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1.  A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration 
de Vries, Paul S. | Chasman, Daniel I. | Sabater-Lleal, Maria | Chen, Ming-Huei | Huffman, Jennifer E. | Steri, Maristella | Tang, Weihong | Teumer, Alexander | Marioni, Riccardo E. | Grossmann, Vera | Hottenga, Jouke J. | Trompet, Stella | Müller-Nurasyid, Martina | Zhao, Jing Hua | Brody, Jennifer A. | Kleber, Marcus E. | Guo, Xiuqing | Wang, Jie Jin | Auer, Paul L. | Attia, John R. | Yanek, Lisa R. | Ahluwalia, Tarunveer S. | Lahti, Jari | Venturini, Cristina | Tanaka, Toshiko | Bielak, Lawrence F. | Joshi, Peter K. | Rocanin-Arjo, Ares | Kolcic, Ivana | Navarro, Pau | Rose, Lynda M. | Oldmeadow, Christopher | Riess, Helene | Mazur, Johanna | Basu, Saonli | Goel, Anuj | Yang, Qiong | Ghanbari, Mohsen | Willemsen, Gonneke | Rumley, Ann | Fiorillo, Edoardo | de Craen, Anton J. M. | Grotevendt, Anne | Scott, Robert | Taylor, Kent D. | Delgado, Graciela E. | Yao, Jie | Kifley, Annette | Kooperberg, Charles | Qayyum, Rehan | Lopez, Lorna M. | Berentzen, Tina L. | Räikkönen, Katri | Mangino, Massimo | Bandinelli, Stefania | Peyser, Patricia A. | Wild, Sarah | Trégouët, David-Alexandre | Wright, Alan F. | Marten, Jonathan | Zemunik, Tatijana | Morrison, Alanna C. | Sennblad, Bengt | Tofler, Geoffrey | de Maat, Moniek P. M. | de Geus, Eco J. C. | Lowe, Gordon D. | Zoledziewska, Magdalena | Sattar, Naveed | Binder, Harald | Völker, Uwe | Waldenberger, Melanie | Khaw, Kay-Tee | Mcknight, Barbara | Huang, Jie | Jenny, Nancy S. | Holliday, Elizabeth G. | Qi, Lihong | Mcevoy, Mark G. | Becker, Diane M. | Starr, John M. | Sarin, Antti-Pekka | Hysi, Pirro G. | Hernandez, Dena G. | Jhun, Min A. | Campbell, Harry | Hamsten, Anders | Rivadeneira, Fernando | Mcardle, Wendy L. | Slagboom, P. Eline | Zeller, Tanja | Koenig, Wolfgang | Psaty, Bruce M. | Haritunians, Talin | Liu, Jingmin | Palotie, Aarno | Uitterlinden, André G. | Stott, David J. | Hofman, Albert | Franco, Oscar H. | Polasek, Ozren | Rudan, Igor | Morange, Pierre-Emmanuel | Wilson, James F. | Kardia, Sharon L. R. | Ferrucci, Luigi | Spector, Tim D. | Eriksson, Johan G. | Hansen, Torben | Deary, Ian J. | Becker, Lewis C. | Scott, Rodney J. | Mitchell, Paul | März, Winfried | Wareham, Nick J. | Peters, Annette | Greinacher, Andreas | Wild, Philipp S. | Jukema, J. Wouter | Boomsma, Dorret I. | Hayward, Caroline | Cucca, Francesco | Tracy, Russell | Watkins, Hugh | Reiner, Alex P. | Folsom, Aaron R. | Ridker, Paul M. | O'Donnell, Christopher J. | Smith, Nicholas L. | Strachan, David P. | Dehghan, Abbas
Human Molecular Genetics  2015;25(2):358-370.
Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
PMCID: PMC4715256  PMID: 26561523
2.  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
3.  Midlife and Late-Life Cardiorespiratory Fitness and Brain Volume Changes in Late Adulthood: Results From the Baltimore Longitudinal Study of Aging 
Higher cardiorespiratory fitness (CRF) is cross-sectionally associated with more conserved brain volume in older age, but longitudinal studies are rare. This study examined whether higher midlife CRF was prospectively associated with slower atrophy, which in turn was associated with higher late-life CRF.
Brain volume by magnetic resonance imaging was determined annually from 1994 to 2003 in 146 participants (M baseline age = 69.6 years). Peak oxygen uptake on a treadmill yielded estimated midlife CRF in 138 and late-life CRF in 73 participants.
