The SIRT1 promoter polymorphic site rs12778366 increases IL-6 related human mortality in the prospective study “Treviso Longeva (TRELONG)”

Studies on sirtuins (SIRT), a family of proteins with deacetylase activity, have provided convergent evidence of the key role of these enzymes in aging-linked physiological functions. The link between SIRT1 and longevity has emerged in model organism but few data are available in humans, in particular relying on longitudinal studies. Here, we assessed whether a genetic variant within SIRT1 gene promoter (rs12778366) was associated to human longevity. We analyzed 586 genomic DNA (gDNA) collected in the study "Treviso Longeva" (TRELONG), including elderly over 70 years of age from the municipality of Treviso, a town in the Northeast of Italy, with a 11-year follow-up. We genotyped SIRT1 rs12778366 by real-time polymerase chain reaction (RT-PCR) allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association between rs12778366 and longevity. When we performed a longitudinal analysis considering mortality as dependent variable, we did not observe an association of rs12778366 with longevity in the whole population (corrected P-value = 0.33). However, when we stratified the TRELONG subjects according to circulating level of interleukin-6 (IL-6), a predictor of disability and mortality, we found that rs12778366 (TC+CC) carriers were at increased risk of mortality in comparison to the TT reference group (corrected P-value = 0.03, HR 1.47). Our data do not support a major role of rs12778366 in human longevity, but the stratified analysis on IL-6 suggests that this variant may be involved in the detrimental effect of high circulating IL-6 in the elderly

Body Mass Index, Cognition, Disability, APOE Genotype, and Mortality: The "Treviso Longeva" Study.

Objectives: The concurrent contributions of dynamic, interrelated late-life parameters, such as body mass index (BMI), cognition, and physical functioning on mortality in the elderly are unclear, as is the influence of APOE genotype. We explored these measures in relation to 7-year mortality in long-lived Italian elderly. Design: A representative, age-stratified, population sample. Setting: The Treviso Longeva (TRELONG) Study, in Treviso, Italy. Participants: Three hundred eleven men and 357 women, aged 70 years and older (mean age 84 +/- 8 years). Measurements: Seven-year mortality, BMI, Mini-Mental State Exam (MMSE) score, Activities of Daily Living (ADL), APOE genotype, and a variety of clinical and survey data. Results: In separate age- and sex-adjusted analyses, BMI =30 kg/m2 was protective. There were no interactions between BMI, MMSE, or ADL. When excluding those dying within 3 years of baseline, only an MMSE <=24 was related to mortality. APOE[Latin Small Letter Open E]4 was not related to mortality. Conclusion: Higher MMSE score, higher ADL score, and higher BMI, independent of age, sex, and other factors, are markers for longer life among northern Italian adults aged 70 years or older. Global cognition, BMI, and physical functioning, assessed by short, simple tests are profound indicators of death within less than a decade

Melatonin and the Charlson Comorbidity Index (CCI): the Treviso Longeva (Trelong) study

Introduction: It has been reported that elderly subjects have a compromised ability to produce melatonin nightly, and that reduced melatonin levels may be a risk factor for cancer. The purpose of this study was to evaluate the relationship between melatonin levels and chronic diseases in a cohort of elderly subjects using the Charlson comorbidity index (CCI). Design: We performed a secondary data analysis of a longitudinal study of a representative, age-stratified, sample population. Setting: The Treviso Longeva (Trelong) study, in Treviso, Italy. Participants: A total of 114 men and 146 women, aged 77 years and older, still alive after 7 years of follow-up. Measurements: As an estimation of serum melatonin secretion levels, urinary 6-sulfatoxymelatonin (aMT6s) was assayed in the urine of 260 elderly subjects using an enzyme-linked immunosorbent assay (ELISA) kit (product 01-EK-M6S, ALPCO Immunoassays, Windham, NH). All aMT6s levels were creatinine standardized ([aMT6s]/[creatinine]), and the CCI was calculated. Results: The melatonin levels decreased with aging despite not reaching statistical significance, and the decrease was more evident in males than in females (40.5 ng vs 47.0 ng aMT6s/mg creatinine, ns). Melatonin levels were significantly lower in patients reporting insomnia (p=0.05). The CCI score was inversely correlated with the levels of melatonin (p=0.03). Melatonin levels of subjects affected by CCI pathologies were significantly lower than those of healthy subjects (p=0.03) and of subjects suffering from diseases not included in the CCI and, therefore, less severe (p=0.03). Conclusion: Melatonin appears to be a marker of disease state and severity, as well as of sleep disorders, in the elderly. These early findings would confirm the protective role of melatonin against several chronic diseases. The benefits of this agent as a possible medication should be more thoroughly clinically tested

