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1.  Association of Plasma Selenium Concentrations with Total IGF-1 Among Older Community-Dwelling Adults: the InCHIANTI Study 
Background and 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.
Selenium and total IGF-1 were measured in 951 men and women ≥65 years from the InCHIANTI study, Tuscany, Italy.
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 (ß ± SE: 43.76±11.2, p=0.0001).After further adjustment for total energy and alcohol intake, serum alanine amino transferase (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).
We found an independent, positive and significant association between selenium and IGF-1 serum levels in community dwelling older adults.
PMCID: PMC3963695  PMID: 20416996
aging; total IGF-1; selenium
2.  The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men 
The role of nutritional status as key factor of successful aging is very well recognized. Among the different mechanisms by which nutrients may exert their beneficial effects is the modulation of the hormonal anabolic milieu, which is significantly reduced with aging. Undernutrition and anabolic hormonal deficiency frequently coexist in older individuals determining an increased risk of mobility impairment and other adverse outcomes. Mineral assessment has received attention as an important determinant of physical performance. In particular, there is evidence that magnesium exerts a positive influence on anabolic hormonal status, including Testosterone, in men. In this review we summarize data from observational and intervention studies about the role of magnesium in Testosterone bioactivity and the potential underlying mechanisms of this relationship in male subjects. If larger studies will confirm these pivotal data, the combination of hormonal and mineral replacements might be adopted to prevent or delay the onset of disability in the elderly.
PMCID: PMC3958794  PMID: 24723948
3.  Determinants and clinical significance of plasma oxidized LDLs in older individuals. A 9 years follow-up study 
Atherosclerosis  2012;226(1):201-207.
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±7.4yrs; 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 r2:0.42; 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 r2:0.15, 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.
PMCID: PMC3529836  PMID: 23141584
Oxidized LDL; Mortality; Cardiovascular Disease; Aging
4.  IGF-1, the Cross Road of the Nutritional, Inflammatory and Hormonal Pathways to Frailty 
Nutrients  2013;5(10):4184-4205.
The decline in functional capacity is a heterogeneous phenomenon in the elderly. An accelerated ageing determines a frail status. It results in an increased vulnerability to stressors for decreased physiological reserves. The early identification of a frail status is essential for preventing loss of functional capacity, and its clinical consequences. Frailty and mobility limitation result from an interplay of different pathways including multiple anabolic deficiency, inflammation, oxidative stress, and a poor nutritional status. However, the age-related decline in insulin-like growth factor 1 (IGF-1) bioactivity deserves special attention as it could represent the ideal crossroad of endocrine, inflammatory, and nutritional pathways to frailty. Several minerals, namely magnesium, selenium, and zinc, appear to be important determinants of IGF-1 bioactivity. This review aims to provide an overview of the potential usefulness of nutrients modulating IGF-1 as potential therapeutic targets in the prevention of mobility limitation occurring in frail older subjects.
PMCID: PMC3820068  PMID: 24152751
ageing; IGF-1; selenium; magnesium; zinc; micronutrients; frailty
5.  Arterial Stiffness and Bone Demineralization: The Baltimore Longitudinal Study of Aging 
American journal of hypertension  2011;24(9):970-975.
Arterial stiffening is one of the hallmarks of vascular aging, and is an important risk factor for cardiovascular morbidity and mortality. Aging is also associated with bone demineralization. Accumulating evidence indicate that arterial stiffness and bone demineralization might share common pathways. The aims of this study were to evaluate whether the association between arterial stiffness and bone demineralization is independent of age, and to explore putative mechanisms that may mediate their relationship.
A cross-sectional analysis was performed using data from 321 men (68 ± 12 years) and 312 women (65 ± 13 years) of the Baltimore Longitudinal Study of Aging. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) and cross-sectional cortical bone area (cCSA) was assessed at the level of the mid-tibia with CT imaging.