Higher midlife CRF was associated with greater middle temporal gyrus, perirhinal cortex, and temporal and parietal white matter, but was not associated with atrophy progression. Slower atrophy in middle frontal and angular gyri was associated with higher late-life CRF, independent of CRF at baseline magnetic resonance imaging.
Higher midlife CRF may play a role in preserving middle and medial temporal volumes in late adulthood. Slower atrophy in middle frontal and angular gyri may predict late-life CRF.
PMCID: PMC4715229  PMID: 25896993
Cardiovascular; Epidemiology; Neuroimaging.
4.  Are Performance Measures Necessary to Predict Loss of Independence in Elderly People? 
The frailty phenotype (FP) proposed by Fried and colleagues (Fried LP, Tangen CM, Walston J, et al.; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146–M156.) requires the administration of performance tests (gait speed, handgrip strength) not always feasible in routine clinical practice. Furthermore, the discriminative capacity of the instrument has been rarely investigated. Aim of this study was to evaluate the discriminative capacity of the FP and compare it with a modified version including only anamnestic information.
Data are from 890 participants of the InCHIANTI study without impairment in activities of daily living (ADL) at baseline (mean age 74 years, women 55%). Frailty was defined by (a) the presence of ≥3 criteria of the FP, and (b) having ≥2 criteria of an anamnestic FP (AFP), not including gait speed and handgrip strength. Sensitivity, specificity, positive and negative predictive values (PPV, NPV) were used to evaluate the discriminative capacity of both definitions for incident disability (ie, loss of at least one ADL), incidence of “accelerated” disability (loss of >2 ADL) over a 6-year follow-up, and 5-years mortality.
FP and AFP yielded a frailty prevalence of 6.4% and 6.5%, respectively; only 32 patients were considered frail by both indices (kappa: .53). For incident disability, FP showed sensitivity = .194, specificity = .963, PPV = .400, and NPV = .903. Similarly, AFP had sensitivity = .129, specificity = .949, PPV = .245, and NPV = .894. Consistent results were found for accelerated disability and mortality.
In our sample, both FP and AFP showed low sensitivity in identifying older people who would die or develop disability, but they could well discriminate people who would not experience adverse outcomes.
PMCID: PMC4715230  PMID: 26273019
Frailty; Disability; Mortality; Predictive value; Sensitivity and specificity.
5.  Gait Speed Predicts Incident Disability: A Pooled Analysis 
Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function.
We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking ¼ – ½ mile or climbing 10 steps within 3 years.
Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from <0.4 to ≥1.4 m/s) with increasingly greater gait speed, 3-year rates of bathing or dressing dependence trended from 10% to 1% in men, and from 15% to 1% in women, while mobility difficulty trended from 47% to 4% in men and 40% to 6% in women. The age-adjusted relative risk ratio per 0.1 m/s greater speed for bathing or dressing dependence in men was 0.68 (0.57–0.81) and in women: 0.74 (0.66–0.82); for mobility difficulty, men: 0.75 (0.68–0.82), women: 0.73 (0.67–0.80). Results were similar for combined disability and mortality. Effects were largely consistent across subgroups based on age, gender, race, body mass index, prior hospitalization, and selected chronic conditions. In the presence of multiple other risk factors for disability, gait speed significantly increased the area under the receiver operator characteristic curve.
In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality.
PMCID: PMC4715231  PMID: 26297942
Gait speed; Disability; Mortality; Mobility; Performance
6.  Low Plasma Klotho Concentrations and Decline of Knee Strength in Older Adults 
Although the “anti-aging hormone” klotho is associated with sarcopenia in mice, the relationship between klotho and muscle strength in older adults is not well known.
Plasma klotho concentrations were measured in 2,734 older adults, aged 71–80 years, who participated in the Health, Aging and Body Composition Study, a prospective observational cohort study conducted in Memphis, TN and Pittsburgh, PA. Knee extension strength was measured using isokinetic dynamometry at baseline and follow-up 2 and 4 years later. Knee extension strength was normalized for weight.
At baseline, participants in the highest tertile of plasma klotho had higher knee extension strength (β = .72, standard error [SE] = .018, p < .0001) compared with those in the lowest tertile in a multivariable linear regression model adjusting for age, sex, race, smoking, study site, C-reactive protein, interleukin-6, and diabetes. Participants in the highest tertile of plasma klotho at baseline had less of a decline in knee strength over 4 years of follow-up (β = −.025, SE = .011, p = .02) compared with those in the lowest tertile in a multivariable linear regression model adjusting for the same covariates above.
