A Conceptual Framework for Understanding the Effects of Stress on Epigenetic Aging.

Stress is increasingly recognized as a key determinant of aging-related health outcomes, yet the pathways linking stress to epigenetic aging remain ill-defined. Here, we outline a multilevel conceptual framework of stress, where stressors interact with resilience (e.g., emotion regulation, social support) and vulnerability to shape acute and repeated or sustained stress responses that mediate long-term aging trajectories. In the context of this framework, we evaluate the evidence across childhood adversity, traumatic events, chronic stressors, and social determinants of health and identify generally consistent effects of stressors on increased epigenetic age in second- and third-generation clocks, which are moderated by resilience and vulnerability. We find clear evidence for mediation of these effects via maladaptive behavioral stress responses as well as more nuanced results suggesting links between maladaptive psychological and physiological stress response pathways and increased epigenetic age. We conclude with recommendations to harmonize stress measurement, analytic approaches, and clock selection using this conceptual framework to advance our mechanistic understanding of the relationship between stress and epigenetic aging.