DNA Methylation Mediates the Association between Cardiometabolic Risk Factors and Cognition: Findings from the Health and Retirement Study.

The association between cardiometabolic risk factors and cognitive function has been well documented, but the underlying mechanisms are not fully understood. This longitudinal study aimed to investigate the potential mediating role of DNA methylation in this association. We conducted the analyses in 3708 participants (mean [SD] age: 67.3 [9.49], women: 57.9%) from the Health and Retirement Study who were assessed in the 2014 to 2020 waves, had Infinium Methylation EPIC BeadChip methylation assays from the 2016 Venous Blood Study, and had cognitive assessment between 2016-2020. Causal mediation analyses were used to test the mediation role of DNA methylation in the associations between cardiometabolic risk factors and cognition, adjusting for demographic, socioeconomic, and lifestyle factors. Hypertension (-0.061 in composite cognitive z-score; 95% CI: (-0.119, -0.004)) and diabetes (-0.134; 95% CI: (-0.198, -0.071)) were significantly associated with worse cognitive function while abnormal BMI and hypercholesterolemia were not. An increased number of cardiometabolic risk factors was associated with worse cognitive function (P=0.002). DNA methylation significantly mediated the association of hypertension (mediated effect on composite cognitive z-score: -0.023; 95% CI: (-0.033, -0.014)), diabetes (-0.022; 95% CI: (-0.032, -0.014)), and obesity (-0.021; 95% CI: (-0.033, -0.011)) with cognitive function, while the mediation effect was not observed for having hypercholesterolemia. The estimated proportions mediated were 37.4% for hypertension and 16.7% for diabetes. DNA methylation may be an important mediator linking cardiometabolic risk factors to worse cognition and might even provide a potential target for dementia prevention.

A platform for post-translational spatiotemporal control of cellular proteins.

Mammalian cells process information through coordinated spatiotemporal regulation of proteins. Engineering cellular networks thus relies on efficient tools for regulating protein levels in specific subcellular compartments. To address the need to manipulate the extent and dynamics of protein localization, we developed a platform technology for the target-specific control of protein destination. This platform is based on bifunctional molecules comprising a target-specific nanobody and universal sequences determining target subcellular localization or degradation rate. We demonstrate that nanobody-mediated localization depends on the expression level of the target and the nanobody, and the extent of target subcellular localization can be regulated by combining multiple target-specific nanobodies with distinct localization or degradation sequences. We also show that this platform for nanobody-mediated target localization and degradation can be regulated transcriptionally and integrated within orthogonal genetic circuits to achieve the desired temporal control over spatial regulation of target proteins. The platform reported in this study provides an innovative tool to control protein subcellular localization, which will be useful to investigate protein function and regulate large synthetic gene circuits.