Plasma klotho concentrations were an independent predictor of changes in knee strength over time in older adults. Further studies are needed to identify the biological mechanisms by which circulating klotho could modify skeletal muscle strength.
PMCID: PMC4706099  PMID: 26359247
Aging; Klotho; Skeletal muscle strength; Sarcopenia
7.  The Multidimensional Prognostic Index predicts in-hospital length of stay in older patients: a multicentre prospective study 
Age and Ageing  2016;45(1):90-96.
Background: prediction of length of stay (LOS) may be useful to optimise care plans to reduce the negative outcomes related to hospitalisation.
Objective: to evaluate whether the Multidimensional Prognostic Index (MPI), based on a Comprehensive Geriatric Assessment (CGA), may predict LOS in hospitalised older patients.
Design: prospective multicentre cohort study.
Setting: twenty Geriatrics Units.
Participants: patients aged 65 and older consecutively admitted to Geriatrics Units.
Measurement: at admission, the CGA-based MPI was calculated by using a validated algorithm that included information on basal and instrumental activities of daily living, cognitive status, nutritional status, the risk of pressures sores, co-morbidity, number of drugs and co-habitation status. According to validated cut-offs, subjects were divided into three groups of risk, i.e. MPI-1 low risk (value ≤0.33), MPI-2 moderate risk (value 0.34–0.66) and MPI-3 severe risk of mortality (value ≥0.67).
Results: two thousand and thirty-three patients were included; 1,159 were women (57.0%). Age- and sex-adjusted mean LOS in patients divided according to the MPI grade was MPI-1 = 10.1 (95% CI 8.6–11.8), MPI-2 = 12.47 (95% CI 10.7–14.68) and MPI-3 = 13.41 (95% CI 11.5–15.7) days (P for trend <0.001). The overall accuracy of the MPI to predict LOS was good (C-statistic 0.74, 95% CI 0.72–0.76). Moreover, a statistically significant trend of LOS means was found even in patients stratified according to their International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) main diagnosis.
Conclusions: the MPI is an accurate predictor of LOS in older patients hospitalised with the most frequent diseases.
PMCID: PMC4711657  PMID: 26764398
older people; length of stay; Multidimensional Prognostic Index; 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
9.  Vitamin D deficiency and airflow limitation in the Baltimore Longitudinal Study of Ageing 
Vitamin D deficiency is common in patients with chronic obstructive pulmonary disease (COPD) and has also been linked to comorbidities often present in COPD.
The aim of this study was to investigate whether vitamin D deficiency was related specifically to airflow limitation or whether vitamin D deficiency was determined by conditions that frequently coexist with COPD: insulin resistance, hypertension, anaemia, obesity and hypercholesterolaemia.
For this cross-sectional analysis, we included 897 subjects from the Baltimore Longitudinal Study of Aging. Subjects taking vitamin D supplements were excluded. Airflow limitation was defined as FEV1/FVC < lower limit of normal. Logistic regression was used to assess the association between vitamin D deficiency (25-hydroxy vitamin D < 20 ng/mL) and possible determinants.
Vitamin D deficiency was not specific for subjects with airflow limitation. Body mass index (BMI) (OR: 1·05, P < 0·03) and obesity (BMI > 30 kg/m2) (OR: 1·9, P < 0·002) were significantly associated with vitamin D deficiency in the adjusted multivariate regression analysis. Physical activity was associated with a decreased risk of vitamin D deficiency.
Airflow limitation was not an independent determinant of vitamin D deficiency. The effect of weight loss and increased physical activity on vitamin D levels should be investigated further in intervention studies.
PMCID: PMC5189918  PMID: 26173468
Airflow limitation; airway obstruction; cardiovascular disease; comorbidities; physical activity; vitamin D
10.  Short Physical Performance Battery and all-cause mortality: systematic review and meta-analysis 
BMC Medicine  2016;14:215.
The Short Physical Performance Battery (SPPB) is a well-established tool to assess lower extremity physical performance status. Its predictive ability for all-cause mortality has been sparsely reported, but with conflicting results in different subsets of participants. The aim of this study was to perform a meta-analysis investigating the relationship between SPPB score and all-cause mortality.