Age was significantly correlated with PWV in men (r=0.38, p<0.0001) and women (r=0.35, p<0.0001). Age was associated with cCSA in women (r=−0.14, p=0.0008), but not in men. Age-adjusted linear regression analysis showed a significant inverse association between PWV and cCSA, in women but not in men. The association between PWV and cCSA remained significant in women after adjusting for age, mean arterial pressure, obesity, menopause, drugs, alcohol intake, physical activity, renal function, serum calcium, and total estradiol concentration.
Independent of age and other shared risk factors, arterial stiffness is inversely related to cortical bone area in women. The sex-specific signaling and molecular pathways that putatively underlie the cross-talk between central arteries and bone are not completely understood.
PMCID: PMC3435100  PMID: 21544148
Arterial Stiffness; Bone Demineralization; Pulse Wave Velocity; Cortical Bone Area; Aging; Baltimore Longitudinal Study of Aging
6.  Dietary habits in women with recurrent idiopathic calcium nephrolithiasis 
Nutrition has been widely recognized to influence the risk of kidney stone formation. Therefore the aim of our study was to assess: a) whether usual diet of women with idiopathic calcium nephrolithiasis (ICN) living in Parma (Northern-Italy) is different compared to healthy controls, b) how their diet differs from Italian National guidelines and c) whether it is related to nephrolithiasis clinical course.
143 women with recurrent ICN (mean age 43 ± 13 ys) and 170 healthy women (mean age 42 ± 11 ys) were enrolled. All women completed a food frequency questionnaire for the last 60-days and a 3-day dietary diary analysed with a dedicated software.
Stone formers showed a higher consumption of sausages, ham, meat and sweets than healthy controls (43.1% vs 11.1%, 29.4% vs 13.9%, 21.6% vs 4.2%, 66.7% vs 18.1%, p < 0.001). The 3-day diary analysis showed an intake of calories, carbohydrates, lipids and non-discretionary sodium about 10% higher than healthy controls (p < 0.001). Finally, after dividing the population into 3 age groups (≤30, 31-40, > 40 years), the differences described above were amplified in the class ≤30 years, where nephrolithiasis presented a more serious course (shorter recurrence interval, greater stone-rate). In this age group the intake of fruit and vegetables was notably lower than guideline recommendations.
We conclude that the usual diet of women with recurrent ICN is different from controls and characterized by low intake of fruits and vegetables and higher consumption of simple sugars and foods with high protein and salt content. This dietary imbalance could play a role in the ICN pathogenesis, especially in younger women.
This work was financed by grants from Italian Ministry of University and Research as part of a larger project about the prevention of kidney stones (PRIN 2005063822) and by Fondazione per la Ricerca Scientifica Termale (FoRST). No potential conflict of interest relevant to this paper was reported.
PMCID: PMC3337252  PMID: 22453026
Idiopathic calcium nephrolithiasis; Diet; Kidney stones; Food frequency
7.  Gonadal Status and physical performance in older men 
Male aging is characterized by a progressive decline in serum testosterone levels and physical performance. Low testosterone levels may be implicated in the decline of physical performance and consequent mobility disability that occurs with aging. During the recent years many consensus reports have advocated that one of the potential effects of testosterone supplementation is the improvement in mobility. However, to the best of our knowledge no study has fully investigated the relationship between gonadal status and objective measures of physical performance in older men and their determinants.
We evaluated 455 ≥ 65 year old male participants of InCHIANTI study a population based study in two municipalities of Tuscany, Italy with complete data on testosterone levels, hand grip strength, cross-sectional muscle area (CSMA), short physical performance battery (SPPB). Linear models were used to test the relationship between gonadal status and determinants of physical performance.
