Metabolomics clocks as a tool to explore mechanisms of aging - Project Summary The past decade has seen extensive research on epigenetic clocks as accurate predictors of age, and of age- related morbidity and mortality. These methylome-based epigenetic clocks hold out the promise of being useful surrogate biomarkers of aging, but they also face considerable challenges. The mechanisms by which these clocks function are not easy to decipher, many of the components of these clocks are not conserved across species, and DNA methylome clocks are not amenable to mechanistic studies in invertebrate models of aging, in which cytosine methylation is rare or absent, greatly limiting the experimental models available to study the mechanisms of these aging clocks. To close this gap, a few researchers have turned to metabolome clocks. The metabolome consists of the small molecules (< ~2000 Da) that make up the structural and functional building blocks of life. Our previous studies have demonstrated the ability of metabolome profiles to predict and explain variation in aging-related traits in diverse organisms, including the first Drosophila metabolome clock, and to validate mechanisms by which metabolites affect aging through dietary and genetic interventions in flies. This work brings the vast resources and experimental flexibility of this well-studied model system to bear on our understanding of biological clocks. This work has led to our central hypotheses that the metabolome clock can predict variation in aging, that it can reveal mechanisms underlying the genetic and environmental determinants of variation in aging-related traits, and can reveal mechanisms behind stochastic variation in aging. Here we propose to test these hypotheses through three specific aims. First, we develop sex- and tissue-specific metabolome clocks for Drosophila, and develop the first longitudinal metabolome clock. The second aim will dissect the mechanisms of metabolites that shape our existing clock, as well new metabolites that arise in our expanded work. and will test the hypothesis that the metabolome clock can be used as a surrogate biomarker to screen geroprotective drugs. The third aim builds on our preliminary data showing that early-age metabolome profiles are associated with stochastic variation for age at death, and will explore evidence for and mechanisms of inheritance of this non-genetic variation. The rationale for the work proposed here is that it will shed light on fundamental mechanisms of aging, through in-depth study of highly evolutionarily conserved metabolic pathways. The long-term goal of this research is to leverage the deep evolutionary conservation of the metabolome for translational applications of metabolomic clocks to improve prediction, prognosis, diagnosis and treatment of aging-related diseases in human populations.
