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1.  The concept of multiple hormonal dysregulation 
Acta bio-medica : Atenei Parmensis  2010;81(Suppl 1):19-29.
Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones that remain stable and anabolic hormones (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Despite the multiple hormonal dysregulation occurring with age, the prevalent line of research in the last decades has tried to explain many age-related phenomena as consequence of one single hormonal derangement with disappointing results. In this review we will list the relationship between hormonal anabolic deficiency and frailty and mortality in older population, providing evidence to the notion that multiple hormonal dysregulation rather than change in single anabolic hormone is a powerful marker of poor health status and mortality. (
PMCID: PMC5220583  PMID: 20518188
Anabolic hormones; frailty; mortality
Recent studies indicate a role for the age-related decline of anabolic hormones, especially testosterone, in the onset of “anemia of aging.” Some of testosterone’s erythropoietic activities are mediated by insulin-like growth factor (IGF)-1, which also seems to have independent erythropoietic effects. However, the associations among IGF-1, anemia, and hemoglobin (Hb) have not been adequately investigated in older populations.
We used data from a representative sample of 953 subjects ≥65 years who participated in the InCHIANTI (Invecchiare in Chianti) Study and were not on growth hormone (GH) or erythropoietin therapy and were not diagnosed with hematologic malignancies or other cancers. Anemia was defined according to the World Health Organization (WHO) criteria by Hb level ≤13 g/dL in males and ≤12 g/dL in females. Backward multiple regression analyses including age, IGF binding protein (IGFBP)-3, testosterone, comorbidities, inflammatory markers, and anemia-related measures were used to address the relationship between IGF-1 and Hb and between IGF-1 and anemia in both sexes.
We found that 46/410 (11.2%) males and 71/543 (13.0%) females were defined as anemic. After adjustment for age, anemic males (100 ± 54 vs. 130 ± 56, P<.001) and females (89.1 ± 48 vs. 110 ± 52, P = .001) exhibited lower IGF-1 levels than their nonanemic counterparts. IGF-1 levels were independently and negatively associated with anemia in males (β ± SE = –0.0005 ± 0.0002, P = .04) but not in females (β ± SE = –0.0002 ± 0.0002, P = .40). In both males (β ± SE = 0.002 ± 0.001, P = .03) and females (β ± SE = 0.002 ± 0.0009, P = .03), IGF-1 levels were independently and positively associated with Hb levels.
In older males but not in females, IGF-1 levels are negatively associated with anemia. IGF-1 levels are independent and positive determinants of Hb concentration in both sexes.
PMCID: PMC5189915  PMID: 26214107
3.  Multiple Hormonal Dysregulation as Determinant of Low Physical Performance and Mobility in Older Persons 
Current pharmaceutical design  2014;20(19):3119-3148.
Mobility-disability is a common condition in older individuals. Many factors, including the age-related hormonal dysregulation, may concur to the development of disability in the elderly. In fact, during the aging process it is observed an imbalance between anabolic hormones that decrease (testosterone, dehydroepiandrosterone sulphate (DHEAS), estradiol, insulin like growth factor-1 (IGF-1) and Vitamin D) and catabolic hormones (cortisol, thyroid hormones) that increase. We start this review focusing on the mechanisms by which anabolic and catabolic hormones may affect physical performance and mobility. To address the role of the hormonal dysregulation to mobility-disability, we start to discuss the contribution of the single hormonal derangement. The studies used in this review were selected according to the period of time of publication, ranging from 2002 to 2013, and the age of the participants (≥65 years). We devoted particular attention to the effects of anabolic hormones (DHEAS, testosterone, estradiol, Vitamin D and IGF-1) on both skeletal muscle mass and strength, as well as other objective indicators of physical performance. We also analyzed the reasons beyond the inconclusive data coming from RCTs using sex hormones, thyroid hormones, and vitamin D (dosage, duration of treatment, baseline hormonal values and reached hormonal levels). We finally hypothesized that the parallel decline of anabolic hormones has a higher impact than a single hormonal derangement on adverse mobility outcomes in older population. Given the multifactorial origin of low mobility, we underlined the need of future synergistic optional treatments (micronutrients and exercise) to improve the effectiveness of hormonal treatment and to safely ameliorate the anabolic hormonal status and mobility in older individuals.