Articles were searched in MEDLINE, the Cochrane Library, Google Scholar, and BioMed Central between July and September 2015 and updated in January 2016. Inclusion criteria were observational studies; >50 participants; stratification of population according to SPPB value; data on all-cause mortality; English language publications. Twenty-four articles were selected from available evidence. Data of interest (i.e., clinical characteristics, information after stratification of the sample into four SPPB groups [0–3, 4–6, 7–9, 10–12]) were retrieved from the articles and/or obtained by the study authors. The odds ratio (OR) and/or hazard ratio (HR) was obtained for all-cause mortality according to SPPB category (with SPPB scores 10–12 considered as reference) with adjustment for age, sex, and body mass index.
Standardized data were obtained for 17 studies (n = 16,534, mean age 76 ± 3 years). As compared to SPPB scores 10–12, values of 0–3 (OR 3.25, 95%CI 2.86–3.79), 4–6 (OR 2.14, 95%CI 1.92–2.39), and 7–9 (OR 1.50, 95%CI 1.32–1.71) were each associated with an increased risk of all-cause mortality. The association between poor performance on SPPB and all-cause mortality remained highly consistent independent of follow-up length, subsets of participants, geographic area, and age of the population. Random effects meta-regression showed that OR for all-cause mortality with SPPB values 7–9 was higher in the younger population, diabetics, and men.
An SPPB score lower than 10 is predictive of all-cause mortality. The systematic implementation of the SPPB in clinical practice settings may provide useful prognostic information about the risk of all-cause mortality. Moreover, the SPPB could be used as a surrogate endpoint of all-cause mortality in trials needing to quantify benefit and health improvements of specific treatments or rehabilitation programs.
The study protocol was published on PROSPERO (CRD42015024916).
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0763-7) contains supplementary material, which is available to authorized users.
PMCID: PMC5178082  PMID: 28003033
Short Physical Performance Battery; All-cause mortality; Physical function; Meta-analysis
11.  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
12.  DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases 
Ligthart, Symen | Marzi, Carola | Aslibekyan, Stella | Mendelson, Michael M. | Conneely, Karen N. | Tanaka, Toshiko | Colicino, Elena | Waite, Lindsay L. | Joehanes, Roby | Guan, Weihua | Brody, Jennifer A. | Elks, Cathy | Marioni, Riccardo | Jhun, Min A. | Agha, Golareh | Bressler, Jan | Ward-Caviness, Cavin K. | Chen, Brian H. | Huan, Tianxiao | Bakulski, Kelly | Salfati, Elias L. | Fiorito, Giovanni | Wahl, Simone | Schramm, Katharina | Sha, Jin | Hernandez, Dena G. | Just, Allan C. | Smith, Jennifer A. | Sotoodehnia, Nona | Pilling, Luke C. | Pankow, James S. | Tsao, Phil S. | Liu, Chunyu | Zhao, Wei | Guarrera, Simonetta | Michopoulos, Vasiliki J. | Smith, Alicia K. | Peters, Marjolein J. | Melzer, David | Vokonas, Pantel | Fornage, Myriam | Prokisch, Holger | Bis, Joshua C. | Chu, Audrey Y. | Herder, Christian | Grallert, Harald | Yao, Chen | Shah, Sonia | McRae, Allan F. | Lin, Honghuang | Horvath, Steve | Fallin, Daniele | Hofman, Albert | Wareham, Nicholas J. | Wiggins, Kerri L. | Feinberg, Andrew P. | Starr, John M. | Visscher, Peter M. | Murabito, Joanne M. | Kardia, Sharon L. R. | Absher, Devin M. | Binder, Elisabeth B. | Singleton, Andrew B. | Bandinelli, Stefania | Peters, Annette | Waldenberger, Melanie | Matullo, Giuseppe | Schwartz, Joel D. | Demerath, Ellen W. | Uitterlinden, André G. | van Meurs, Joyce B. J. | Franco, Oscar H. | Chen, Yii-Der Ida | Levy, Daniel | Turner, Stephen T. | Deary, Ian J. | Ressler, Kerry J. | Dupuis, Josée | Ferrucci, Luigi | Ong, Ken K. | Assimes, Themistocles L. | Boerwinkle, Eric | Koenig, Wolfgang | Arnett, Donna K. | Baccarelli, Andrea A. | Benjamin, Emelia J. | Dehghan, Abbas
Genome Biology  2016;17:255.
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.
We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.
We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1119-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5151130  PMID: 27955697
Inflammation; DNA methylation; Epigenome-wide association study; C-reactive protein; Body mass index; Diabetes; Coronary heart disease
13.  LRP5 gene polymorphism and cortical bone 
Background and aims
There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macro-architectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (vBMD) and macro-architectural bone parameters in a population-based sample of men and women.