BODY MASS INDEX, LIFESTYLES, PHYSICAL PERFORMANCE AND COGNITIVE DECLINE: THE "TREVISO LONGEVA (TRELONG)" STUDY

The relative contributions of risk factors, as body mass index (BMI), depression, chronic diseases, smoking, and lifestyles (as physical and performance activity, social contacts and reading habit) to cognitive decline in the elderly are unclear. We explored these variables in relation to 7-year cognitive decline in long-lived Italian elderly. Design: Secondary data analysis of a longitudinal study of a representative, agestratified, population sample. Setting: The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. Participants: 120 men and 189 women, age 77 years and older (mean age 80.2 \ub1 6.9 years) survivors after seven years of follow up. Measurements: Cognitive decline measured as difference between Mini-Mental State Examination (MMSE) score in 2003 and in 2010; Body mass index (BMI), handgrip, Short Physical Performance Battery (SPPB) score, social contacts, reading habit, sight, hearing, schooling, mediterranean diet and multiple clinical and survey data recorded at baseline in 2003. Results: In separate univariate analyses, age, SPPB score < 5, depressive symptoms (GDS) and more comorbidities (CCI) were associated with greater cognitive decline. Otherwise higher BMI, higher handgrip, reading habit, non-deteriorated sight and hearing, and schooling were protective. In a final multivariate model, age and higher BMI were associated with greater cognitive decline while reading habits was protective. SPPB score < 5 tends, though weakly, to be associated with greater cognitive decline. These associations remained with multivariate adjustment for gender, schooling, Charlson co-morbidity index (CCI) and baseline MMSE. Conclusion: Age and higher baseline BMI, independent of gender, and other confounding factors, are risk factors for cognitive decline. Reading habit plays a protective role seven years later among northern Italian adults aged 70 years or older. Low physical performance tends, though weakly, to be associated with greater cognitive decline

Insulin-like growth factor 1 receptor polymorphism rs2229765 and circulating interleukin-6 level affect male longevity in a population-based prospective study (Treviso Longeva- TRELONG).

Insulin-like growth factor 1 (IGF-1) signaling modulation has been associated with increased lifespan in model organisms, while high levels of circulating interleukin-6 (IL-6) are a marker of disability and mortality. In the prospective, population-based "Treviso Longeva"--TRELONG Study from Italy (n = 668, age range 70-105.5 years at baseline, followed for seven years) we investigated the effects of survival on the IGF-1 receptor (IGF-1R) gene polymorphism rs2229765, the IL-6 gene promoter polymorphism rs1800795, and plasma concentrations of IGF-1 and IL-6, alone or in combination. We found a sex-dependent effect for the IGF-1R rs2229765 polymorphism, as male carriers of the homozygous A/A genotype survived longer, while the IL-6 rs1800795 genotype did not influence overall or sex-specific longevity. Higher IL-6 levels were more detrimental for survival among males than females, while IGF-1 had no dose-response effect. These findings sustain the hypothesis that sex-specific longevity relies on detectable differences in genetic and biochemical parameters between males and females

Melatonin and the Charlson Comorbidity Index (CCI): the Treviso Longeva (Trelong) study.

