Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age.

DNA methylation (DNAm) is an emerging estimator of biological aging, i.e., the often-defined "epigenetic clock", with a unique accuracy for chronological age estimation (DNAmAge). In this pilot longitudinal study, we examine the hypothesis that intensive relaxing training of 60 days in patients after myocardial infarction and in healthy subjects may influence leucocyte DNAmAge by turning back the epigenetic clock. Moreover, we compare DNAmAge with another mechanism of biological age, leucocyte telomere length (LTL) and telomerase. DNAmAge is reduced after training in healthy subjects (p = 0.053), but not in patients. LTL is preserved after intervention in healthy subjects, while it continues to decrease in patients (p = 0.051). The conventional negative correlation between LTL and chronological age becomes positive after training in both patients (p < 0.01) and healthy subjects (p < 0.05). In our subjects, DNAmAge is not associated with LTL. Our findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. Our study reveals that DNAmAge may represent an accurate tool to measure the effectiveness of lifestyle-based interventions in the prevention of age-related diseases.

Complex relationships between occupation, environment, DNA adducts, genetic polymorphisms and bladder cancer in a case-control study using a structural equation modeling.

DNA adducts are considered an integrate measure of carcinogen exposure and the initial step of carcinogenesis. Their levels in more accessible peripheral blood lymphocytes (PBLs) mirror that in the bladder tissue. In this study we explore whether the formation of PBL DNA adducts may be associated with bladder cancer (BC) risk, and how this relationship is modulated by genetic polymorphisms, environmental and occupational risk factors for BC. These complex interrelationships, including direct and indirect effects of each variable, were appraised using the structural equation modeling (SEM) analysis. Within the framework of a hospital-based case/control study, study population included 199 BC cases and 213 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). No indirect paths were found, disproving hypothesis on association between PBL DNA adducts and BC risk. DNA adducts were instead positively associated with occupational cumulative exposure to AAs (p = 0.028), whereas XRCC1 Arg 399 (p<0.006) was related with a decreased adduct levels, but with no impact on BC risk. Previous findings on increased BC risk by packyears (p<0.001), coffee (p<0.001), cumulative AAs exposure (p = 0.041) and MnSOD (p = 0.009) and a decreased risk by MPO (p<0.008) were also confirmed by SEM analysis. Our results for the first time make evident an association between occupational cumulative exposure to AAs with DNA adducts and BC risk, strengthening the central role of AAs in bladder carcinogenesis. However the lack of an association between PBL DNA adducts and BC risk advises that these snapshot measurements are not representative of relevant exposures. This would envisage new scenarios for biomarker discovery and new challenges such as repeated measurements at different critical life stages.

CYP1A2 polymorphisms, occupational and environmental exposures and risk of bladder cancer.

Cytochrome P4501A2 (CYP1A2) is a key enzyme for activation of bladder carcinogens. Polymorphisms in the 5'-noncoding promoter region of CYP1A2 gene [mainly -2467T/delT(rs35694136) and -163C/A(rs762551)], are crucial in modifying CYP1A2 activity in smokers. Within the framework of a hospital-based case/control study, we investigated the relationship between CYP1A2 polymorphisms, occupational/environmental exposures and bladder cancer (BC) risk. The study population included 185 BC cases and 180 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs). A case-only design was applied to study the interaction between CYP1A2 -2467T/delT (or -163C/A) and occupational and environmental factors. Multiple logistic regression showed a significantly increased risk among heavy smokers (> or =50 packyears; OR 5.6, 95% CI: 2.5-12.5) and heavy coffee drinkers (>5 cups/day; OR 3.1, 95% CI: 1.2-7.9). Exposure to AAs showed a significant trend of BC risk with increasing cumulative exposure (CE) (P = 0.04), with heavy smoking as possible confounder. A decreased risk was noted for large leaf vegetable consumption, with significant trend from <1/month to >3 times/week (P = 0.008). The case-only analysis showed an interaction between -2467T/delT and tobacco smoking >25 packyears (P = 0.04); no interaction was detected between such polymorphisms and coffee consumption, dietary habits and occupational exposure to AAs. No effects were shown with -163C/A genotype as well as no overall effect of CYP1A2 by itself on BC risk. This is the first study suggesting that CYP1A2 -2467T/delT modifies the effect of cigarette smoking on BC risk.