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

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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 a frailty clock that includes 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 of a different strain. To test this hypothesis I will complete a battery of health assessments, including blood collection for novel peptide biomarker detection, in male and female UM-HET3 mice every 3 months from 15 months of age until death. I will use regression modelling of all measured outcomes to develop an optimized `bAFRAID clock' that predicts time to death in mice. I will complete this part of the project at Harvard Medical School in the lab of Dr David Sinclair, who will act as my mentor and is an internationally recognised expert in the biology of aging. I will receive additional training in biomarker modelling and peptidomics from experts Drs Steve Horvath and Steve Gygi. For the independent phase of this award, I will use longitudinal assessments, and cutting-edge epigenetic tools to investigate the relationship between epigenetic changes and the AFRAID clock. This will increase our understanding of whether epigenetic mechanisms underly the onset of frailty in aging. The completion of this project and the proposed training will position me in an ideal position to achieve my career goal of becoming an independent researcher with a lab focused on understanding the mechanisms of frailty in aging.