Aug 2026· Neuroscience and Biobehavioral Reviews· Vol 190, pp.
106924
· 0 citations· 180 references
Medicine
TL;DR
A narrative review integrates previously distinct lines of research to delineate proposed pathways through which OT regulates stress and inflammation in aging and ADRD and provides a structured synthesis of recent studies to evaluate evidence for IN-OT as a therapeutic for mitigating stress and inflammation.
Abstract
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.
Psychological stress arises when individuals perceive demands as exceeding their capacity to cope. Social stress can be acute, such as giving a presentation, producing transient increases in heart rate, blood pressure, and neuroendocrine activation, or chronic, in which stressors persist over extended periods. Chronic psychosocial stress disrupts immune homeostasis and contributes to anxiety, depression, and post-traumatic stress, while also increasing risk for infections, inflammatory and autoimmune diseases, cardiovascular disease, metabolic dysfunction, and cancer. Persistent stress engages interconnected neuroendocrine–immune networks, including the hypothalamic–pituitary–adrenal axis, the sympathetic–adrenomedullary system, and the gut microbiota–brain–immune axis, leading to sustained glucocorticoid and catecholamine signaling, gut dysbiosis, impaired barrier integrity, and altered microbial metabolite profiles. In this review, we summarize the molecular and cellular mechanisms by which these axes remodel innate and adaptive immunity and shape disease susceptibility. Using social defeat and social isolation in mice as model systems, we highlight how chronic social stress reprograms immune responses in key tissues, including the lung, brain, and gut.
William P. Lafuse, Murugesan V. S. Rajaram· Cells· 0 citations
Chronic stress is increasingly recognized as a major contributor to systemic disease. Prolonged or repeated activation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathoadrenal systems may contribute to glucocorticoid receptor resistance and chronic low-grade inflammation, although stress-related responses vary depending on stressor characteristics, population, age, sex, health status, and study design. Elevated levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), oxidative stress, and NF-κB activation contribute to immune dysfunction, neuroinflammation, metabolic disturbances, reproductive and endocrine imbalance, as well as structural and functional alterations in stress-sensitive brain regions. Prolonged exposure to stress may contribute to the development of neuropsychiatric, cardiovascular, metabolic, neurodegenerative, and malignant diseases, highlighting the need for effective strategies to mitigate the detrimental consequences of chronic stress. Given the limitations and adverse effects associated with conventional pharmacological approaches, increasing attention has been directed toward natural bioactive compounds. Terpenes represent a diverse class of phytochemicals with reported anti-inflammatory, antioxidant, and neuromodulatory properties. Terpenes such as limonene and β-caryophyllene, as well as terpenoids such as linalool, may modulate NF-κB, MAPK, and Nrf2 signaling pathways and interact with the endocannabinoid system, thereby attenuating neuroinflammation, oxidative stress, and stress-induced immune dysregulation. This review summarizes current evidence regarding the mechanisms linking chronic stress, HPA axis dysfunction, and systemic disease, with particular emphasis on endocrine, immune, and nervous system alterations. In addition, it critically evaluates the mechanistic and translational potential of terpenes as possible indirect neuroimmune and redox modulators of stress-related pathophysiology.
Dušica M Kočović, Sanja Momčilović, Tamara Svetozarević· International Journal of Mol...· 0 citations
Alcohol use disorder is a chronic relapsing condition with significant neurobiological, psychological, and social implications. Relapse, defined as the resumption of clinically significant alcohol consumption following abstinence, represents a major barrier to sustained recovery. Emerging evidence indicates that the gut-brain axis may contribute to relapse vulnerability through persistent peripheral and central biological alterations. Chronic alcohol consumption can induce intestinal dysbiosis and disrupt epithelial integrity. This increases intestinal permeability and facilitates the translocation of bacterial endotoxins. These processes may promote systemic inflammation and sustained neuroimmune activation. Also, this can alter glutamatergic, dopaminergic, and GABAergic signaling pathways involved in cravings, negative emotions, and stress sensitivity. Alcohol-related dysbiosis also modifies microbial metabolites, including short-chain fatty acids and tryptophan catabolites, potentially reinforcing inflammatory and neurochemical imbalances. Comorbid depression may further amplify these interactions by enhancing pro-inflammatory signaling and emotional dysregulation. This could increase the risk of relapse. Preclinical studies suggest that microbiota-targeted interventions, such as strain-specific probiotics, fecal microbiota transplantation, and postbiotics including butyrate derivatives, can restore intestinal barrier function, attenuate neuroinflammation, and reduce relapse-like behaviors in experimental models. However, clinical translation remains limited, and longitudinal studies specifically evaluating relapse outcomes are insufficient. This narrative review integrates mechanistic and translational evidence linking gut dysbiosis, intestinal barrier dysfunction, systemic inflammation, and neuroimmune activation to relapse vulnerability in AUD. By situating relapse within an integrated gut-brain framework, we propose that microbiota-informed strategies may represent promising adjunctive approaches to complement existing relapse-prevention treatments.