We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21–94 yrs). Trabecular vBMD (vBMDt, mg/cm3), cortical vBMD (vBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower vBMDt in men (p<0.05), and lower vBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women.
These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women.
PMCID: PMC5139676  PMID: 21116122
Cortical bone area; LRP5 gene polymorphism; osteoporosis; peripheral bone quantitative computed tomography (pQCT); volumetric BMD
14.  Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study 
Journal of Alzheimer's disease : JAD  2016;53(3):1043-1052.
The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints.
The objective of this study was to determine if the presence of MCR increases the risk of falls in older people.
Individual participant data (n = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts.
The mean age of participants was 74.9 (SD 6.8) years and 44% (n = 2728) were male. Overall 33.9% (n = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51).
MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic.
PMCID: PMC5139681  PMID: 27340851
Cognition; dementia; falls; gait
15.  Vitamin D status, functional decline, and mortality in peripheral artery disease 
Associations of vitamin D levels with prospectively measured functional decline and mortality in people with lower extremity peripheral artery disease (PAD) are unknown. We determined whether lower baseline vitamin D levels are associated with a faster decline in functional performance and higher mortality among people with and without PAD. A total of 658 participants (395 with PAD) underwent baseline measurement of 25-hydroxyvitamin D (DiaSorin radioimmunoassay), a 6-minute walk test, 4-meter walking velocity and the Short Physical Performance Battery (SPPB), and were followed annually for up to 4 years. Analyses were adjusted for age, sex, race, body mass index, comorbidities, the ankle–brachial index, and other confounders. Among participants with PAD, lower baseline vitamin D levels were associated with a faster decline in the 6-minute walk (vitamin D < 30 nmol/L: −70.0 feet/year; vitamin D 30 to < 50 nmol/L: −72.3 feet/year; vitamin D 50 to < 75 nmol/L: −35.5 feet/year; vitamin D 75 to < 120 nmol/L: −35.9 feet/year; p trend=0.012). PAD participants with vitamin D < 30 nmol/L had a faster decline in the SPPB and 6-minute walk compared to those with levels of 50 to < 75 (p=0.034 and p=0.04, respectively). Among participants without PAD, lower vitamin D was associated with a faster decline in the fast 4-meter walking velocity (p trend=0.003). There were no significant associations of baseline vitamin D levels with all-cause or cardiovascular disease mortality in PAD or non-PAD participants. In conclusion, among individuals with and without PAD, low vitamin D status was associated with a faster decline in some measures of functional performance but was not related to mortality.
PMCID: PMC5139679  PMID: 24442622
exercise; intermittent claudication; peripheral arterial disease; peripheral vascular diseases; walking
16.  Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men 
Gait speed predicts functional decline, disability, and death and is considered a biomarker of biological aging. Changes in gait speed in persons aging with HIV may provide an important method of gauging health and longevity in an under assessed population. The objective of this study was to evaluate and quantify the rate of gait speed decline in HIV infected (HIV+) men compared to HIV uninfected (HIV−) men.
The study was nested in the Multicenter AIDS Cohort Study (MACS). The primary outcome was usual gait speed in meters per second (m/s) measured between 2007 and 2013. Differences in the rate of gait speed decline and the incidence of clinically slow gait (<1.0 m/s) were assessed using multivariate linear regression models and Cox proportional hazards models, respectively.
A total of 2,025 men (973 HIV+ and 1,052 HIV−) aged 40 and older contributed 21,187 person-visits (9,955 HIV+ and 11,232 HIV−) to the analysis. Average gait speeds at age 50 years were 1.24 m/s and 1.19 m/s in HIV− and HIV+ men, respectively (p <0.001). In fully adjusted models, gait speed decline averaged 0.009 m/s per year after age 50 (p <0.001); this decline was 0.025 m/s per year greater in HIV+ men (p <0.001). Moreover, HIV+ men had a 57% greater risk of developing clinically slow gait (aHR=1.57, 95% CI: 1.27 – 1.91).
These findings indicate a faster rate of functional decline in HIV-infected men, suggesting greater risks of disability and death with advancing age.
PMCID: PMC4624470  PMID: 26102450
gait speed; HIV-infection; functional decline; disability; aging
17.  Priorities and trends in the study of proteins in eye research, 1924–2014 
Proteomics. Clinical applications  2015;9(0):1105-1122.