According to baseline serum levels of total testosterone, three different groups of older men were created: 1) severely hypogonadal (N= 23),total testosterone levels ≤230 ng /dl; 2) moderately hypogonadal (N=88), total testosterone >230 and <350 ng/dL), and 3) eugonadal (N=344), testosterone levels ≥350 ng/dL. With increased severity of hypogonadal status, participants were significantly older while their BMI was substantially similar. In the age and BMI adjusted analysis, there was a significant difference in hemoglobin levels, hand grip strength and SPPB score (p for trend<0.001) among −3 groups, with severely hypogonadal men having lower values of hemoglobin, muscle strength and physical performance. We found no association between testosterone group assignment and calf muscle mass and 4 meter walking speed. In the multivariate analysis grip strength (p for trend=0.004) and haemoglobin (p for trend <0.0001) but not SPPB and other determinants of physical performance were significantly different between the 3 groups.
In older men, gonadal status is independently associated with some determinants (hemoglobin and muscle strength) of physical performance.
PMCID: PMC3142745  PMID: 20937007
testosterone; physical performance; older men
8.  High Dose Isoflavones do not improve Metabolic and Inflammatory Parameters in Androgen Deprived Men with Prostate Cancer 
Journal of andrology  2010;32(1):40-48.
The profound hypogonadism that occurs with androgen-deprivation therapy (ADT) for prostate cancer (PCa) results in complications such as diabetes and metabolic syndrome that predispose to cardiovascular disease. Since phytoestrogens have been associated with an improvement in metabolic parameters, we evaluated their role in men undergoing ADT.
To evaluate the effects of high-dose isoflavones on metabolic and inflammatory parameters in men undergoing ADT.
This was a randomized, double-blind, placebo-controlled, 12-week pilot study. Participants were randomly assigned to receive 20 g of soy protein containing 160 mg of total isoflavones vs taste-matched placebo (20 g whole milk protein). The study was conducted at a tertiary care center in the United States.
Thirty-three men (isoflavones=17, placebo=16) undergoing ADT for PCa completed this pilot study. Mean age in the two groups was 69 years and majority of men were Caucasians. Mean duration of ADT in both groups was approximately 2 years (P=0.70). The two groups were well-matched at baseline. After 12-weeks of intervention, there was no significant difference in either metabolic or inflammatory parameters between the two groups.
High-dose isoflavones over a course of 12-weeks do not improve metabolic or inflammatory parameters in androgen deprived men.
PMCID: PMC3005077  PMID: 20798386
Atherosclerosis  2010;213(1):319-324.
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.
Data from 997 older community dwelling individuals (age ≥ 65 years; females: 56.2%) enrolled the InChianti study were analyzed. 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-ATPIII criteria; 309 individuals (31%) resulted affected by MS.
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.
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.
PMCID: PMC2963692  PMID: 20869059
metabolic syndrome; interleukin-6; sgp130; pathway; trans-signalling
10.  Genetic Determinants of Serum Testosterone Concentrations in Men 
PLoS Genetics  2011;7(10):e1002313.
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
Author Summary
Testosterone is the most important testicular androgen in men. Low serum testosterone concentrations are associated with cardiovascular morbidity, metabolic syndrome, type 2 diabetes mellitus, atherosclerosis, osteoporosis, sarcopenia, and increased mortality risk. Thus, there is growing evidence that serum testosterone is a valuable biomarker of men's overall health status. Studies in male twins indicate that there is a strong heritability of serum testosterone. Here we perform a large-scale genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations. By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.
PMCID: PMC3188559  PMID: 21998597
11.  Adipocytokines and the metabolic syndrome among older persons with and without obesity - the InCHIANTI Study 
Clinical endocrinology  2010;73(1):55-65.
Adipose tissue-derived inflammation may contribute to metabolic alterations and eventually to the metabolic syndrome (MetS). The purpose of this study was to: 1) examine the role of adipocytokines in the association between obesity and the MetS; and 2) to determine whether the association is different in obese and non-obese persons.
Cross-sectional population-based InCHIANTI study.
944 community-dwelling adults aged 65 years and older living in Tuscany, Italy.
Obesity was defined as body mass index ≥ 30 kg/m2 and MetS as ≥ 3 of the ATP-III criteria. Circulating levels of CRP, IL-6, IL-1ra, IL-18, TNF-α R1, adiponectin, resistin, and leptin were measured. Additionally, insulin resistance was determined using the homeostasis model assessment (HOMA-IR).