PMCID: PMC5155505  PMID: 24050169
Multiple hormonal derangement; mobility; muscle function; older persons
4.  Genomewide meta‐analysis identifies loci associated with IGF‐I and IGFBP‐3 levels with impact on age‐related traits 
Teumer, Alexander | Qi, Qibin | Nethander, Maria | Aschard, Hugues | Bandinelli, Stefania | Beekman, Marian | Berndt, Sonja I. | Bidlingmaier, Martin | Broer, Linda | Cappola, Anne | Ceda, Gian Paolo | Chanock, Stephen | Chen, Ming‐Huei | Chen, Tai C. | Chen, Yii‐Der Ida | Chung, Jonathan | Del Greco Miglianico, Fabiola | Eriksson, Joel | Ferrucci, Luigi | Friedrich, Nele | Gnewuch, Carsten | Goodarzi, Mark O. | Grarup, Niels | Guo, Tingwei | Hammer, Elke | Hayes, Richard B. | Hicks, Andrew A. | Hofman, Albert | Houwing‐Duistermaat, Jeanine J. | Hu, Frank | Hunter, David J. | Husemoen, Lise L. | Isaacs, Aaron | Jacobs, Kevin B. | Janssen, Joop A. M. J. L. | Jansson, John‐Olov | Jehmlich, Nico | Johnson, Simon | Juul, Anders | Karlsson, Magnus | Kilpelainen, Tuomas O. | Kovacs, Peter | Kraft, Peter | Li, Chao | Linneberg, Allan | Liu, Yongmei | Loos, Ruth J. F. | Lorentzon, Mattias | Lu, Yingchang | Maggio, Marcello | Magi, Reedik | Meigs, James | Mellström, Dan | Nauck, Matthias | Newman, Anne B. | Pollak, Michael N. | Pramstaller, Peter P. | Prokopenko, Inga | Psaty, Bruce M. | Reincke, Martin | Rimm, Eric B. | Rotter, Jerome I. | Saint Pierre, Aude | Schurmann, Claudia | Seshadri, Sudha | Sjögren, Klara | Slagboom, P. Eline | Strickler, Howard D. | Stumvoll, Michael | Suh, Yousin | Sun, Qi | Zhang, Cuilin | Svensson, Johan | Tanaka, Toshiko | Tare, Archana | Tönjes, Anke | Uh, Hae‐Won | van Duijn, Cornelia M. | van Heemst, Diana | Vandenput, Liesbeth | Vasan, Ramachandran S. | Völker, Uwe | Willems, Sara M. | Ohlsson, Claes | Wallaschofski, Henri | Kaplan, Robert C.
Aging Cell  2016;15(5):811-824.
The growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.
PMCID: PMC5013013  PMID: 27329260
aging; genomewide association study; growth hormone axis; IGF‐I; IGFBP‐3; longevity
During the aging process in men testosterone (T) levels progressively fall and inflammatory biomarkers increase. Although a relationship between these two phenomena has been tested in previous clinical trials, there is inconclusive evidence about the potential anti-inflammatory action of T.
A total of 108 healthy men >65 years with serum T concentration <475 ng/dL were recruited by direct mailings to alumni of the University of Pennsylvania and Temple University, and randomized to 60-cm2 T or placebo patch for 36-months. Ninety-six subjects completed the trial. Information and stored serum specimens from this trial were used to test the hypothesis of T inhibitory effect on inflammation. 70 men (42 in the T group) who had banked specimens available for assays of T, C-reactive protein (CRP), Tumor necrosis factor (TNF)-alpha, soluble TNF-alpha receptor-1 (TNFR1), interleukin-6 (IL-6) and soluble IL-6 receptors (sIL6r and sgp130) at multiple time points, were evaluated.
The mean age ± SD at baseline was 71.8 ± 4.9 years. Testosterone replacement therapy for 36 months did not induce a significant decrease in inflammatory markers. A trend toward a significant increase was observed in the placebo group for TNF-alpha (p=0.03) and sgp130 (p=0.01). Significant differences, in estimated means of TNFR1 (but not of other inflammatory markers), with lower levels in T group, were observed at 36 month-time point. In T-treated subjects we found an almost significant treatment-time interaction term TNFR1 (p=0.02) independent of total body fat content assessed by DXA. No serious adverse effect was observed.
Transdermal T treatment of older men for 36 months is not associated with significant changes in inflammatory markers.
PMCID: PMC5012420  PMID: 25100359
testosterone; inflammatory markers; older men
7.  Lung ultrasound and chest x-ray for detecting pneumonia in an acute geriatric ward 
Medicine  2016;95(27):e4153.
Our aim was to compare the accuracy of lung ultrasound (LUS) and standard chest x-ray (CXR) for diagnosing pneumonia in older patients with acute respiratory symptoms (dyspnea, cough, hemoptysis, and atypical chest pain) admitted to an acute-care geriatric ward.
We enrolled 169 (80 M, 89 F) multimorbid patients aged 83.0 ± 9.2 years from January 1 to October 31, 2015. Each participant underwent CXR and bedside LUS within 6 hours from ward admission. LUS was performed by skilled clinicians, blinded to CXR results and clinical history. The final diagnosis (pneumonia vs no-pneumonia) was established by another clinician reviewing clinical and laboratory data independent of LUS results and possibly prescribing chest contrast-enhanced CT. Diagnostic parameters of CXR and LUS were compared with McNemar test on the whole cohort and after stratification for Rockwood Clinical Frailty Scale.
