Oxytocin as regulator of stress and inflammation in aging

Chronic stress and inflammation are potent determinants of negative health trajectories across adulthood, contributing to the progression of neurodegenerative diseases. In aging, these processes become increasingly intertwined, forming a feedforward loop in which chronic stress activates pro-inflammatory cascades in the brain and body, while pro-inflammatory cytokines stimulate stress-response pathways. Together, these interactions accelerate neuronal vulnerability, cognitive decline, and even Alzheimer's disease and Related Dementia (ADRD) pathology. The neuropeptide oxytocin (OT), a modulator of neurophysiological and social-affiliative processes, may buffer against stress and inflammation. There is evidence suggesting that OT dampens hypothalamic-pituitary-adrenal (HPA) axis reactivity, reduces pro-inflammatory cytokines, and promotes adaptive behaviors that restore physiological balance and promote healthy coping. OT can be synthetically produced and delivered via intranasal administration (IN-OT), providing a potential means of enhancing OT signaling. Understanding OT's role in aging, however, remains limited but of high relevance, also given the convergence of stress and inflammatory cascades in ADRD. This narrative review integrates previously distinct lines of research to delineate proposed pathways through which OT regulates stress and inflammation in aging and ADRD. Using systematic search strategies, this review also provides a structured synthesis of recent studies to evaluate evidence for IN-OT as a therapeutic for mitigating stress and inflammation, with discussion of its potential application in aging and ADRD. Research gaps and future directions are offered regarding OT's mechanisms of action, moderators of IN-OT's treatment response, and enhanced attention to midlife in IN-OT research on stress and inflammation in older adults as well as individuals with ADRD.