The prevalence of the MetS was 32%. Both overall and abdominal obesity were significantly associated with the MetS after adjusting for inflammatory cytokines, adipokines and lifestyle factors. After adjusting for multiple confounders and HOMA-IR, IL-1ra, TNF-α R1 and adiponectin (p < 0.05) remained significantly associated with the MetS. Having multiple cytokines in the highest tertile increased the likelihood of having the MetS in both obese (p for trend 0.002) and non-obese persons (p for trend 0.001) independent of insulin resistance.
Non-obese and obese individuals who develop an intense pro-inflammatory state may be more prone to develop the MetS than those with lower levels of inflammation.
PMCID: PMC2888845  PMID: 19878507
adipocytokines; adiponectin; cytokines; inflammation; metabolic syndrome; obesity
12.  Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms 
PLoS Genetics  2011;7(4):e1002025.
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Author Summary
Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date. Here we take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, we show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.
PMCID: PMC3077384  PMID: 21533175
13.  Estradiol and Metabolic Syndrome in Older Italian Men: the InCHIANTI Study 
Journal of andrology  2008;31(2):155-162.
The increasing prevalence of metabolic syndrome (MS) with age in older men has been linked with decreasing testosterone levels. Interestingly, while testosterone levels decline with age, estradiol (E2) levels remain relatively stable resulting in a decreased testosterone/estradiol ratio. Because E2 levels tend to be elevated in morbid obesity, insulin resistance and diabetes, it is reasonable to hypothesize that high E2 levels are associated with MS in older men.
We studied the relationship of total and free E2 with MS after adjustment for multiple confounders including age, BMI, smoking, alcohol consumption, physical activity, interleukin-6 (IL-6), fasting insulin and testosterone.
452 men 65 yr or older (age range 65–96) had complete data on estradiol, testosterone, fasting insulin, sex hormone binding globulin, interleukin-6 (IL-6), and albumin. Concentrations of free estradiol and free testosterone were calculated using the mass action equations. MS was defined according to ATPIII criteria.
Participants with MS had significantly higher serum free and total E2 (p<.001) (p=0.003). After adjusting for confounders, including age, smoking, alcohol consumption, physical activity, log (IL-6), log (insulin), participants with higher log (total E2) (OR: 2.31, 95 % CI 1.39–4.70, p=0.02) and higher log (free E2) (OR: 2.69, 1.38–5.24, p<0.001) had an increased risk of having MS. Log (free E2) (p=0.04) maintained significant correlation with MS even after further adjustment for BMI.
In older men high E2 is independently associated with MS. Whether confirmed in other studies, assessment of E2 should be also considered in older men. Whether changes in this hormonal pattern play a role in the development of MS should be further tested in longitudinal studies.
PMCID: PMC2842460  PMID: 19059904
estradiol; metabolic syndrome; older men
14.  Anabolic and Catabolic Biomarkers As Predictors of Muscle Strength Decline: The InCHIANTI Study 
Rejuvenation Research  2010;13(1):3-11.
Poor muscle strength is a major public health concern in older persons, predisposing to functional limitations, increased fall risk, and higher mortality. Understanding risk factors for muscle strength decline may offer opportunities for prevention and treatment. One of the possible causes of muscle strength decline is imbalance between catabolic and anabolic signaling. This study aims to examine whether high levels of multiple catabolic and low levels of multiple anabolic biomarkers predict accelerated decline of muscle strength.
In a representative sample of 716 men and women aged ≥65 years in the InCHIANTI study we measured C-reactive protein, interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1RA), tumor necrosis factor-α receptor 1 as well as dehydroepiandrosterone sulfate (DHEA-S), insulin-like growth factor-1, and bioavailable testosterone. Biomarker values were divided into tertiles and the numbers of catabolic/anabolic biomarkers in the highest/lowest tertile were calculated. Hand-grip strength was measured at baseline and 3- and 6-year follow up.