Diagnostic accuracy for pneumonia (96 patients) was significantly higher in LUS (0.90, 95% confidence interval [CI] 0.83–0.96) compared with CXR (0.67, 95%CI 0.60–0.74, P < 0.001). LUS had a better sensitivity (0.92, 95%CI 0.86–0.97 vs 0.47, 95%CI 0.37–0.57) and negative predictive value (0.95, 95% CI 0.83–0.96 vs 0.57, 95%CI 0.48–0.56). In those patients with frailty (n = 87 with Rockwood Clinical Frailty Scale ≥5), LUS maintained a high diagnostic accuracy, but CXR did not (P = 0.0003). Interobserver agreement for LUS, calculated in a subsample of 29 patients, was high (k = 0.90).
In multimorbid patients admitted to an acute geriatric ward, LUS was more accurate than CXR for the diagnosis of pneumonia, particularly in those with frailty. A wider use of LUS should be implemented in this setting.
PMCID: PMC5058863  PMID: 27399134
bedside ultrasound; chest radiography; chest ultrasound; frailty; geriatric care; pneumonia
8.  Gut microbiota composition and Clostridium difficile infection in hospitalized elderly individuals: a metagenomic study 
Scientific Reports  2016;6:25945.
The gut microbiota composition of elderly hospitalized patients with Clostridium difficile infection (CDI) exposed to previous antibiotic treatment is still poorly investigated. The aim of this study was to compare the microbiota composition by means of 16S rRNA microbial profiling among three groups of hospitalized elderly patients (age ≥ 65) under standard diet including 25 CDI-positive (CDI group), 29 CDI-negative exposed to antibiotic treatment (AB+ group) and 30 CDI-negative subjects not on antibiotic treatment (AB− group). The functional properties of the gut microbiomes of CDI-positive vs CDI-negative subjects were also assessed by shotgun metagenomics. A significantly lower microbial diversity was detected in CDI samples, whose microbiomes clustered separately from CDI-negative specimens. CDI was associated with a significant under-representation of gut commensals with putative protective functionalities, including Bacteroides, Alistipes, Lachnospira and Barnesiella, and over-representation of opportunistic pathogens. These findings were confirmed by functional shotgun metagenomics analyses, including an in-depth profiling of the Peptostreptococcaceae family. In CDI-negative patients, antibiotic treatment was associated with significant depletion of few commensals like Alistipes, but not with a reduction in species richness. A better understanding of the correlations between CDI and the microbiota in high-risk elderly subjects may contribute to identify therapeutic targets for CDI.
PMCID: PMC4863157  PMID: 27166072
9.  Nutrition and Inflammation in Older Individuals: Focus on Vitamin D, n-3 Polyunsaturated Fatty Acids and Whey Proteins 
Nutrients  2016;8(4):186.
Chronic activation of the inflammatory response, defined as inflammaging, is the key physio-pathological substrate for anabolic resistance, sarcopenia and frailty in older individuals. Nutrients can theoretically modulate this phenomenon. The underlying molecular mechanisms reducing the synthesis of pro-inflammatory mediators have been elucidated, particularly for vitamin D, n-3 polyunsaturated fatty acids (PUFA) and whey proteins. In this paper, we review the current evidence emerging from observational and intervention studies, performed in older individuals, either community-dwelling or hospitalized with acute disease, and evaluating the effects of intake of vitamin D, n-3 PUFA and whey proteins on inflammatory markers, such as C-Reactive Protein (CRP), interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). After the analysis, we conclude that there is sufficient evidence for an anti-inflammatory effect in aging only for n-3 PUFA intake, while the few existing intervention studies do not support a similar activity for vitamin D and whey supplements. There is need in the future of large, high-quality studies testing the effects of combined dietary interventions including the above mentioned nutrients on inflammation and health-related outcomes.
PMCID: PMC4848655  PMID: 27043616
vitamin D; omega-3; whey; casein; geriatric; inflammatory markers
10.  Models for preclinical studies in aging-related disorders: One is not for all 
Preclinical studies are essentially based on animal models of a particular disease. The primary purpose of preclinical efficacy studies is to support generalization of treatment–effect relationships to human subjects. Researchers aim to demonstrate a causal relationship between an investigational agent and a disease-related phenotype in such models. Numerous factors can muddle reliable inferences about such cause-effect relationships, including biased outcome assessment due to experimenter expectations. For instance, responses in a particular inbred mouse might be specific to the strain, limiting generalizability. Selecting well-justified and widely acknowledged model systems represents the best start in designing preclinical studies, especially to overcome any potential bias related to the model itself. This is particularly true in the research that focuses on aging, which carries unique challenges, mainly attributable to the fact that our already long lifespan makes designing experiments that use people as subjects extremely difficult and largely impractical.
