BACKGROUND: Although both vitamin D (25-hydroxyvitamin D [25(OH)D]) insufficiency and the frailty syndrome are more prevalent in women than men, sex-specific associations have not been explored. We estimated sex-specific associations of low 25(OH)D with frailty. Vitamin D insufficiency can result in hyperparathyroidism, and thus, parathyroid hormone (PTH) was explored as a potential mediator in the relationship between 25(OH)D levels and frailty. METHODS: The sample included 444 male and 561 female participants aged 65 years and older from the InCHIANTI study for whom 25(OH)D levels and frailty information were available. Frailty was defined as the presence of at least three of the five following criteria: slowness, weakness, low energy expenditure, exhaustion, and weight loss. Logistic regression models estimated the association between serum levels of 25(OH)D and PTH with frailty, controlling for potential confounders. RESULTS: Independent of covariates, men with 25(OH)D <50 nmol/L had greater odds of frailty than those with 25(OH)D >/=50 nmol/L (odds ratio [OR]= 4.94, 95% confidence interval [CI]= 1.80-13.61). In women, the adjusted OR for frailty (95% CI) was 1.43 (0.58-3.56). The 25(OH)D ORs differed between men and women (p =.041). ORs changed little after controlling for PTH. However, when low energy expenditure was excluded from the frailty definition, adjusted OR for frailty in men (95% CI) was 2.18 (0.59-8.04); controlling for PTH attenuated this OR by 32%. In women, the OR (95% CI) for frailty (low energy expenditure excluded) was 1.54 (0.31-7.58) and was attenuated by 6% after controlling for PTH. CONCLUSIONS: Vitamin D insufficiency was associated with frailty in men, but not in women. RESULT: suggest that PTH mediates the relationship between 25(OH)D and nonenergy expenditure aspects of frailty.

STUDY DESIGN.: Clinicoepidemiologic study in the Chianti area (Tuscany, Italy). OBJECTIVE.: To evaluate whether performance measures of lower extremity function confounds the association of low back pain (LBP) with self-report disability in specific basic and instrumental activities of daily living (IADLs). SUMMARY OF BACKGROUND DATA.: LBP is high prevalent in older population and has a negative impact on functional status. Studies on the pathway leading from LBP to disability are limited and often the role played by important confounders is not considered. METHODS.: A total of 956 InCHIANTI study participants aged 65 and older able to complete performance-based tests of lower extremity function were included in this analysis. LBP was defined as a self-report of back pain "quite often-almost every day" in the past 12 months. Lower extremity function was evaluated administering the Short Physical Performance Battery. In addition, participants were asked to walk on a 7-m course and collect an object from the ground. Depressive symptoms (CES-D score), trunk flexion-extension range of motion, and hip-knee-foot pain were also considered in the pathway from LBP to disability. RESULTS.: Compared with participants who did not report LBP, those with LBP were more likely to report difficulty in performing most activities of daily living. LBP was also associated with disability in the activities of bathing, doing the laundry, performing heavy household chores, cutting toenails, shopping, and carrying a shopping bag. The association between LBP and disability in selected ADLs and IADLs was no longer statistical significant, after adjustment for performance in lower extremity function, with exception of the activity of "carrying a shopping bag". CONCLUSION.: The cross-sectional association between LBP and self-reported disability, in specific tasks is modulated by performance measures. Specific performance-based tests that explore the functional consequences of LBP may help design specific interventions of disability prevention and treatment in patients with LBP.

OBJECTIVES: To investigate the relationship between circulating uric acid (UA) levels and plasma antioxidants and whether antioxidant levels modulate the association between UA and physical function. DESIGN: Cross-sectional. SETTING: Community-based. PARTICIPANTS: Nine hundred sixty-six elderly persons participating in the baseline assessment of the Invecchiare in Chianti Study. MEASUREMENTS: UA, carotenoid, tocopherol, and selenium concentrations were assayed. Physical function was measured using the Short Physical Performance Battery (SPPB) and difficulties in instrumental activities of daily living (IADLs). Potential confounders were assessed using standardized methods. RESULTS: Total carotenoids (P=.008), in particular alpha-carotene (P=.02), lutein (P<.001), zeaxanthin (P<.001), lycopene (P=.07), cryptoxanthin (P=.29), and selenium (P=.04) were inversely associated with UA levels. Total tocopherols (P=.06) and alpha-tocopherol (P=.10) had a positive trend across UA levels. SPPB (P=.01) and IADL disability (P=.002) were nonlinearly distributed across the UA quintiles. Participants within the middle UA quintile (4.8-5.3 mg/dL) were less disabled in IADLs and had better SPPB scores than those in the extreme UA quintiles. There was a significant interaction between UA and selenium in the model predicting SPPB score (P=.02). CONCLUSION: UA levels are inversely associated with circulating carotenoids and selenium. Participants with intermediate UA levels had a higher prevalence of good physical functions, higher SPPB scores, and lower IADL disability. This study suggests that older subjects with intermediate UA levels may have an optimum balance between proinflammatory and antioxidant compounds that may contribute to better physical performance.