In adjusted linear mixed models, higher concentration of IL-6 (p = 0.02) and IL-1RA (p = 0.04) as well as lower levels of DHEA-S (p = 0.01) predicted muscle strength decline. After combining all inflammatory markers, the rate of decline in grip strength was progressively greater with the increasing number of dysregulated catabolic biomarkers (p = 0.01). No effect on accelerated muscle strength decline was seen according to number of dysregulated anabolic hormones.
Having multiple elevated catabolic biomarkers is a better predictor of muscle strength decline than a single biomarker alone, suggesting that a catabolic dysregulation is at the core of the mechanism leading to muscle strength decline with aging.
PMCID: PMC2883504  PMID: 20230273
15.  Relationship Between Higher Estradiol Levels and 9-Year Mortality in Older Women: The Invecchiare in Chianti Study 
To investigate the relationship between total estradiol (E2) levels and 9-year mortality in older postmenopausal women not taking hormone replacement therapy (HRT).
Population-based study of persons living in the Chianti geographic area (Tuscany, Italy).
A representative sample of 509 women aged 65 and older with measures of total E2.
Serum total E2 was measured at the University of Parma using ultrasensitive radioimmunoassay (RIA).
Women who died (n = 135) during 9 years of follow up were older; had higher total E2 levels; and were more likely to have evidence of stroke, hypertension, diabetes mellitus, and congestive heart failure at baseline than survivors. Higher E2 levels were associated with a greater likelihood of death (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 1.01–1.06), and the relationship was independent of age, waist:hip ratio, C-reactive protein, education, cognitive function, physical activity, caloric intake, smoking, and chronic disease (HR = 1.08 pg/mL, 95% CI = 1.03–1.13, P = .003). The excessive risk of death associated with higher total E2 was not attenuated after adjustment for total testosterone (HR = 1.12, 95% CI = 1.02–1.18, P<.001) and after further adjustment for insulin resistance evaluated using the homeostasis model assessment (HR = 1.07, 95% CI = 1.03–1.17, P<.001).
Total E2 was highly predictive of death after more than 5 years (HR = 1.42: CI 1.01–1.91, P = .04) and not predictive of death for less than 5 years (P = .78).
Higher total E2 concentration predicts mortality in older women not taking HRT.
PMCID: PMC2798148  PMID: 19737330
estradiol; older postmenopausal women; mortality
16.  Elevated C-reactive protein levels and metabolic syndrome in the elderly 
Atherosclerosis  2008;203(2):626-632.
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 (≥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 >3 mg/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.
PMCID: PMC2710530  PMID: 18845301
Metabolic syndrome; C-reactive protein; Systemic inflammation; Waist circumference; Elderly
17.  Uric Acid and Dementia in Community-Dwelling Older Persons 
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.
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.
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.
In a population-based sample, high circulating UA levels are associated with an increased likelihood to be affected by a dementia syndrome.
PMCID: PMC2820317  PMID: 19339776
Uric acid; Risk; Dementia; Inflammation; Aging
18.  Plasma Polyunsaturated Fatty Acids and Age-Related Physical Performance Decline 
Rejuvenation research  2009;12(1):25-32.
Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998–2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001–2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score ≤9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n−3 PUFA, and n−6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n−3 PUFA (β = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (β = −0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB ≤9). In fully adjusted logistic models, baseline n−3 PUFA levels were inversely related to the risk of developing a decline in SPPB to ≤9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08–0.53), while the n−6/n−3 ratio was associated with a higher risk of SPPB decline to ≤9 (OR = 5.23; 95% CI = 2.02–13.51). In multivariate regression models, the n−6/n−3 ratio was associated with a longer time to walk 7 m (β = 0.396, p = 0.037). n−3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n−6/n−3 ratio was associated with higher risk of developing poor physical performance and slower walking speed.
