In a dynamically changing global landscape, the imminent threat of climate change is evident in rising temperatures, raising concerns about intermittent heat waves leading to acute and chronic heat stress, where the aging population is especially vulnerable1. Heat stress due to the deployment of troops in the Southwest Asian region and ..during combat training in arid regions also have a deleterious effect on the health of aging Veterans. The Southwest Asia regional climate is hot and arid, which exposes military personnel to intense heat and sunlight during the day, posing long-term health consequences for veterans2. Heat stress, a heat-related illness, occurs when the body's cooling mechanisms fail, leading to a rapid increase in the body temperature3 and cause pathophysiological changes and fatalities, with excess mortality linked to summertime temperatures surpassing long-term averages and heat extremes due to heatwaves4. Recent CDC data reports over three thousand deaths in about two years solely due to heat exposure, indicating a gradual increase in heat stress-related deaths with age, peaking among those aged fifty-five to sixty-four5. Various factors, including housing conditions, limited mobility, financial constraints, psychological issues, ignorance, and comorbid conditions, heighten the elderly's susceptibility to heat stress6...

... Alarming predictions estimate over a ninety percent increase in heat stress-associated deaths in New York by 2050 and up to a seven-fold increase in California by 20907,8.

Heat stress intricately affects vital organ systems, particularly the cerebral and hepatic domains9. In the neurophysiological landscape, heat stress induces cellular perturbations, leading to cerebral edema10. Experimental animal models showed acute heat stress activating astrocytic processes, causing neuronal damage in the cerebral cortex11. Simultaneously, the neuroinflammatory environment, marked by microglial activation, pro-inflammatory cytokine release, and blood–brain barrier (BBB) disruption, contributes to cognitive decline, compromises adult neurogenesis, and age-related pathologies, significantly impacting the geriatric population12,13. The liver, an indispensable organ of metabolic orchestration, maintains pivotal processes encompassing ammonia purification, biosynthesis of vitamins and minerals, energy homeostasis, and the regulation of fundamental physiological equilibrium14. Intriguingly, the liver emerges as a remarkably sensitive organ to the toxic effects of heat stress. Acute thermal stress instigates metabolic perturbations in the liver via oxidative stress15. In a chronic heat stress milieu, the liver succumbs to apoptosis triggered by endoplasmic reticulum (ER) stress, concomitant impairment in ammonium detoxification, elevation of plasma-ammonia levels, and aggravated hepatic pathologies16. Additionally, heat stress was known to promote dysfunction in hepatic autophagy, thereby unveiling its multifaceted capacity to inflict hepatic damage17. To date, no studies have investigated the integrative effects of heat stress on the liver and brain axis beyond specific organ-level pathologies and molecular intricacies. Therefore, this study aimed to uncover the molecular interplays of the liver-brain connection in heat stress-related pathologies together with individual organ-specific pathological changes using transcriptome approaches...