Background: The biological action of uric acid (UA) in humans is controversial. UA is considered an antioxidant compound, but preclinical evidence suggests a proinflammatory action. Epidemiological studies found that hyperuricemia is associated with conditions leading to dementia. Our aim is to investigate the relationship between UA levels and dementia in older persons. Methods: Cross-sectional study performed in 1,016 community-dwelling older persons participating in the InCHIANTI study. Participants underwent determination of circulating UA levels and neuropsychological evaluation. A multivariate logistic regression model was used to estimate the probability of participants belonging to the highest and middle UA tertile to be affected by dementia compared to those in the lowest tertile. Results: Demented persons had higher UA levels (p = 0.001) and the prevalence of persons affected by dementia increased across UA tertiles (p < 0.0001). Independent of several confounders, persons belonging to the highest UA tertile had a threefold (OR = 3.32; 95% CI: 1.06-10.42) higher probability to suffer from a dementia syndrome while those in the middle UA tertile tended to have a higher probability of being demented compared to those in the lowest tertile. Conclusion: In a population-based sample, high circulating UA levels are associated with an increased likelihood to be affected by a dementia syndrome.

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.

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.

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

AIMS: We examined the relationship between plasma selenium levels at enrollment and allcause mortality over a 6-year period among participants in the InCHIANTI study. METHODS: 1042 men and women >/=65 years from the InCHIANTI study, a population- based study of older adults living in the Chianti region of Tuscany, a population-based cohort in Tuscany, Italy. Plasma selenium was measured at enrollment (1998-2000), and vital status was ascertained until May 2006. RESULTS: During follow-up, 237 participants (22.7%) died. At enrollment, mean (SD) plasma selenium concentrations among participants who survived or died were 0.96 (0.14) and 0.87 (0.18) mumol/L (p<0.0001), respectively. The proportion of participants who died, from lowest to highest quartile of selenium, was 41.3, 27.0, 18.1 and 13.5%(p<0.0001 by Mantel-Haenszel chi-square). After adjusting for age, sex, education, and chronic diseases, adults in the lowest quartile of plasma selenium at enrollment had higher mortality compared with those in the highest quartile (Hazard Ratio (HR) 1.60, 95% Confidence Interval (CI) 1.04-2.47, p=0.034). CONCLUSION: Low plasma selenium may be an independent predictor of mortality among older adults living in the community.

OBJECTIVES: To examine whether activity restriction specifically induced by fear of falling (FF) contributes to greater risk of disability and decline in physical function. DESIGN: Prospective cohort study. SETTING: Population-based older cohort. PARTICIPANTS: Six hundred seventy-three community-living elderly (>/=65) participants in the Invecchiare in Chianti Study who reported FF. MEASUREMENTS: FF, fear-induced activity restriction, cognition, depressive symptoms, comorbidities, smoking history, and demographic factors were assessed at baseline. Disability in activities of daily living (ADLs) and instrumental activities of daily living (IADLs) and performance on the Short Performance Physical Battery (SPPB) were evaluated at baseline and at the 3-year follow-up. RESULTS: One-quarter (25.5%) of participants did not report any activity restriction, 59.6% reported moderate activity restriction (restriction or avoidance of <3 activities), and 14.9% reported severe activity restriction (restriction or avoidance of >/=3 activities). The severe restriction group reported significantly higher IADL disability and worse SPPB scores than the no restriction and moderate restriction groups. Severe activity restriction was a significant independent predictor of worsening ADL disability and accelerated decline in lower extremity performance on SPPB over the 3-year follow-up. Severe and moderate activity restriction were independent predictors of worsening IADL disability. Results were consistent even after adjusting for multiple potential confounders. CONCLUSION: In an elderly population, activity restriction associated with FF is an independent predictor of decline in physical function. Future intervention studies in geriatric preventive care should directly address risk factors associated with FF and activity restriction to substantiate long-term effects on physical abilities and autonomy of older persons.

