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PurposeDietary guidelines recommend to limit egg consumption to 4 servings per week but the relation between egg intake and health outcomes is still controversial. To evaluate the association of egg consumption and mortality risk in Italian adults and to investigate nutritional factors and serum lipids as potentially explaining such associations.MethodsLongitudinal analysis on 20,562 men and women aged ≥ 35y, free from cardiovascular disease (CVD) and cancer belonging to the Moli-sani Study cohort (enrolled 2005–2010) followed up for a median of 8.2 years.ResultsIn multivariable-adjusted analysis as compared to low intake (> 0 ≤ 1 egg/week), eating > 4 eggs/week led to an increased risk of all-cause (Hazard ratio [HR] = 1.50; 95%CI 1.13–1.99), CVD (HR = 1.75; 1.07–2.87) and cancer mortality (HR = 1.52; 0.99–2.33). Similarly, an intake of 2–4 eggs/week was associated with higher all-cause (HR = 1.22; 1.01–1.46) and CVD mortality risk (HR = 1.43; 1.03–1.97). An increase of 1 egg per week was associated with higher mortality risk among high-risk individuals, such as those with hypertension and hyperlipidaemia. Dietary cholesterol explained about 43.0% and 39.3% (p values < 0.0001) of the association of eggs with all-cause and CVD mortality, respectively, while serum lipids (e.g., total cholesterol) accounted for a small proportion of egg-mortality relation.ConclusionsAmong Italian adults, high egg consumption leads to an increased risk of all-cause and CVD mortality, with the risk being evident even at the recommended intake of 2–4 eggs per week. A substantial part of this association was likely due to the egg contribution to dietary cholesterol. Our findings suggest limiting the consumption of eggs in the diet and these results should be considered in the development of dietary guidelines and updates.

PurposeTo evaluate in an Italian general population, the association with mortality of a traditional Mediterranean diet (MD) and non-Mediterranean dietary (non-MD) patterns, and their combined effect, and to test some biomarkers of cardiovascular (CVD) risk as potential mediators of such associations.MethodsLongitudinal analysis on 22,849 men and women aged ≥ 35 years, recruited in the Moli-sani Study (2005–2010), followed up for 8.2 years (median). The MD was assessed by the Mediterranean diet score (MDS). The Dietary Approaches to Stop Hypertension (DASH), the Palaeolithic diet, and the Nordic diet were chosen as reportedly healthy non-MD patterns. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated by multivariable Cox regression.ResultsParticipants reaching higher MDS or DASH diet score experienced lower risk of both all-cause (HR 0.77; 95% CI 0.66–0.90 and 0.81; 0.69–0.96, respectively, highest vs lowest quartile) and CVD (0.77; 0.59–1.00 and 0.81; 0.69–0.96, respectively) death risk; risk reduction associated with the Palaeolithic diet was limited to total and other cause death, whereas the Nordic diet did not alter risk of mortality. Increasing adherence to MD was associated with higher survival in each stratum of non-MD diets. Biomarkers of glucose metabolism accounted for 7% and 21.6% of the association between either MDS or DASH diet, respectively, with total mortality risk.ConclusionsBoth the traditional MD and DASH diet may reduce risk of all-cause mortality among Italians, as well as risk of dying from cardiovascular causes. The Palaeolithic diet did not appear to reduce cardiovascular risk, while the Nordic eating pattern was unlikely to be associated with any substantial health advantage.

Background/Objectives: Neuromedin U (NMU) is a highly conserved gene encoding a neuropeptide involved in the regulation of feeding behavior and energy homeostasis. We aimed to analyze the association between NMU genetic and epigenetic variations and cardio-metabolic parameters in an Italian population to identify the role of these variants in cardio-metabolic risk. Methods: A total of 4028 subjects were randomly selected from the Moli-sani study cohort. NMU haplotypes were estimated using seven SNPs located in the gene body and in the promoter region; DNA methylation levels in the promoter region, previously associated with lipid-related variables in the same population, were also used. Results: Among the haplotypes inferred, the haplotype carrying the highest number of minor variants (frequency 16.6%), when compared with the most frequent haplotype, was positively associated with insulin levels, HOMA-IR, and diastolic blood pressure, and negatively with HDL-cholesterol. The multivariable analysis that considered methylation levels along with their interactions with SNPs showed that increased methylation levels in two close CpG sites were associated with higher levels of lipid-related variables. Conclusions: This study supports a role for NMU as a regulator of human metabolism. This finding suggests that NMU could be a potential target for preventive interventions against coronary and cerebrovascular diseases, and that NMU genetic and epigenetic variability may serve as a biomarker for cardio-metabolic risk.

Neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD) suffer from the lack of risk-predictive circulating biomarkers, and clinical diagnosis occurs only when symptoms are evident. Among potential biomarkers, platelet parameters have been associated with both disorders. However, these associations have been scarcely investigated at the genetic level. Here, we tested genome-wide coheritability based on common genetic variants between platelet parameters and PD/AD risk, through Linkage Disequilibrium Score Regression. This revealed a significant genetic correlation between platelet distribution width (PDW), an index of platelet size variability, and PD risk (r [SE] = 0.080 [0.034]; p = 0.019), which was confirmed by a summary-summary polygenic score analysis, where PDW explained a small but significant proportion PD risk (<1%). AD risk showed no significant correlations, although a negative trend was observed with PDW (rg [SE] =-0.088 [0.053]; p=0.096), in line with previous epidemiological reports. These findings suggest the existence of limited shared genetic bases between PDW and PD and warrant further investigations to clarify the genes involved in this relation. Additionally, they suggest that the association between platelet parameters and AD risk is more environmental in nature, prompting an investigation into which factors may influence these traits.

Background Polypharmacy, defined as taking ≥ 5 different daily medications, is common in older adults and has been linked with neuropsychiatric/neurological and other health conditions. To clarify the potential molecular implications, we tested the hypothesis that polypharmacy may influence DNA methylation (DNAm) patterns in aging, in a longitudinal Italian cohort (N = 1,098; mean (SD) age at recruitment: 58.8 (5.6) years, 51.3% women; median (IQR) follow-up 12.6 (1.1) years). Results We tested associations of polypharmacy with several DNAm aging clocks (Hannum, Horvath, GrimAge, DNAmPhenoAge, DunedinPACE), through linear mixed models incrementally adjusted for age, sex, education, prevalent health conditions and lifestyles, leukocyte counts and residual batch effects. This revealed significant positive associations of GrimAge acceleration and DunedinPACE with the switch to polypharmacy status during follow-up (Beta (SE): 0.024 (0.008) and0.0012 (0.0004)). While the association of GrimAge was driven by a DNAm-based surrogate of tissue inhibitor metalloproteinase 1 (TIMP-1), no significant association was detected for component CpGs of DunedinPACE. When we tested associations of polypharmacy with 668,413 CpGs epigenome-wide, we observed no statistically significant findings (top hit: cg07675998; chr11q13.1; Beta (SE) = 0.009 (0.002); p  = 1.5 × 10 –6 ). However, these showed significant enrichments of several biological functions and pathways related to renal tissue, lipoproteins, inflammatory and immune response. Conclusions These findings suggest an influence of polypharmacy on accelerated epigenetic aging and on altered methylation patterns in the genome, suggesting a potential implication of pathways related to renal tissue development, lipoproteins and cholesterol homeostasis, inflammatory and immune response, in line with previous proteomic analyses of polypharmacy mouse models. These observations also suggest potential targets for mitigating disruptive effects of polypharmacy on elderly health.

PurposeNutrition is an important, modifiable, environmental factor affecting human health by modulating epigenetic processes, including DNA methylation (5mC). Numerous studies investigated the association of nutrition with global and gene-specific DNA methylation and evidences on animal models highlighted a role in DNA hydroxymethylation (5hmC) regulation. However, a more comprehensive analysis of different layers of nutrition in association with global levels of 5mC and 5hmC is lacking. We investigated the association between global levels of 5mC and 5hmC and human nutrition, through the stratification and analysis of dietary patterns into different nutritional layers: adherence to Mediterranean diet (MD), main food groups, macronutrients and micronutrients intake.MethodsELISA technique was used to measure global 5mC and 5hmC levels in 1080 subjects from the Moli-sani cohort. Food intake during the 12 months before enrolment was assessed using the semi-quantitative EPIC food frequency questionnaire. Complementary approaches involving both classical statistics and supervised machine learning analyses were used to investigate the associations between global 5mC and 5hmC levels and adherence to Mediterranean diet, main food groups, macronutrients and micronutrients intake.ResultsWe found that global DNA methylation, but not hydroxymethylation, was associated with daily intake of zinc and vitamin B3. Random Forests algorithms predicting 5mC and 5hmC through intakes of food groups, macronutrients and micronutrients revealed a significant contribution of zinc, while vitamin B3 was reported among the most influential features.ConclusionWe found that nutrition may affect global DNA methylation, suggesting a contribution of micronutrients previously implicated as cofactors in methylation pathways.

AbstractObjectiveTo jointly analyse two food dimensions, the Food Standards Agency Nutrient Profiling System (FSAm-NPS), used to derive the Nutri-Score front-of-pack label, and the NOVA classification in relation to mortality.DesignProspective cohort study.SettingMoli-sani Study, Italy 2005-10.Participants22 895 participants (mean age 55 (SD 12) years; 48% men).Main outcomes measuresAssociations between dietary exposures and mortality risk, assessed using multivariable cause specific Cox proportional hazard models controlled for known risk factors.ResultsA total of 2205 deaths occurred during 272 960 person years of follow-up. In the highest quarter of the FSAm-NPS index compared with the lowest quarter, multivariable adjusted hazard ratios for all cause and cardiovascular mortality were 1.19 (95% confidence interval 1.04 to 1.35; absolute risk difference 4.3%, 95% confidence interval 1.4% to 7.2%) and 1.32 (1.06 to 1.64; 2.6%, 0.3% to 4.9%), respectively. The hazard ratios were 1.19 (1.05 to 1.36; absolute risk difference 9.7%, 5.0% to 14.3%) and 1.27 (1.02 to 1.58; 5.0%, 1.2% to 8.8%), respectively, for all cause and cardiovascular mortality when the two extreme categories of ultra-processed food intake were compared. When these two indices were analysed jointly, the magnitude of the association of the FSAm-NPS dietary index with all cause and cardiovascular mortality was attenuated by 22.3% and 15.4%, respectively, whereas mortality risks associated with high ultra-processed food intake were not altered.ConclusionsAdults with the lowest quality diet, as measured using the FSAm-NPS dietary index (underpinning the Nutri-Score), and the highest ultra-processed food consumption (NOVA classification) were at the highest risk for all cause and cardiovascular mortality. A significant proportion of the higher mortality risk associated with an elevated intake of nutrient poor foods was explained by a high degree of food processing. In contrast, the relation between a high ultra-processed food intake and mortality was not explained by the poor quality of these foods.

