Can Strengthening Stress Resilience Slow Biological Aging? A Hypothesis-Generating Framework for Study Design, Measurement Harmonization, and Intervention Development

Prolonged psychological stress has been associated with accelerated biological aging, but the possibility that strengthening stress resilience may slow biological aging remains largely untested. This gap reflects the rare pre-specification of resilience and biological aging endpoints within the same trial, the separate development of resilience neuroscience instruments and geroscience biomarker panels, and the infrequent evaluation of stress-related interventions against biological aging outcomes. In this hypothesis-generating narrative review, we propose a framework that treats three neurobehavioral systems implicated in stress resilience—hippocampal pattern separation, prefrontal cognitive control, and reward-system engagement—as candidate targets. The design pillar pairs an outcome-based resilience measure with a pre-specified hierarchy of biological aging endpoints, led by DunedinPACE, and links four working hypotheses to explicit estimands. The harmonization pillar specifies a minimum core measurement set collected in the same participants at matched time points. In the intervention pillar, psychological, social, and pharmacological programs test the target engagement hypothesis and document the engagement of their neurobehavioral target, so that changes in biological aging markers can be examined in relation to the targeted system. The proposed approach can generate falsifiable predictions on whether strengthening resilience may slow biological aging in humans, a necessary step before the effects on healthspan or lifespan can be examined.