lowest tertile (Hazards Ratio obtained by considering carotenoids level as an ordinal variable 0.81, 95%; CI 0.65-0.99; P for trend = 0.046). CONCLUSIONS: Low plasma carotenoids are an independent risk factor for mortality among older adults living in the community.