PMCID: PMC2674224  PMID: 19196012
19.  Plasma Polyunsaturated Fatty Acids and Age-Related Physical Performance Decline 
Rejuvenation Research  2009;12(1):25-32.
Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998–2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001–2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score ≤9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n-3 PUFA, and n-6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n-3 PUFA (β = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (β = −0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB ≤9). In fully adjusted logistic models, baseline n-3 PUFA levels were inversely related to the risk of developing a decline in SPPB to ≤9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08–0.53), while the n-6/n-3 ratio was associated with a higher risk of SPPB decline to ≤9 (OR = 5.23; 95% CI = 2.02–13.51). In multivariate regression models, the n-6/n-3 ratio was associated with a longer time to walk 7 m (β = 0.396, p = 0.037). n-3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n-6/n-3 ratio was associated with higher risk of developing poor physical performance and slower walking speed.
PMCID: PMC2674224  PMID: 19196012
20.  Thyroid Function Abnormalities and Cognitive Impairment in the Elderly. Results of the InCHIANTI Study 
To investigate thyroid function testing abnormalities in older persons and to explore the relationship between thyroid dysfunction and cognition.
Cross-sectional study
1171 men and women aged 23-102 yrs
Thyroid function was evaluated by measuring plasma concentrations of thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Cognition was evaluated by the Mini Mental State Examination (MMSE).
Prevalence of overt and subclinical thyroid dysfunction was evaluated in different age groups (<65 versus ≥65 years). Age trends in TSH, FT4, and FT3 were examined in euthyroid participants. The cross-sectional association of thyroid dysfunction with MMSE score was evaluated adjusting for confounders.
Both subclinical hypothyroidism and subclinical hyperthyroidism were more prevalent in older than in younger participants (Subclinical hypothyroidism, 0.4 % vs 3.5 % in younger vs older participants, respectively, P<.03 Subclinical hyperthyroidism, 1.9 % vs 7.8 % in younger vs older participants, respectively, P<.002). In euthyroid participants TSH and FT3 declined with age while FT4 increased. Old participants with subclinical hyperthyroidism had a lower MMSE score than euthyroid subjects (22.61 ± 6.88 vs 24.72 ± 4.52, P<.03). In adjusted analyses, participants with subclinical hyperthyroidism were significantly more likely to have cognitive dysfunction (HR: 2.26, P= .003).
Subtle age-related changes in FT3, FT4 and TSH occur in individuals who remain euthyroid. Subclinical hyperthyroidism is the most prevalent thyroid dysfunction in Italian older persons and is associated with cognitive impairment.
PMCID: PMC2631617  PMID: 19054181
Thyroid function; Aging; Cognition
21.  Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes 
Human Molecular Genetics  2009;19(3):535-544.
Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 × 10−5], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
PMCID: PMC2798726  PMID: 19933169
22.  Effects of High-Dose Isoflavones on Metabolic and Inflammatory Markers in Healthy Postmenopausal Women 
Menopause (New York, N.Y.)  2009;16(2):395-400.
After menopause, women experience changes in body composition, especially increase in fat mass. Additionally, advancing age, decreased physical activity and increased inflammation may predispose them to develop type-2 diabetes. Isoflavones have been shown to improve metabolic parameters in postmenopausal women. However, the effect of isoflavones on adipo-cytokines remains unclear.
To evaluate the effect of high dose isoflavones on inflammatory and metabolic markers in postmenopausal women.
Study Design
We measured glucose, insulin and adipokines/cytokines in 75 healthy postmenopausal women who were randomized to receive 20 gm of soy protein with 160 mg of total isoflavones (64mg genistein, 63 mg diadzein, 34 mg glycitein) or 20 gm of soy protein placebo for 12 weeks. Women on estrogen discontinued therapy at least three months prior to the study. The supplements were given in a powder form and consumed once daily with milk or other beverages.