Diliana Pérez-Reytor, Eduardo Isla, Ítalo M Urrutia et al.· Current Neuropharmacology· 0 citations
The hypothalamic-pituitary-adrenal (HPA) axis coordinates the physiological stress response by driving glucocorticoid (GC) secretion. While acute glucocorticoid signaling supports adaptive cognitive and metabolic responses, sustained activation of this system can produce hippocampal atrophy, impaired synaptic plasticity, and long-term cognitive dysfunction. Alzheimer's disease (AD), characterized by extracellular amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), arises from interactions among genetic variants, epigenetic regulation, and environmental exposures. Here, we review clinical, epidemiological, and translational evidence implicating chronic stress and glucocorticoid exposure as a potent environmental risk factor for AD. Human observations linking stress exposure to cognitive impairment are complemented by clinical hypercortisolemia paradigms, which highlight the sensitivity of hippocampal circuits to prolonged cortisol exposure. The detrimental impact of stress on cognition is mediated by GC-responsive genes implicated in AD or, conversely, by AD genes that also respond to GCs. Animal models further support causality, showing that chronic stress or glucocorticoid exposure exacerbates Aβ accumulation, tau pathology, synaptic dysfunction, and cognition in AD-relevant systems. Finally, stress and GC exposure regulate GC or AD genes through epigenetic mechanisms, which can encode cumulative stress exposure and bias trajectories toward neurodegeneration. The involvement of stress in AD elucidates molecular mechanisms underlying its complex pathology but also provides a promising avenue of investigation for AD therapy and intervention strategies.
Xiu-Han Li, Alisha Greenstein, Cynthia A. Munro et al.· Journal of Neuroimmunology· 0 citations
Human psychoneuroimmunology research has demonstrated that stress, depression, and close relationships reliably shape immune and endocrine function in ways that matter for health. Across studies of examination stress, laboratory stressors, marital discord, cancer survivorship, and dementia caregiving, psychosocial adversity predicts more infections, weaker vaccine responses and faster erosion of vaccine protection, slower wound healing, heightened inflammation, and accelerated cellular aging. Depression also sensitizes immune function, producing larger inflammatory responses when individuals encounter stressors. Loneliness, low support, and distressed relationships can amplify stress reactivity and are linked to greater inflammatory and metabolic vulnerability, including postprandial inflammatory and endothelial responses. More recent work has extended these pathways to the gut microbiome and intestinal permeability (leaky gut), integrating microbial, neuroendocrine, and immune mechanisms. Collectively, the evidence supports a biobehavioral model in which social stress accelerates immune aging and increases risk for inflammation-related disease, while behavioral and nutritional interventions can modify these trajectories.
Janice K Kiecolt-Glaser· Annual Review of Psychology· 0 citations
Post-traumatic stress disorder (PTSD) is a severe psychiatric condition associated with persistent emotional dysregulation, cognitive impairment, and structural alterations in limbic and prefrontal brain regions. Growing evidence indicates that chronic inflammation and abnormal processing of pro-inflammatory cytokines are central components of PTSD pathophysiology. Activation of the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) and caspase-1 promotes the proteolytic maturation of pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) into their active forms, amplifying neuroinflammatory signaling. Sustained microglial activation and disrupted neuron-microglia-astrocyte communication contribute to synaptic dysfunction and impaired neuroplasticity. In parallel, dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis) interacts with inflammatory pathways, leading to altered stress responses and persistent immune activation. Clinical studies have demonstrated associations between circulating inflammatory mediators, including IL-18 and IL-1β, and the severity of emotional inhibition, sleep disturbances, and maladaptive coping strategies in PTSD. Moreover, inflammatory activity has been linked to volumetric and microstructural changes in the hippocampus, amygdala, and prefrontal cortex observed in chronic PTSD. These findings support the concept that the processing of pro-inflammatory cytokines is a central mechanism in PTSD rather than a secondary consequence of stress exposure. Understanding the molecular pathways underlying cytokine maturation and neuroimmune signaling may contribute to improved biomarker-based diagnostics and the development of targeted therapeutic interventions.
