Abstract
A strong association exists between exposure to life stressors and accelerated aging in humans and animal models. However, the molecular mechanisms that underlie the adverse effect of stress on aging remain poorly characterized, and there is a paucity of prognostic predictors of stress-induced disease outcomes and life expectancy. To address this gap, we developed mathematical models to predict remaining lifespan based on healthspan data across two independent cohorts which were part of a large study (350 + mice) on social stress and aging in mice. We then relate remaining lifespan to changes in DNA methylation, due to its strong association with age as well as environmental factors such as stress exposure. Multivariate multiple regression identified blood glucose as a major trait associated with DNA methylation. An independent neural network analysis also identified blood glucose among the traits most associated with mortality risk. Finally, elastic net regression identified several DNA methylation sites, including Ptp4a3, Lrrc3b, Adgrb1, Mron5, and Gm6549, which represent possible targets at the intersection of glucose, stress and survival. Overall, the main finding of our analysis is that epigenetic biomarkers of mortality risk reveal an association with blood glucose levels, informing on individual life trajectories shaped by the impact of chronic social stress.