Mean age in the placebo and active groups was similar (p=0.4). Average time since menopause was 9 yrs and two-thirds of the women underwent natural menopause. There was no significant difference in the BMI at baseline between the groups [placebo (25.1 kg/m2), active (26 kg/m2)] and it did not change significantly during the study. At baseline, placebo group had significantly higher levels of TNF-α (p<0.0001), otherwise there was no difference in any other parameter. After 12 weeks of treatment, there were significant positive changes in TNF-α levels within the placebo group (p<0.0001) and adiponectin levels within the isoflavones group (p=0.03). Comparison of pre-post change between the groups showed a small but significant increase in serum adiponectin levels in the isoflavone group (p=0.03) compared to placebo. No significant changes were seen in any other parameter between the two groups.
Healthy, normal-weight postmenopausal women may not experience improvement in metabolic parameters when given high dose isoflavones despite an increase in serum adiponectin levels. Role of isoflavones in obese and insulin resistant postmenopausal women needs exploration.
PMCID: PMC2695501  PMID: 18981951
23.  Glucose and Insulin Measurements from the Glucose Tolerance Test and Mortality Prediction 
Diabetes care  2008;31(5):1026-1030.
To verify what information from oral glucose tolerance testing (OGTT) independently predicts mortality.
Research Design and Methods
1401 initially non-diabetic participants from the Baltimore Longitudinal Study of Aging, aged 17–95 years, with one or more OGTT (median=2, range 1–8) with insulin and glucose measurements measured every 20 minutes over 2 hours. Proportional hazard using the longitudinally collected data and Bayesian model averaging were used to examine the association of OGTT measurements individually and grouped with mortality adjusting for covariates.
Participants were followed for a median 20.3 years (range 0.5 – 40 years). The first hour OGTT glucose and insulin levels increased only modestly with age; whereas levels during the second hour increased more than 4% per decade. Individually, the 100-and 120-minute glucose measures and the fasting and 100-minute insulin levels were all independent predictors of mortality. When all measures were considered together, only higher 120-minute glucose was a significant independent risk factor for mortality.
The steeper rise with age of the OGTT 2-hour glucose values and the prognostic primacy of the 120 minute glucose value for mortality is consistent with previous reports and suggests the value of using the OGTT in clinical practice.
PMCID: PMC2430037  PMID: 18268070
24.  Usefulness of Uric Acid to Predict Changes in C-Reactive Protein and Interleukin-6 in 3-Year Period in Italians Aged 21 to 98 Years 
The American journal of cardiology  2007;100(1):115-121.
The role of uric acid (UA) in the process of atherothrombosis is controversial. Although serum UA has powerful antioxidant properties, epidemiological studies showed that UA was a risk factor for cardiovascular diseases and was positively associated with proinflammatory markers. Relations between baseline UA and changes in UA circulating levels with C-reactive protein (CRP) and interleukin-6 (IL-6) after 3 years of follow-up in a cohort of 892 Italian men and women aged 21 to 98 years was investigated. Subjects had complete baseline and follow-up data for UA, inflammatory markers, and covariates. An autoregressive approach was used to study such a relation. In adjusted analyses, baseline UA and changes in UA predicted a 3-year change in CRP (p = 0.028), but not IL-6 (p = 0.101). The relation between UA and CRP persisted after adjustment for baseline IL-6. Subjects with high UA at baseline had a progressively higher probability of developing clinically relevant increased IL-6 (>2.5 pg/ml) and CRP (>3 mg/L) during 3 years. In conclusion, our study suggests that in a population-based cohort, baseline UA and changes in circulating UA during 3 years of follow-up predict changes in circulating CRP independent of relevant confounders, including baseline IL-6.
PMCID: PMC2674322  PMID: 17599452
25.  The Interplay Between Uric Acid and Antioxidants in Relation to Physical Function in Older Persons 
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.
Nine hundred sixty-six elderly persons participating in the baseline assessment of the Invecchiare in Chianti Study.
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.
Total carotenoids (P =.008), in particular α-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 α-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).
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.
PMCID: PMC2669302  PMID: 17661959
uric acid; antioxidants; metabolism; inflammation; physical function; disability

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