Model of chronic mitochondrial stress leads to tmbim-2-dependent spatiotemporal Ca ²⁺ waves to coordinate neuronal-to-intestinal UPR ^mt activation and aging. Persistent disturbances in neuronal mitochondrial function induce TMBIM-2-dependent calcium (Ca²⁺) oscillations, fostering the release of neurotransmitters to orchestrate a systemic response to mitochondrial stress. Notably, TMBIM2 expression diminishes with aging in neurons across diverse organisms, including C. elegans, mice, and humans. Intriguingly, augmenting TMBIM2 levels through overexpression demonstrates a protective effect against age-related deterioration in aversive learning and imparts an extended lifespan in C. elegans. These findings underscore the pivotal role of TMBIM-2 in mediating the interplay between chronic neuronal mitochondrial perturbations, calcium dynamics, and the broader physiological responses associated with aging.