Introduction: It has been reported that elderly subjects have a compromised ability to produce melatonin nightly, and that reduced melatonin levels may be a risk factor for cancer. The purpose of this study was to evaluate the relationship between melatonin levels and chronic diseases in a cohort of elderly subjects using the Charlson comorbidity index (CCI). Design: We performed a secondary data analysis of a longitudinal study of a representative, age-stratified, sample population. Setting: The Treviso Longeva (Trelong) study, in Treviso, Italy. Participants: A total of 114 men and 146 women, aged 77 years and older, still alive after 7 years of follow-up. Measurements: As an estimation of serum melatonin secretion levels, urinary 6-sulfatoxymelatonin (aMT6s) was assayed in the urine of 260 elderly subjects using an enzyme-linked immunosorbent assay (ELISA) kit (product 01-EK-M6S, ALPCO Immunoassays, Windham, NH). All aMT6s levels were creatinine standardized ([aMT6s]/[creatinine]), and the CCI was calculated. Results: The melatonin levels decreased with aging despite not reaching statistical significance, and the decrease was more evident in males than in females (40.5 ng vs 47.0 ng aMT6s/mg creatinine, ns). Melatonin levels were significantly lower in patients reporting insomnia (p=0.05). The CCI score was inversely correlated with the levels of melatonin (p=0.03). Melatonin levels of subjects affected by CCI pathologies were significantly lower than those of healthy subjects (p=0.03) and of subjects suffering from diseases not included in the CCI and, therefore, less severe (p=0.03). Conclusion: Melatonin appears to be a marker of disease state and severity, as well as of sleep disorders, in the elderly. These early findings would confirm the protective role of melatonin against several chronic diseases. The benefits of this agent as a possible medication should be more thoroughly clinically tested

Factors related to disability: Evidence from the \u201cTreviso Longeva (TRELONG) Study\u201d

Prolongation of life is an important public health goal as long as there is an emphasis on the quality of life (QoL) and independent living. Diminishing abilities to ambulate and participate in activities of daily living point to a serious decline in functional health, increasing the risk of institutionalization and death. In our work we found a pattern of factors associated with disability, especially cognitive impairment, as well as stroke, physical activity and performance, reading, and the nutritional biomarkers, blood albumin and high-density lipoprotein cholesterol (HDL-C). The attention to this cluster of markers, suggesting multidimensional prevention, may have unexpected good effects against disability

Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study "Treviso Longeva (TRELONG)

Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to investigate whether variants within SIRT3 gene were associated to human longevity. We analyzed 549 genomic DNA collected during the prospective study \u201cTreviso Longeva,\u201d including elderly over 70 years of age from the municipality of Treviso, a small city in the northeast of Italy. We genotyped SIRT3 rs3825075, rs4980329, and rs11555236 single nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a dependent variable, we observed an association of SIRT3 rs11555236 and rs4980329 with longevity in the whole population (p values corrected for potential confounders= 0.04 and 0.03, respectively). After stratification according to gender, the same SNPs were associated to female longevity only (p values corrected for potential confounders=0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer within the SIRT3 gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3 protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for the (T) allele. We suggest that SIRT3 genetic variability might be relevant for the modulation of human longevity in the Italian population

The Treviso dementia (TREDEM) study: a biomedical, neuroradiological, neuropsychological and social investigation on dementia in the North-east of Italy

The incidence of dementia increases exponentially with age but knowledge of real disease-modifying interventions is still limited. Objectives: To describe the study design and methods of a large prospective cohort study aimed at exploring the complex underlying relationships existing among cognition, frailty, and health-related events in older persons with cognitive impairment. Design: Prospective cohort study of a representative population of outpatients attending the Treviso Cognitive Impairment Center between 2000 and 2010. Setting: The TREVISO DEMENTIA (TREDEM) Study conducted in Treviso, Italy. Participants: 490 men and 874 women, mean age 79.1 \ub1 7.8 years (range 40.2\u2013100 years). Measurements: Physiological data, biochemical parameters, clinical conditions, neuroradiological parameters (e.g., brain atrophy and cerebral vascular lesions identified by computerized tomography scans), neuropsychological assessment, and physical function markers were measured at baseline. Patients were followed-up to 10 years. Results: The final sample included in the study was predominantly composed of women and characterized by an initial physical function impairment and increased vascular risk profile. Cognitive function of the sample population showed moderate cognitive impairment (Mini Mental State Examination 20.2 \ub1 6.3; Clinical Dementia Rating 1.2 \ub1 0.7), and a prevalence of vascular dementia of 26.9%. Cortical, subcortical and hippocampus atrophy were all significantly correlated with age and cognitive function. Conclusion: Results obtained from the preliminary analyses conducted in the TREDEM study suggest that the database will support the accomplishment of important goals in understanding the nature of cognitive frailty and neurodegenerative diseases