F. Lauretani

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (pu200a=u200a1.8×10−57), CCL4L1 (pu200a=u200a3.9×10−21), IL18 (pu200a=u200a6.8×10−13), LPA (pu200a=u200a4.4×10−10), GGT1 (pu200a=u200a1.5×10−7), SHBG (pu200a=u200a3.1×10−7), CRP (pu200a=u200a6.4×10−6) and IL1RN (pu200a=u200a7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (pu200a=u200a6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

The hormonal pathway to cognitive impairment in older men

In older men there is a multiple hormonal dysregulation with a relative prevalence of catabolic hormones such as thyroid hormones and cortisol and a decline in anabolic hormones such as dehydroepiandrosterone sulphate, testosterone and insulin like growth factor 1 levels. Many studies suggest that this catabolic milieu is an important predictor of frailty and mortality in older persons. There is a close relationship between frailty and cognitive impairment with studies suggesting that development of frailty is consequence of cognitive impairment and others pointing out that physical frailty is a determinant of cognitive decline. Decline in cognitive function, typically memory, is a major symptom of dementia. The “preclinical phase” of cognitive impairment occurs many years before the onset of dementia. The identification of relevant modifiable factors, including the hormonal dysregulation, may lead to therapeutic strategies for preventing the cognitive dysfunction. There are several mechanisms by which anabolic hormones play a role in neuroprotection and neuromodulation. These hormones facilitate recovery after brain injury and attenuate the neuronal loss. In contrast, elevated thyroid hormones may increase oxidative stress and apoptosis, leading to neuronal damage or death. In this mini review we will address the relationship between low levels of anabolic hormones, changes in thyroid hormones and cognitive function in older men. Then, giving the contradictory data of the literature and the multi-factorial origin of dementia, we will introduce the hypothesis of multiple hormonal derangement as a better determinant of cognitive decline in older men.

Changes in anthropometric measures in men and women across the life-span: findings from the InCHIANTI study.

Summary¶¶Objectives: To describe the age distribution of anthropometric parameters in a population-based sample of older persons.¶Methods: Cross-sectional survey of a population-based sample of persons over a wide age-range living in the Chianti area, Italy, between 1998 to 2000. Total cohort: 1 453 men and women, of whom 424 younger than 65 and 1 029 aged 65 years or older. Participation rate: 69.4 % in < 65 yrs and 91.6 % in ≤ 65 yrs. Analytical cohort: anthropometric measures were available for 1 266 subjects.¶Results: Height and weight declined with increasing age in both sexes. In men, Body mass index (BMI) increased with age up to age 45—54 and then it declined. In women, it reached its maximum at age 65—74 and remained higher than in men in each corresponding age group above 65 years of age. Waist-to-hip ratio (WHR) progressively increased in men up to age 55—64 and then slightly declined. In women WHR steadily increased over the entire age range.¶Conclusions: Height and weight decline with age, regardless to differences in body size attributable to secular trend. In both sexes, important fat redistribution occurs between 45 and 54 years and in older women the increase in WHR mostly reflects a reduction of fat deposits in the hips. This information may be relevant for a correct interpretation of changes in WHR in older persons. However, these findings were obtained in a cross-sectional study and should be verified in a longitudinal perspective.

Relationship between use of proton pump inhibitors and igf system in older subjects

Objectivesto investigate the effects of proton pump inhibitors (PPIs) on the insulin-like-growth factor 1(IGF-1) system in the elderly.Designcross-sectional.SettingInCHIANTI study.Participants938 older subjects (536 women, 402 men, mean age 75.7±7.4 years).Measurementscomplete data on age, sex, BMI, liver function, medications, dietary intake, IGF-1, IGF-binding protein-1 and -3 (IGFBP-1, IGFBP-3).ResultsParticipants were categorized by PPI use, identifying 903 PPI non users and 35 users. After adjusting for age, male PPI users (107.0 ± 69.6 vs 127.1 ± 55.8, p<0.001) and female PPI users (87.6 ± 29.1 vs 107.6 ± 52.3, p=0.03) had lower IGF-1 levels than non-users. IGFBP-1 levels were similar in the two groups in both sexes. In whole population, after adjustment for age and sex, PPI users had lower IGF-1 levels 81.9 [61.1–113.8] than nonusers 110 [77.8–148.6], p=0.02. After further adjustment for BMI, albumin, liver function, C-reactive protein, Interleukin-6, number of medications, ACE-inhibitors use, caloric intake, protein intake, physical activity, glycemia, and IGFBP-1, the use of PPIs remained significantly and negatively associated with IGF-1 levels (β±SE=−19.60±9.83, p=0.045).ConclusionUse of PPIs was independently and negatively associated with IGF-1 levels.