PMCID: PMC4811343  PMID: 27042427
aging; animal models; rodents; swine; cardiovascular medicine; preclinical studies; frailty; multimorbidity
11.  The association of serum procalcitonin and high-sensitivity C-reactive protein with pneumonia in elderly multimorbid patients with respiratory symptoms: retrospective cohort study 
BMC Geriatrics  2016;16:16.
Serum procalcitonin and high-sensitivity C-reactive protein (hs-CRP) elevations have been associated with pneumonia in adults. Our aim was to establish their diagnostic usefulness in a cohort of hospitalized multimorbid patients ≥65 years old admitted to hospital with acute respiratory symptoms.
With a retrospective cohort study design, all multimorbid patients ≥65 years-old with acute respiratory symptoms admitted to an internal medicine hospital ward in Italy from January to August 2013 were evaluated. Pneumonia diagnosis, comorbidities expressed through Cumulative Illness Rating Scale (CIRS), setting of living, length of stay, serum hs-CRP and procalcitonin at admission were collected for each patient. Data were analyzed with Mann-Whitney’s U test and multivariate Cox logistic regression analysis. A Receiver Operating Characteristic (ROC) curve was used to verify each biomarker’s association with pneumonia diagnosis.
Four hundred fifty five patients (227 M) were included in the study, of whom 239 with pneumonia (138 M, mean age 80 ± 13) and 216 without pneumonia (89 M, mean age 80 ± 14). After adjustment for age and sex, median levels of hs-CRP were significantly higher in patients with pneumonia (116 mg/L, IQR 46.5–179.0, vs 22.5 mg/dl, IQR 6.9–84.4, p < 0.0001), while procalcitonin median levels were not (0.22 ng/ml IQR 0.12–0.87, vs 0.15 ng/ml, IQR 0.10–0.35, p = 0.08). The ROC analysis showed that, unlike procalcitonin, hs-CRP values were predictive of pneumonia (AUC 0.76, 95 % CI 0.72–0.79, p < 0.0001, cut-off value 61 mg/L), even after adjustment for possible confounders including nursing home residence and dementia. Serum hs-CRP levels >61 mg/L were independently associated with a 3.59-fold increased risk of pneumonia (OR 3.59, 95 % CI 2.35–5.48, p < 0.0001).
In elderly multimorbid patients who require hospital admission for respiratory symptoms, serum hs-CRP testing seems to be more useful than procalcitonin for guiding the diagnostic process when clinical suspicion of pneumonia is present. Procalcitonin testing might hence be not recommended in this setting.
PMCID: PMC4715290  PMID: 26772604
Procalcitonin; High-sensitivity C-reactive protein; Pneumonia; Multimorbid elderly
12.  The Role of the Multiple Hormonal Dysregulation in the Onset of “Anemia of Aging”: Focus on Testosterone, IGF-1, and Thyroid Hormones 
Anemia is a multifactorial condition whose prevalence increases in both sexes after the fifth decade of life. It is a highly represented phenomenon in older adults and in one-third of cases is “unexplained.” Ageing process is also characterized by a “multiple hormonal dysregulation” with disruption in gonadal, adrenal, and somatotropic axes. Experimental studies suggest that anabolic hormones such as testosterone, IGF-1, and thyroid hormones are able to increase erythroid mass, erythropoietin synthesis, and iron bioavailability, underlining a potential role of multiple hormonal changes in the anemia of aging. Epidemiological data more consistently support an association between lower testosterone and anemia in adult-older individuals. Low IGF-1 has been especially associated with anemia in the pediatric population and in a wide range of disorders. There is also evidence of an association between thyroid hormones and abnormalities in hematological parameters under overt thyroid and euthyroid conditions, with limited data on subclinical statuses. Although RCTs have shown beneficial effects, stronger for testosterone and the GH-IGF-1 axis and less evident for thyroid hormones, in improving different hematological parameters, there is no clear evidence for the usefulness of hormonal treatment in improving anemia in older subjects. Thus, more clinical and research efforts are needed to investigate the hormonal contribution to anemia in the older individuals.
PMCID: PMC4686706  PMID: 26779261
13.  Multimorbidity in elderly hospitalised patients and risk of Clostridium difficile infection: a retrospective study with the Cumulative Illness Rating Scale (CIRS) 
BMJ Open  2015;5(10):e009316.
To identify the role of chronic comorbidities, considered together in a literature-validated index (Cumulative Illness Rating Scale, CIRS), and antibiotic or proton-pump inhibitor (PPI) treatments as risk factors for hospital-acquired Clostridium difficile infection (CDI) in elderly multimorbid hospitalised patients.
Retrospective cohort study.
Subacute hospital geriatric care ward in Italy.
505 (238 male (M), 268 female (F)) elderly (age ≥65) multimorbid patients.