To identify the proteins that are relevant to eye research and develop assays for the study of a set of these proteins.
Experimental Design
We conducted a bibliometric analysis by merging gene lists for human and mouse from the National Center for Biotechnology Information FTP site and combining them with PubMed references that were retrieved with the search terms “eye”[MeSH Terms] OR “eye”[All Fields] OR “eyes”[All Fields].
For human and mouse eye studies, respectively, the total number of publications was 13,525 and 23,895, and the total number of proteins was 4,050 and 4,717. For proteins in human and mouse eye studies, respectively, 88.7% and 81.7% had five or fewer citations. The top fifty most intensively studied proteins for human and mouse eye studies were generally in the areas of photoreceptors and phototransduction, inflammation and angiogenesis, neurodevelopment, lens transparency, and cell cycle and cellular processes. We proposed selected reaction monitoring assays that were developed in silico for the top fifty most intensively studied proteins in human and mouse eye research.
Conclusions and clinical relevance
We conclude that scientists engaged in eye research tend to focus on the same proteins. Newer resources and tools in proteomics can expand the investigations to lesser-known proteins of the eye.
PMCID: PMC4695326  PMID: 26123431
biological processes; eye; human proteome project; proteomics; mass spectrometry; mouse
18.  Intra-individual lap time variation of the 400-m walk, an early mobility indicator of executive function decline in high-functioning older adults? 
Age  2015;37(6):115.
Higher intra-individual lap time variation (LTV) of the 400-m walk is cross-sectionally associated with poorer attention in older adults. Whether higher LTV predicts decline in executive function and whether the relationship is accounted for by slower walking remain unanswered. The main objective of this study was to examine the relationship between baseline LTV and longitudinal change in executive function. We used data from 347 participants aged 60 years and older (50.7 % female) from the Baltimore Longitudinal Study of Aging. Longitudinal assessments of executive function were conducted between 2007 and 2013, including attention (Trails A, Digit Span Forward Test), cognitive flexibility and set shifting (Trails B, Delta TMT: Trials B minus Trials A), visuoperceptual speed (Digit Symbol Substitution Test), and working memory (Digit Span Backward Test). LTV and mean lap time (MLT) were obtained from the 400-m walk test concurrent with the baseline executive function assessment. LTV was computed as variability of lap time across ten 40-m laps based on individual trajectories. A linear mixed-effects model was used to examine LTV in relation to changes in executive function, adjusted for age, sex, education, and MLT. Higher LTV was associated with greater decline in performance on Trails B (β = 4.322, p < 0.001) and delta TMT (β = 4.230, p < 0.001), independent of covariates. Findings remained largely unchanged after further adjustment for MLT. LTV was not associated with changes in other executive function measures (all p > 0.05). In high-functioning older adults, higher LTV in the 400-m walk predicts executive function decline involving cognitive flexibility and set shifting over a long period of time. High LTV may be an early indicator of executive function decline independent of MLT.
PMCID: PMC5005853  PMID: 26561401
Lap time variation; Executive function; Longitudinal study; Aging
20.  Frailty as a Predictor of the Incidence and Course of Depressed Mood 
Late-life depression and physical frailty are supposed to be reciprocally associated, however, longitudinal studies are lacking.
This study examines whether physical frailty predicts a higher incidence of depression, as well as a less favorable course of depression.
A population-based cohort study of 888 people aged 65 years and over with follow-up measures at 3, 6, and 9 years. Cox proportional hazards models adjusted for age, sex, education, smoking, alcohol usage, and global cognitive functioning were applied to calculate the incidence of depressed mood in those nondepressed at baseline (n = 699) and remission in those with depressed mood at baseline (n = 189). Depressed mood onset or remission was defined as crossing the cut-off score of 20 points on the Center for Epidemiological Studies-Depression Scale combined with a relevant change in this score. Physical frailty was based on the presence of ≥3 out of 5 components (ie, weight loss, weakness, slowness, exhaustion, and low physical activity level).
A total of 214 out of 699 (30.6%) nondepressed persons developed depressed mood during follow-up. Physical frailty predicted the onset of depressed mood with a hazard rate of 1.26 (95% confidence interval 1.09–1.45, P = .002). Of the 189 persons with depressed mood at baseline, 96 (50.8%) experienced remission during follow-up. Remission was less likely in the presence of a higher level of physical frailty (hazard rate = 0.72, 95% confidence interval 0.58–0.91, P = .005).