PP096-SUN: Inverse Relationship Between Carotenoids and Estradiol Levels in Older Women: Implication for Estrogen-Dependent Cancers?

Rationale: The HSCT patients have a tendency to lower serum vitamin D (VD). There is an important role in the regulation of VD and lymphocyte function T. The VD has an immunomodulatory effect that correlates with an increased incidence of Chronic GVHD and may increase mortality in this group of patients. Additionally, serum vitamin D levels are related to bacterial infection, ICU and relapse after HSCT. Objective: Analyse the relationship between disability and serum levels of vitamin D and risk of developing Acute GVHD. Methods: Retrospective study in Oncology and Hematology Department of the Albert Einstein Hospital (HIAE), with 19 patients (10 women, 9 men), adults (>18 years) who underwent HSCT, 42% of allogeneic related, 37% of unrelated allogeneic and 21% haploidential. The mean age was 46 years (±16) and weight 67 kg (±17). Of these patients, 59% had normal body mass index (BMI) (kg/m2), 21% overweight, 5% obese and 16% malnutrition. The exam for measurement of serum vitamin D (25-hydroxyvitamin D) was requested at the time of admission of the patient before the start of HSCT. The results of serum VD were classified into 50 nmol/ml normal. Results: There was a significant and negative correlation between BMI and serum levels of VD (rp = 0.5). 53% of patients had GVHD, but there was no significant relationship of the same with the other variables. There was a trend GVHD in the presence of low serum vitamin D also present in 53% of cases. Conclusion: GVHD is a disease with a high risk for patients undergoing HSCT, having great impact on the quality of life. Overweight and obese patients who have lower levels of VD should be better monitored, as tending to a higher risk of developing this complication.

Clinical and Biochemical Evaluation Changes Over Aging

It is widely recognized that the assessment of diseases status performed according to the traditional dichotomy “no disease vs. disease” is insufficient to understand the complexity of problems that influence health and well being in older persons. This concept was recognized long ago by geriatricians and implemented in the paradigm of “Comprehensive Geriatric Assessment”. Accordingly, many researchers and clinicians have proposed that the direct assessment of physical and cognitive function provides the essential information that is needed to design effective interventions in frail older persons. However, this approach has never been completely translated into clinical practice and many geriatricians claim that the administration of any available medical treatment is still conditioned to a previous diagnosis of specific diseases and hypotheses about specific pathophysiological pathways. Furthermore, significant changes in health status may occur and be amenable to effective treatment long before any clear effect on physical and cognitive function is detected.

Understanding the physiological and functional consequences of menopause: The PROSALMEN study

Background and aims: Women live longer and are more often affected by disability and poor health than men. The mechanism underlying this sex-related “mortality-morbidity” paradox is still unclear but it has been suggested that the physiological and functional changes occurring during the menopausal transition play an important role. The aim of PROSALMEN (PROgetto SALute MENopausa: Health in Menopause Project) is to study in great detail how these changes affect the integrity and function of the physiologic subsystems that are relevant to the maintenance of an active and healthy life-style during the aging process. Methods: PROSALMEN is a cross-sectional comparison of age-matched pre- and post-menopausal women. Thirty post-m enopausal women, aged 48–58 years, were enrolled in the study together with 30 age-matched pre-menopausal controls. A number of clinical, biological and functional parameters were collected assessing the integrity and level of function of the physiological subsystems that are important for mobility. Furthermore, we collected information on risk factors, medical conditions and symptoms that frequently develop or become clinically evident after menopause, including the most important elements of the classical post-m enopausal syndrome. Conclusions: This rich dataset will be used to start dissecting the causal pathway leading from menopause to damages in the musculoskeletal system and, in turn, to reduced physical function. The final goal is to understand how and to what extent changes in health behavior and pharmacological treatments in addition to hormone replacement therapy (HRT) may counteract these processes.