Main outcome measures
The relationship between CDI and CIRS Comorbidity Score, number of comorbidities, antibiotic, antifungal and PPI treatments, and length of hospital stay was assessed through age-adjusted and sex-adjusted and multivariate logistic regression models. The CIRS Comorbidity Score was handled after categorisation in quartiles.
Mean age was 80.7±11.3 years. 43 patients (22 M, 21 F) developed CDI. The prevalence of CDI increased among quartiles of CIRS Comorbidity Score (3.9% first quartile vs 11.1% fourth quartile, age-adjusted and sex-adjusted p=0.03). In the multivariate logistic regression analysis, patients in the highest quartile of CIRS Comorbidity Score (≥17) carried a significantly higher risk of CDI (OR 5.07, 95% CI 1.28 to 20.14, p=0.02) than patients in the lowest quartile (<9). The only other variable significantly associated with CDI was antibiotic therapy (OR 2.62, 95% CI 1.21 to 5.66, p=0.01). PPI treatment was not associated with CDI.
Multimorbidity, measured through CIRS Comorbidity Score, is independently associated with the risk of CDI in a population of elderly patients with prolonged hospital stay.
PMCID: PMC4636642  PMID: 26503394
Multimorbidity; Clostridium difficile; Elderly; Proton pump inhibitors; Antibiotic
14.  Mild thyroid hormone excess is associated with a decreased physical function in elderly men 
In the adult, subclinical hyperthyroidism (Shyper) may alter skeletal muscle mass and strength. However, whether these effects are present in elderly subjects is not known. We explored the relationship between mild hyperthyroidism and physical function in a population-based sample of older persons.
In a cross-sectional analysis, calf muscle cross-sectional area (CMA), handgrip strength, nerve conduction velocity (NCV), and Short Physical Performance Battery (SPPB) scores were compared between 364 euthyroid (Eut) and 28 Shyper men as well as between 502 Eut and 39 Shyper women. In a longitudinal analysis, we evaluated the relationship between baseline plasma TSH, FT3 and FT4 and the 3-year change in SPPB score in 304 men and 409 women who were euthyroid at enrolment.
At the cross-sectional analysis, Shyper men, but not women, had a significantly (p = 0.02) lower SPPB score than Eut controls, although with comparable CMA, grip strength and NCV, and were more likely to have poor physical performance (odds ratio = 2.97, p< 0.05). Longitudinal analysis showed that in Eut men higher baseline FT4 was significantly (p=0.02) predictive of a lower SPPB score at the 3-year follow-up.
Even a modest thyroid hormone excess is associated with a reduced physical function in elderly men.
PMCID: PMC4588067  PMID: 21875391
Subclinical hyperthyroidism; physical function; elderly male
15.  Relationship between Carotenoids, Retinol, and Estradiol Levels in Older Women 
Nutrients  2015;7(8):6506-6519.
Background. In vitro evidence suggests anti-estrogenic properties for retinol and carotenoids, supporting a chemo-preventive role of these phytochemicals in estrogen-dependent cancers. During aging there are significant reductions in retinol and carotenoid concentrations, whereas estradiol levels decline during menopause and progressively increase from the age of 65. We aimed to investigate the hypothesis of a potential relationship between circulating levels of retinol, carotenoids, and estradiol (E2) in a cohort of late post-menopausal women. Methods. We examined 512 women ≥ 65 years from the InCHIANTI study. Retinol, α-caroten, β-caroten, β-criptoxantin, lutein, zeaxanthin, and lycopene levels were assayed at enrollment (1998–2000) by High-Performance Liquid Chromatography. Estradiol and testosterone (T) levels were assessed by Radioimmunometry (RIA) and testosterone-to-estradiol ratio (T/E2), as a proxy of aromatase activity, was also calculated. General linear models adjusted for age (Model 1) and further adjusted for other confounders including Body Mass Index (BMI) BMI, smoking, intake of energy, lipids, and vitamin A; C-Reactive Protein, insulin, total cholesterol, liver function, and testosterone (Model 2) were used to investigate the relationship between retinol, carotenoids, and E2 levels. To address the independent relationship between carotenoids and E2 levels, factors significantly associated with E2 in Model 2 were also included in a fully adjusted Model 3. Results. After adjustment for age, α-carotene (β ± SE = −0.01 ± 0.004, p = 0.02) and β-carotene (β ± SE = −0.07 ± 0.02, p = 0.0007) were significantly and inversely associated with E2 levels. α-Carotene was also significantly and positively associated with T/E2 ratio (β ± SE = 0.07 ± 0.03, p = 0.01). After adjustment for other confounders (Model 2), the inverse relationship between α-carotene (β ± SE = −1.59 ± 0.61, p = 0.01), β-carotene (β ± SE = −0.29 ± 0.08, p = 0.0009), and E2 persisted whereas the relationship between α-carotene and T/E2 ratio was attenuated (β ± SE = 0.22 ± 0.12, p = 0.07). In a fully adjusted model (Model 3), only β-carotene (β ± SE = −0.05 ± 0.02, p = 0.03) was significantly and inversely associated with E2 levels independent of α-carotene. No association was found between retinol, total non-pro-vitamin A carotenoids, lutein, zeaxanthin, and lycopene, and E2 levels. Conclusions: In older women, β-carotene levels are independently and inversely associated with E2.
