👤 Antonio Terracciano

Personality traits are associated with cognitive resilience to dementia-related neuropathology. This study examines whether personality traits are related to cognitive resilience to accelerated epigenetic aging. Participants were adults aged from 50 to 98 years (N = 2926, 58% female, Mean age = 68.72, SD = 9.57) from the Health and Retirement Study (HRS). Data on cognition and epigenetic aging measures (GrimAge and DunedinPoAM38) were obtained in 2016. Data on personality, demographic factors, and clinical, behavioral, and psychological covariates were obtained in 2014/2016. Cognitive resilience was defined as the residual from the regression of cognition on epigenetic aging measures. Controlling for demographic factors, linear regression analyses indicated that higher neuroticism was associated with worse-than-expected cognition relative to one's epigenetic aging for both GrimAge and DunedinPoAM38 epigenetic measures. Higher conscientiousness and openness were related to better-than-expected cognition relative to one's epigenetic aging across the two measures. Logistic regression further indicated that higher neuroticism was associated with a lower likelihood of cognitive resilience to accelerated epigenetic aging, whereas higher conscientiousness and openness were related to a higher likelihood of cognitive resilience. These associations were partially accounted for by disease burden, sleep quality, physical activity, smoking, depressive symptoms, childhood adversity, lifetime trauma, and APOE e4 status, and persisted when participants with cognitive impairment were excluded. There was little evidence that age or sex moderated the associations. The present study expands the literature on resilience from neuropathology to a broader systemic impact of aging to provide novel evidence that personality traits are associated with cognitive resilience to accelerated epigenetic aging. Show less

Cardiac fibrosis occurs in a wide range of cardiac diseases and is characterised by the transdifferentiation of cardiac fibroblasts into myofibroblasts these cells produce large quantities of extracellular matrix, resulting in myocardial scar. The profibrotic process is multi-factorial, meaning identification of effective treatments has been limited. The antifibrotic effect of the bile acid ursodeoxycholic acid (UDCA) is established in cases of liver fibrosis however its mechanism and role in cardiac fibrosis is less well understood. In this study, we used cellular models of cardiac fibrosis and living myocardial slices to characterise the macroscopic and cellular responses of the myocardium to UDCA treatment. We complemented this approach by conducting RNA-seq on cardiac fibroblasts isolated from dilated cardiomyopathy patients. This allowed us to gain insights into the mechanism of action and explore whether the IL-11 and TGFβ/WWP2 profibrotic networks are influenced by UDCA. Finally, we used fibroblasts from a TGR5 KO mouse to confirm the mechanism of action. We found that UDCA reduced myofibroblast markers in rat and human fibroblasts and in living myocardial slices, indicating its antifibrotic action. Furthermore, we demonstrated that the treatment of UDCA successfully reversed the profibrotic IL-11 and TGFβ/WWP2 gene networks. We also show that TGR5 is the most highly expressed UDCA receptor in cardiac fibroblasts. Utilising cells isolated from a TGR5 knock-out mouse, we identified that the antifibrotic effect of UDCA is attenuated in the KO fibroblasts. This study combines cellular studies with RNA-seq and state-of-the-art living myocardial slices to offer new perspectives on cardiac fibrosis. Our data confirm that TGR5 agonists, such as UDCA, offer a unique pathway of action for the treatment of cardiac fibrosis. Medicines for cardiac fibrosis have been slow to clinic and have the potential to be used in the treatment of multiple cardiac diseases. UDCA is well tolerated in the treatment of other diseases, indicating it is an excellent candidate for further in-human trials. Show less