Because physical frailty predicts both the onset and course of late-life depressed mood, physical frailty should receive more attention in mental health care planning for older persons as well as its interference with treatment. Future studies into the pathophysiological mechanisms may guide the development of new treatment opportunities for these vulnerable patients.
PMCID: PMC5127267  PMID: 25737263
Depression; frailty; older persons; InCHIANTI
21.  Aging and Multimorbidity: New Tasks, Priorities, and Frontiers for Integrated Gerontological and Clinical Research 
Aging is characterized by rising susceptibility to development of multiple chronic diseases and, therefore, represents the major risk factor for multimorbidity. From a gerontological perspective, the progressive accumulation of multiple diseases, which significantly accelerates at older ages, is a milestone for progressive loss of resilience and age-related multisystem homeostatic dysregulation. Because it is most likely that the same mechanisms that drive aging also drive multiple age-related chronic diseases, addressing those mechanisms may reduce the development of multimorbidity. According to this vision, studying multimorbidity may help to understand the biology of aging and, at the same time, understanding the underpinnings of aging may help to develop strategies to prevent or delay the burden of multimorbidity. As a consequence, we believe that it is time to build connections and dialogue between the clinical experience of general practitioners and geriatricians and the scientists who study aging, so as to stimulate innovative research projects to improve the management and the treatment of older patients with multiple morbidities.
PMCID: PMC5125299  PMID: 25958334
Multimorbidity; multiple morbidities; aging; chronic disease
22.  Chronic Low-Calorie Sweetener Use and Risk of Abdominal Obesity among Older Adults: A Cohort Study 
PLoS ONE  2016;11(11):e0167241.
Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity.
Participants and Methods
We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0–28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-calorie sweetener use with longitudinal outcomes—body mass index, waist circumference, obesity and abdominal obesity—with outcome status assessed at the visit following low-calorie sweetener ascertainment to minimize the potential for reverse causality. All models were adjusted for year of visit, age, sex, age by sex interaction, race, current smoking status, dietary intake (caffeine, fructose, protein, carbohydrate, and fat), physical activity, diabetes status, and Dietary Approaches to Stop Hypertension score as confounders.
With median follow-up of 10 years, low-calorie sweetener users had 0.80 kg/m2 higher body mass index (95% confidence interval [CI], 0.17–1.44), 2.6 cm larger waist circumference (95% CI, 0.71–4.39), 36.7% higher prevalence (prevalence ratio = 1.37; 95% CI, 1.10–1.69) and 53% higher incidence (hazard ratio = 1.53; 95% CI 1.10–2.12) of abdominal obesity than low-calorie sweetener non-users.
Low-calorie sweetener use is independently associated with heavier relative weight, a larger waist, and a higher prevalence and incidence of abdominal obesity suggesting that low-calorie sweetener use may not be an effective means of weight control.
PMCID: PMC5120853  PMID: 27880832
23.  Effect of ghrelin on bone mass density: The InChianti study 
Bone  2011;49(2):257-263.
Ghrelin is a stomach secreted hormone, believed to play an important role in energy balance and in food intake. Experimental studies have shown a positive effect of ghrelin on bone metabolism, but both in vivo and clinical findings have been contradictory. We aimed to investigate the effect of ghrelin on volumetric BMD in a large cohort of elderly subjects.
We have studied 401 women (mean age 75.1 years, range 65–94) and 306 men (mean age 73.9 years, range 65–94) from the InChianti study, which included measurements of BMD using quantitative CT of the tibia and of body composition using bio impedancemetry. Serum ghrelin was measured using ELISA. We excluded participants with diabetes, hyperthyroidism, using hormone replacement or glucocorticoid therapy. We evaluated the correlation of ghrelin with total, trabecular, and cortical BMD using Pearson's coefficient, and linear regression models to estimate the association between ghrelin and BMD controlling for potential confounders.
In women, after correction for potential confounders, ghrelin was associated with trabecular BMD (β = 7.08, P<0.02), but not with total or cortical BMD. In men, adjusted multivariable models showed a nearly significant association between serum ghrelin and trabecular BMD (β = 4.99, P = 0.069) and no association with either cortical or total BMD.
Serum ghrelin is positively correlated with trabecular BMD in a cohort of elderly healthy Italian women. The fact that trabecular is more metabolically active than cortical bone and the larger number of females might explain this selective association.