PMCID: PMC4555135  PMID: 26251919
estrogens; carotenoids; retinol; elderly; women
16.  Insulin resistance and systemic inflammation, but not metabolic syndrome phenotype, predict 9 years mortality in older adults 
Atherosclerosis  2014;235(2):538-545.
Although metabolic syndrome (MS) is a typical condition of middle-aged/older person, the association between MS and mortality risk has not been confirmed in people over 65 years. We hypothesized that while in the elderly MS phenotype might lose its value in predicting mortality risk, the two core factors of MS, i.e. insulin resistance (IR) and low-grade systemic inflammation (LGSI) would not.
1011 community-dwelling older individuals (InCHIANTI study) were included. MS phenotype was defined by NCEP-ATP-III criteria. IR was calculated by HOMA; high-sensitivity C-reactive protein was measured by ELISA. Subjects were divided into four groups based on presence/absence of IR (HOMA ≥2.27) and LGSI (hs-CRP ≥ 3g/L): Group 1: no IR/LGSI (reference); Group 2: LGSI only; Group 3: IR only; Group 4: IR+LGSI. Hazard Ratios (HR) for 9-years cardiovascular (CVD) and total mortality, according to IR/LGSI groups, were estimated in subjects with (n.311) and without MS by Cox model.
31.8% of subjects with MS phenotype had no IR, 45.3% had no LGSI; moreover, 51% of subjects with both IR and LGSI didn’t display the MS phenotype. MS phenotype was not associated with CVD (HR:1.29; 95%C.I.:0.92–1.81) or total (HR:1.07; 95%C.I.:0.86–1.34) mortality risk, whereas the presence of IR plus LGSI was associated with increased CVD (no MS: HR 2.07, 95%CI:1.12–3.72; MS: HR 9.88, 95%CI:2.18–4), and overall (no MS: HR 1.72, 95%CI:1.001–3.17; MS: HR 1.51, 95%CI:1.02–2.28) mortality risk. The presence of IR (HR: 6.90, 95%CI:1.45–32) or LGSI (HR 7.56, 95%CI:1.63–35) was associated with CVD mortality, only among individuals with MS phenotype.
Among community dwelling older individuals, IR and LGSI, but not MS phenotype, was associated with 9-years overall and CVD mortality risk. Since a reduced “overlap” between MS phenotype and its physiopathological core (IR and LGSI) might be present with aging, we suggest that the definition of MS might be more holistic in advanced age, and probably comprise the measurement of IR and LGSI.
PMCID: PMC4156965  PMID: 24956526
Insulin Resistance; C Reactive Protein; Mortality; Metabolic Syndrome; Elderly
17.  Relationship between vitamin D and inflammatory markers in older individuals 
Age  2014;36(4):9694.
In older persons, vitamin D insufficiency and a subclinical chronic inflammatory status frequently coexist. Vitamin D has immune-modulatory and in vitro anti-inflammatory properties. However, there is inconclusive evidence about the anti-inflammatory role of vitamin D in older subjects. Thus, we investigated the hypothesis of an inverse relationship between 25-hydroxyvitamin D (25(OH)D) and inflammatory markers in a population-based study of older individuals. After excluding participants with high-sensitivity C-reactive protein (hsCRP) ≥ 10 mg/dl and those who were on chronic anti-inflammatory treatment, we evaluated 867 older adults ≥65 years from the InCHIANTI Study. Participants had complete data on serum concentrations of 25(OH)D, hsCRP, tumor necrosis factor (TNF)-α, soluble TNF-α receptors 1 and 2, interleukin (IL)-1β, IL-1 receptor antagonist, IL-10, IL-18, IL-6, and soluble IL-6 receptors (sIL6r and sgp130). Two general linear models were fit (model 1—adjusted for age, sex, and parathyroid hormone (PTH); model 2—including covariates of model 1 plus dietary and smoking habits, physical activity, ADL disability, season, osteoporosis, depressive status, and comorbidities). The mean age was 75.1 ± 17.1 years ± SD. In model 1, log(25OH-D) was significantly and inversely associated with log(IL-6) (β ± SE = −0.11 ± 0.03, p = <0.0001) and log (hsCRP) (β ± SE = −0.04 ± 0.02, p = 0.04) and positively associated with log(sIL6r) (β ± SE = 0.11 ± 0.04, p = 0.003) but not with other inflammatory markers. In model 2, log (25OH-D) remained negatively associated with log (IL-6) (β ± SE = −0.10 ± 0.03, p = 0.0001) and positively associated with log(sIL6r) (β ± SE = 0.11 ± 0.03, p = 0.004) but not with log(hsCRP) (β ± SE = −0.01 ± 0.03, p = 0.07). 25(OH)D is independently and inversely associated with IL-6 and positively with sIL6r, suggesting a potential anti-inflammatory role for vitamin D in older individuals.