Previous studies have shown that heat shock stress may activate transposable elements (TEs) in Drosophila and other organisms. Such an effect depends on the disruption of a chaperone complex that is normally involved in biogenesis of Piwi-interacting RNAs (piRNAs), the largest class of germline-enriched small noncoding RNAs implicated in the epigenetic silencing of TEs. However, a satisfying picture of how chaperones could be involved in repressing TEs in germ cells is still unknown. Here we show that, in Drosophila, heat shock stress increases the expression of TEs at a posttranscriptional level by affecting piRNA biogenesis through the action of the inducible chaperone Hsp70. We found that stress-induced TE activation is triggered by an interaction of Hsp70 with the Hsc70−Hsp90 complex and other factors all involved in piRNA biogenesis in both ovaries and testes. Such interaction induces a displacement of all such factors to the lysosomes, resulting in a functional collapse of piRNA biogenesis. This mechanism has clear evolutionary implications. In the presence of drastic environmental changes, Hsp70 plays a key dual role in increasing both the survival probability of individuals and the genetic variability in their germ cells. The consequent increase of genetic variation in a population potentiates evolutionary plasticity and evolvability.

BackgroundBody mass index (BMI) is the most frequently used adiposity measure, yet it is unable to differentiate fat mass from lean mass. Relative fat mass (RFM) has been proposed as an alternative. This paper aims to study RFM and BMI association with mortality in a general Italian population and potential mediators of such association.Methods20,587 individuals from the Moli-sani cohort were analysed (mean age = 54 ± 11, women = 52%, median follow up = 11.2 years, interquartile range = 1.96 years). Cox regressions were used to assess BMI, RFM, and their interactive association with mortality. Dose-response relationships were computed with spline regression, mediation analysis was performed. All analyses were separated for men and women.ResultsMen and women with BMI > 35 kg/m2 and men in the 4th quartile of RFM showed an independent association with mortality (HR = 1.71, 95% CI = 1.30–2.26 BMI in men, HR = 1.37, 95%CI = 1.01–1.85 BMI in women, HR = 1.37 CI 95% = 1.11–1.68 RFM in men), that was lost once adjusted for potential mediators. Cubic splines showed a U-shaped association for BMI in men and women, and for RFM in men. Mediation analysis showed that 46.5% of the association of BMI with mortality in men was mediated by glucose, C reactive protein, forced expiratory volume in 1 s (FEV1), and cystatin C; 82.9% of the association of BMI in women was mediated by HOMA index, cystatin C and FEV1; lastly, 55% of RFM association with mortality was mediated by glucose, FEV1 and cystatin C. Regression models including BMI and RFM showed that RFM drives most of the risk in men, but is not predictive in women.ConclusionsThe association between anthropometric measures and mortality was U shaped and it was largely dependent on sex. Associations were mediated by glucose metabolism, renal and lung function. Public health interventions should mainly focus on people with severe obesity or impaired metabolic, renal, or respiratory function.

Chromosomal interactions connect distant enhancers and promoters on the same chromosome, activating or repressing gene expression. PEAR1 encodes the Platelet-Endothelial Aggregation Receptor 1, a contact receptor involved in platelet function and megakaryocyte and endothelial cell proliferation. PEAR1 expression during megakaryocyte differentiation is controlled by DNA methylation at its first CpG island. We identified a PEAR1 cell-specific methylation sensitive region in endothelial cells and megakaryocytes that showed strong chromosomal interactions with ISGL20L2, RRNAD1, MRLP24, HDGF and PRCC, using available promoter capture Hi-C datasets. These genes are involved in ribosome processing, protein synthesis, cell cycle and cell proliferation. We next studied the methylation and expression profile of these five genes in Human Umbilical Vein Endothelial Cells (HUVECs) and megakaryocyte precursors. While cell-specific PEAR1 methylation corresponded to variability in expression for four out of five genes, no methylation change was observed in their promoter regions across cell types. Our data suggest that PEAR1 cell-type specific methylation changes may control long distance interactions with other genes. Further studies are needed to show whether such interaction data might be relevant for the genome-wide association data that showed a role for non-coding PEAR1 variants in the same region and platelet function, platelet count and cardiovascular risk.