BACKGROUND: Recent studies suggest an association between polyunsaturated fatty acids (PUFAs) and the development of chronic kidney disease. The aim of this study was to examine the relationship between PUFAs and renal function in older adults. METHODS: We performed a cross-sectional and prospective analysis of 931 adults,>/=65 years old, enrolled in the InCHIANTI study, a population-based cohort in Tuscany, Italy. Plasma PUFAs were measured at enrollment, and creatinine clearance was estimated by the Cockcroft-Gault equation at baseline and after 3-year follow-up. RESULTS: At enrollment, participants with higher creatinine clearance had higher concentrations of HDL cholesterol, total plasma PUFAs, plasma n-3 fatty acid (FA), and plasma n-6 FA and lower triglycerides. From enrollment to the 3-year follow-up visit, creatinine clearance declined by 7.8 (12.2) mL/min (P <0.0001). Baseline total plasma PUFAs, n-3 FA, n-6 FA, and linoleic, linolenic, and arachidonic acids were strong independent predictors of less steep decline in creatinine clearance from baseline to follow-up (P <0.0001, after adjusting for baseline creatinine clearance). After adjusting for baseline creatinine, baseline total plasma PUFAs, n-3 FA, and linoleic, linolenic, and arachidonic acids were negatively associated with creatinine at 3-year follow-up. Participants with higher plasma PUFAs at enrollment had a lower risk of developing renal insufficiency, defined by a creatinine clearance <60 mL/min, during 3-year follow-up. CONCLUSION: High PUFA concentrations, both n-3 FA and n-6 FA, may attenuate the age-associated decline in renal function among older community-dwelling women and men.

Aging is frequently accompanied by a proinflammatory state with adverse health consequences. This state is commonly assessed by markers in serum, either in isolation or ad hoc combination. We sought, alternatively, to develop scores summarizing multiple markers in accordance with biology on inflammatory regulation and evaluate their value added for discriminating functional outcomes in older adults. Data came from InCHIANTI (Invecchiare in Chianti; Aging in the Chianti Area) study participants age 65 years and older. Serum concentrations of seven inflammatory biomediators were subjected to latent variable analysis implementing a biological model of counterbalancing up- and down-regulation processes. Resulting process constructs were approximated by principal component scores; these, and individual markers, were evaluated as predictors of mobility impairment and frailty status in regression analyses, adjusting for key confounders. The biomediators' interrelationships were well predicted by the hypothesized biology. The up-regulation score was independently associated with worsened mobility functioning and frailty risk. For mobility, the association was stronger than, persisted independently of, and accounted for association with each biomediator. The down regulation score was associated with frailty outcomes. We conclude that systemic inflammation is relevant to the process that leads to functional loss in older persons and can be validly measured through biologically informed summary of inflammatory markers.

OBJECTIVE: The association between low serum 25-hydroxyvitamin D [25(OH)D] concentration and cognitive decline has been investigated by only a few studies, with mixed results. The objective of this cross-sectional population-based study was to examine the association between serum 25(OH)D deficiency and cognitive impairment while taking confounders into account. METHODS: The subjects, 752 women aged >/=75 years from the Epidémiologie de l'Ostéoporose (EPIDOS) cohort, were divided into 2 groups according to serum 25(OH)D concentrations (either deficient,<10 ng/mL, or nondeficient,>/=10 ng/mL). Cognitive impairment was defined as a Pfeiffer Short Portable Mental State Questionnaire (SPMSQ) score <8. Age, body mass index, number of chronic diseases, hypertension, depression, use of psychoactive drugs, education level, regular physical activity, and serum intact parathyroid hormone and calcium were used as potential confounders. RESULTS: Compared with women with serum 25(OH)D concentrations >/=10 ng/mL (n = 623), the women with 25(OH)D deficiency (n = 129) had a lower mean SPMSQ score (p < 0.001) and more often had an SPMSQ score <8 (p = 0.006). There was no significant linear association between serum 25(OH)D concentration and SPMSQ score (beta =-0.003, 95% confidence interval -0.012 to 0.006, p = 0.512). However, serum 25(OH)D deficiency was associated with cognitive impairment (crude odds ratio [OR]= 2.08 with p = 0.007; adjusted OR = 1.99 with p = 0.017 for full model; and adjusted OR = 2.03 with p = 0.012 for stepwise backward model). CONCLUSIONS: 25-Hydroxyvitamin D deficiency was associated with cognitive impairment in this cohort of community-dwelling older women.