PMCID: PMC4150893  PMID: 25086618
Vitamin D; Inflammation; Inflammatory markers; Elderly subjects
18.  Prevalence and Clinical Correlates of Sarcopenia in Community-Dwelling Older People: Application of the EWGSOP Definition and Diagnostic Algorithm 
Muscle impairment is a common condition in older people and a powerful risk factor for disability and mortality. The aim of this study was to apply the European Working Group on Sarcopenia in Older People criteria to estimate the prevalence and investigate the clinical correlates of sarcopenia, in a sample of Italian community-dwelling older people.
Cross-sectional analysis of 730 participants (74% aged 65 years and older) enrolled in the InCHIANTI study. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People criteria using bioimpedance analysis for muscle mass assessment. Logistic regression analysis was used to identify the factors independently associated with sarcopenia.
Sarcopenia defined by the European Working Group on Sarcopenia in Older People criteria increased steeply with age (p < .001), with 31.6% of women and 17.4% of men aged 80 years or older being affected by this condition. Higher education (odds ratio: 0.85; 95% CI: 0.74–0.98), lower insulin-like growth factor I (lowest vs highest tertile, odds ratio: 3.89; 95% CI: 1.03–14.1), and low bioavailable testosterone (odds ratio: 2.67; 95% CI: 1.31–5.44) were independently associated with the likelihood of being sarcopenic. Nutritional intake, physical activity, and level of comorbidity were not associated with sarcopenia.
Sarcopenia identified by the European Working Group on Sarcopenia in Older People criteria is a relatively common condition in Italian octogenarians, and its prevalence increases with aging. Correlates of sarcopenia identified in this study might suggest new approaches for prevention and treatment of sarcopenia.
PMCID: PMC3968828  PMID: 24085400
Sarcopenia; Community-dwelling older people; Frail elderly.
The present study evaluates the effects of a 6-month treatment with an ACE-inhibitor (ie, fosinopril) on serum concentrations of total IGF-1 and IGF binding protein (IGFBP)-3 in older adults at high risk for cardiovascular disease.
Data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study, a double-blind, crossover, randomized, placebo-controlled trial.
Participants were recruited from the communities of Winston Salem, NC, and Greensboro, NC.
Subjects ≥55 years old with high cardiovascular disease risk profile.
The intervention consisted of 6-month administration of fosinopril vs. placebo.
Serum concentrations of total IGF-1 and IGFBP-3 were measured in 100 participants of the TRAIN study at baseline, 6-month and 12-month follow-up visits. Differences in total IGF-1 and IGFBP-3 concentrations were assessed using two-sided paired t-tests.
The mean age of participants (47% women) was 66.5 (standard deviation 7.2) years. Serum concentrations of total IGF-1 were significantly higher after 6-month treatment with fosinopril compared to placebo (203.73 ng/mL vs 194.24 ng/mL; p=0.02): After ACE-inhibitor intervention, significantly higher serum IGFBP-3 concentrations compared to controls (4308.81 ng/mL vs 4086.93 ng/mL; p=0.03) were also reported.
A six-month treatment with fosinopril increases systemic levels of total IGF-1 and IGFBP-3 in older adults with high cardiovascular risk profile. This may represent a potential biological explanation to the beneficial effects of ACE-inhibition on stroke, ischemic heart disease and insulin resistance.
PMCID: PMC4311891  PMID: 20617288
Angiotensin Converting Enzyme inhibitor; Insulin like growth factor 1; Insulin like growth factor binding protein 3; older adults
20.  Insulin-Like Growth Factor-1 Bioactivity Plays a Prosurvival Role in Older Participants 
The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second–third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP-1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all-cause mortality in older population.
PMCID: PMC3805296  PMID: 23671288
IGF-1 bioactivity; IGF-binding proteins; Mortality; Older participants.
21.  Comorbidities and Disease Severity as Risk Factors for Carbapenem-Resistant Klebsiella pneumoniae Colonization: Report of an Experience in an Internal Medicine Unit 
PLoS ONE  2014;9(10):e110001.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging multidrug-resistant nosocomial pathogen, spreading to hospitalized elderly patients. Risk factors in this setting are unclear. Our aims were to explore the contribution of multi-morbidity and disease severity in the onset of CRKP colonization/infection, and to describe changes in epidemiology after the institution of quarantine-ward managed by staff-cohorting.