PMCID: PMC5119485  PMID: 21501701
Ghrelin; Bone mass; pQCT; Aged; 65 years and older; Cross-sectional studies
24.  Comparison of 24-h volume and creatinine-corrected total urinary polyphenol as a biomarker of total dietary polyphenols in the Invecchiare InCHIANTI study 
Analytica chimica acta  2011;704(1-2):110-115.
Polyphenols have beneficial effects on several chronic diseases but assessing polyphenols intake from self-reported dietary questionnaires tends to be inaccurate and not very reliable. A promising alternative is to use urinary excretion of polyphenols as a proxy measure of intake. The best method to assess urinary excretion is to collect 24-h urine. However, since collecting 24-h urine method is expensive, time consuming and may be difficult to implement in large population-based studies, measures obtained from spot urine normalized by creatinine are commonly used. The purpose of the study was to evaluate the correlation between polyphenols dietary intake and total urinary polyphenol excretion (TPE), expressed by both 24-h volume and urinary creatinine normalization in 928 participants from the InCHIANTI study. Dietary intake data were collected using a validated food frequency questionnaire. Urinary TPE was analyzed by Folin–Ciocalteau assay. Both urinary TPE expression models were statistically correlated (r = 0.580), and the partial correlation coefficient improved (pr = 0.722) after adjusting for the variables that modify the urinary creatinine excretion (i.e. gender, age, BMI, physical activity and renal function). In crude models, polyphenol intake was associated with TPE corrected by 24-h volume (r = 0.211; P < 0.001), but not with creatinine normalization (r = 0.014; P = 0.692). However, urinary TPE expressed by creatinine correction was significantly correlated with dietary polyphenols after adjusting for covariates (pr = 0.113; P = 0.002). We conclude that urinary TPE expressed by 24-h volume is a better biomarker of polyphenol dietary intake than by urinary creatinine normalization. After covariate adjustment, both can be used for studying the relationships between polyphenol intake and health in large-scale epidemiological studies.
PMCID: PMC5119503  PMID: 21907027
Polyphenols; Urine 24-h; Creatinine normalization; Biomarker; InCHIANTI study
25.  A Multidimensional Prognostic Index (MPI) based on a comprehensive geriatric assessment predicts short- and long-term all-cause mortality in older hospitalized patients with transient ischemic attack 
Journal of neurology  2011;259(4):670-678.
A multidimensional impairment may influence the clinical outcome of acute diseases in older patients. The aim of the current study was to evaluate whether a Multidimensional Prognostic Index (MPI) based on a comprehensive geriatric assessment (CGA) predicts short- and long-term all-cause mortality in older patients hospitalized for transient ischemic attack (TIA). In this prospective study with 1-year follow-up, 654 patients aged 65 and older with a diagnosis of TIA according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM 435.x) were enrolled. A standardized CGA that included information on functional (activities of daily living, ADL, and Instrumental ADL), cognitive status (Short Portable Mental Status Questionnaire), nutrition (Mini Nutritional Assessment), risk of pressure sores (Exton-Smith Scale), comorbidities (Cumulative Illness Rating Scale), medications and co-habitation status was used to calculate the MPI for mortality using a previously validated algorithm. Higher MPI values were significantly associated with higher 1-month all-cause mortality (incidence rates: MPI-1 low risk = 0.32%, MPI-2 moderate risk = 5.36%, MPI-3 high risk = 10.42%; p < 0.001), 6-month all-cause mortality (MPI-1 = 1.95%, MPI-2 = 9.77%, MPI-3 = 27.22%; p < 0.001) and 12-month all-cause mortality (MPI-1 = 5.19%, MPI-2 = 16.47%, MPI-3 = 44.32%; p < 0.001). Age- and gender-adjusted Cox regression analyses demonstrated that MPI was a significant predictor of all-cause mortality. MPI showed a significant high discriminatory power with an area under the receiver operating characteristics (ROC) curve of 0.819, 95% CI = 0.749–0.888 for 1-month mortality, 0.799, 95% CI = 0.738–0.861 for 6-month mortality and 0.770, 95% CI = 0.716–0.824 for 12-month mortality. The MPI, calculated from information collected in a standardized CGA, appeared to be effective in estimating short- and long-term all-cause mortality in older patients hospitalized for TIA.
PMCID: PMC5119506  PMID: 21947223
Transient ischemic attack (TIA); All-cause mortality; Risk factor; Multidimensional Prognostic Index (MPI); Aging; Comprehensive geriatric assessment (CGA)

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