Development of a Predictive Frailty Clock & Longitudinal Investigation of its Epigenetic Determinants

Project summary/abstract Longevity studies in mice are expensive and time-consuming, and there are currently no measures that can predict mortality in a mouse at an earlier time-point. Additionally, there are very few measures of the overall health of mice that can be assessed longitudinally. In humans, frailty can predict mortality with greater power than the DNA methylation clock. In my early postdoctoral work I have validated a mouse frailty index, that increases with age, is associated with mortality and age-related pathologies, and is sensitive to interventions. In the Sinclair lab I have used machine learning modelling of this mouse frailty index to make the Analysis of Frailty in Death (AFRAID) clock that can predict the lifespan of male C57BL/6 mice aged 21 months or older with accuracy of approximately 1.7 months. We hypothesis that frailty clocks that include a range of measures including physiological and molecular measures (blood-based Analysis of Frailty in Death, bAFRAID) will accurately predict lifespan in younger, female mice and different strains. To test this hypothesis I will use previously collected longitudinal health and molecular data from C57BL/6 mice, as well as collect lifelong health data, plus blood and stool samples, from UM-HET3 mice. I will use regression modelling of all measured outcomes to develop optimized ‘bAFRAID clocks’ that predict time to death in mice of both strains, and both sexes. For Aim 2, I will test the hypothesis that epigenetic dysregulation underlies the development of frailty in mice. I will use longitudinal assessments, and cutting-edge epigenetic tools (including TIMEseq for DNA methylation and CUT&Tag for histone modifications) to investigate the relationship between epigenetic changes and the bAFRAID clocks. Completion of this project will provide important tools for the field, and allow us to understand whether epigenetic changes precede the development of frailty in mice.