This study explores the relationship between chronic intractable back pain and physical self-efficacy and alexithymia in 112 women sampled from a large university-based health center. Fifty-nine women suffering from chronic back pain were compared with 53 control subjects. Results note that women with chronic intractable back pain had significantly higher scores on the measure of alexithymia and lower scores on the measure of physical self-efficacy compared with control subjects. The predictive model was useful in correctly classifying 81.4% of back pain subjects. Perceived self-presentation confidence was protective, and being married and increased age were associated with the risk of having chronic back pain.

OBJECTIVES: To investigate the characteristics of older adults who develop high interleukin-6 (IL-6) levels at 3-year follow-up. DESIGN: Population-based study of adults living in Tuscany, Italy. SETTING: Community. PARTICIPANTS: Adults aged 65 and older and were selected for this study. Of 1,155 baseline participants aged 65 and older, 741 had IL-6 measurements at baseline and 3-year follow-up. MEASUREMENTS: The uppermost quartile of IL-6 was used as the threshold for defining high IL-6 (>/=4.18 pg/mL). Serum IL-6 levels were assessed using enzyme immunoassay. RESULTS: Of the 581 participants with IL-6 levels less than 4.18 pg/mL at baseline, 106 (18.2%) had developed high IL-6 at follow-up. Although women had lower IL-6 levels at baseline than men, the risk of developing high IL-6 did not differ according to sex. High adiposity, defined as a body mass index of 30.0 kg/m(2) or higher (odds ratio (OR)=2.63, 95% confidence interval (CI)=1.40-4.96), and large waist circumference, defined as 102 cm or greater for men and 88 cm or greater for women (OR=2.05, 95% CI=1.24-3.40), were significant predictors of developing high IL-6 at follow-up. Other significant predictors were presence of three or more chronic diseases (OR=3.66, 95% CI=1.54-8.70), higher baseline IL-6 (OR=1.82, 95% CI=1.39-2.38) and higher white blood cell count (OR=1.24, 95% CI=1.06-1.45). Faster walking speed associated with decreased risk of progressing to elevated IL-6 (OR=0.83, 95% CI=0.74-0.92). CONCLUSION: Older age, greater adiposity, slower walking speed, higher disease burden, and higher white blood cell count were associated with greater risk of IL-6 elevation over a 3-year period. Future research should target older adults with these characteristics to prevent progression to a proinflammatory state.

OBJECTIVES: To examine the relationship between functional limitations and pain across a spectrum of age, ranging from mid life to advanced old age. DESIGN: Cross-sectional study. SETTING: The 2004 Health and Retirement Study (HRS), a nationally representative study of community-living persons aged 50 and older. PARTICIPANTS: Eighteen thousand five hundred thirty-one participants in the 2004 HRS. MEASUREMENTS: Participants who reported that they were often troubled by pain that was moderate or severe most of the time were defined as having significant pain. For each of four functional domains, subjects were classified according to their degree of functional limitation: mobility (able to jog 1 mile, able to walk several blocks, able to walk one block, unable to walk one block), stair climbing (able to climb several flights, able to climb one flight, not able to climb a flight), upper extremity tasks (able to do 3, 2, 1, or 0), and activity of daily living (ADL) function (able to do without difficulty, had difficulty but able to do without help, need help). RESULTS: Twenty-four percent of participants had significant pain. Across all four domains, participants with pain had much higher rates of functional limitations than subjects without pain. Participants with pain were similar in terms of their degree of functional limitation to participants 2 to 3 decades older. For example, for mobility, of subjects aged 50 to 59 without pain, 37% were able to jog 1 mile, 91% were able to walk several blocks, and 96% were able to walk one block without difficulty. In contrast, of subjects aged 50 to 59 with pain, 9% were able to jog 1 mile, 50% were able to walk several blocks, and 69% were able to walk one block without difficulty. Subjects aged 50 to 59 with pain were similar in terms of mobility limitations to subjects aged 80 to 89 without pain, of whom 4% were able to jog 1 mile, 55% were able to walk several blocks, and 72% were able to walk one block without difficulty. After adjustment for demographic characteristics, socioeconomic status, comorbid conditions, depression, obesity, and health habits, across all four measures, participants with significant pain were at much higher risk for having functional limitations (adjusted odds ratio (AOR)=2.85, 95% confidence interval (CI)=2.20-3.69, for mobility; AOR=2.84, 95% CI=2.48-3.26, for stair climbing; AOR=3.96, 95% CI=3.43-4.58, for upper extremity tasks; and AOR=4.33; 95% CI=3.71-5.06, for ADL function). CONCLUSION: Subjects with pain develop the functional limitations classically associated with aging at much earlier ages.