Methods and Findings
With a case-control design, we evaluated 133 CRKP-positive patients (75 M, 58 F; mean age 79±10 years) and a control group of 400 CRKP-negative subjects (179 M, 221 F; mean age 79±12 years) admitted to Internal Medicine and Critical Subacute Care Unit of Parma University Hospital, Italy, during a 10-month period. Information about comorbidity type and severity, expressed through Cumulative Illness Rating Scale-CIRS, was collected in each patient. During an overall 5-month period, CRKP-positive patients were managed in an isolation ward with staff cohorting. A contact-bed isolation approach was established in the other 5 months. The effects of these strategies were evaluated with a cross-sectional study design. CRKP-positive subjects had higher CIRS comorbidity index (12.0±3.6 vs 9.1±3.5, p<0.0001) and CIRS severity index (3.2±0.4 vs 2.9±0.5, p<0.0001), along with higher cardiovascular, respiratory, renal and neurological disease burden than control group. CIRS severity index was associated with a higher risk for CRKP-colonization (OR 13.3, 95%CI6.88–25.93), independent of comorbidities. Isolation ward activation was associated with decreased monthly incidence of CRKP-positivity (from 16.9% to 1.2% of all admissions) and infection (from 36.6% to 22.5% of all positive cases; p = 0.04 derived by Wilcoxon signed-rank test). Mortality rate did not differ between cases and controls (21.8% vs 15.2%, p = 0.08). The main limitations of this study are observational design and lack of data about prior antibiotic exposure.
Comorbidities and disease severity are relevant risk factors for CRKP-colonization/infection in elderly frail patients. Sanitary measures may have contributed to limit epidemic spread and rate of infection also in internal medicine setting.
PMCID: PMC4198186  PMID: 25335100
22.  Testosterone, Sex Hormone-Binding Globulin and the Metabolic Syndrome in Men: An Individual Participant Data Meta-Analysis of Observational Studies 
PLoS ONE  2014;9(7):e100409.
Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably.
We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components.
Data sources
Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE.
Study Eligibility Criteria
Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men.
We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied.
Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension.
Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.
PMCID: PMC4096400  PMID: 25019163
23.  Thyroid STAtus and 6-Year Mortality in Elderly People Living in a Mildly Iodine-Deficient Area: The Aging in the Chianti Area (InCHIANTI) Study 
The relationship between thyroid dysfunction and mortality in elderly subjects is still undefined. In this population study we tested the hypothesis that in older subjects, living in a mildly iodine-deficient area, thyroid dysfunction may be associated with increased mortality independent of potential confounders.
Longitudinal study
Total of 951 subjects aged 65 years and older
Plasma thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) concentrations and demographic features were evaluated in participants of the Aging in the Chianti Area (InCHIANTI) study, aged 65 years or older. Participants were classified according to thyroid function test. Kaplan-Meier survival and Cox proportional hazards models adjusted for confounders were used in the analysis.
A total of 819 participants were euthyroid, 83 had Subclinical hyperthyroidism (SHyper), and 29 had Subclinical hypothyroidism (SHypo). Overt Hypo- and Hyperthyroidism were found in 5 and 15 subjects, respectively. During a median of six-years of follow-up, N 210 deaths occurred (22.1 %) of which 98 (46.6%) due to cardiovascular causes. Kaplan–Meier analysis revealed higher overall mortality for SHyper (P<0.04) as compared to euthyroid subjects. After adjusting for multiple confounders, participants with SHyper (Hazard Ratio[HR]:1.65; 95% Confidence Interval [CI]: 1.02–2.69) had significantly higher all-cause mortality than those with normal thyroid function. No significant association was found between SHyper and cardiovascular mortality.
In euthyroid subjects, TSH was found to be predictive of a reduced risk of all-cause mortality (HR: 0.76; 95% CI, 0.57–0.99)
SHyper is an independent risk factor for all-cause mortality in the older population. Low-normal circulating TSH should be carefully monitored in euthyroid elderly individuals.
PMCID: PMC3686888  PMID: 23647402
subclinical hyperthyroidism; aging; mortality
24.  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
25.  Estimating Glomerular Filtration Rate in Older People 
BioMed Research International  2014;2014:916542.
We aimed at reviewing age-related changes in kidney structure and function, methods for estimating kidney function, and impact of reduced kidney function on geriatric outcomes, as well as the reliability and applicability of equations for estimating glomerular filtration rate (eGFR) in older patients. CKD is associated with different comorbidities and adverse outcomes such as disability and premature death in older populations. Creatinine clearance and other methods for estimating kidney function are not easy to apply in older subjects. Thus, an accurate and reliable method for calculating eGFR would be highly desirable for early detection and management of CKD in this vulnerable population. Equations based on serum creatinine, age, race, and gender have been widely used. However, these equations have their own limitations, and no equation seems better than the other ones in older people. New equations specifically developed for use in older populations, especially those based on serum cystatin C, hold promises. However, further studies are needed to definitely accept them as the reference method to estimate kidney function in older patients in the clinical setting.
PMCID: PMC3977451  PMID: 24772439

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