Chronic psychosocial stress: A primary driver of sleep apnea onset in rats and humans

Poor sleep quality and chronic psychosocial stress are interrelated risk factors for hypertension, metabolic disease, and neuropsychiatric disorders. Sleep apnea (SA) is a respiratory disorder that disrupts sleep, affecting ~1 billion adults worldwide. However, the origins of SA remain incompletely understood. Clinically, activation of the stress pathways is often considered a consequence of SA rather than a causal factor. Here, we combined preclinical experiments with Mendelian randomization (MR) analysis to show that chronic psychosocial stress is a primary driver of SA onset. In adult rats, 3 wk of social isolation (SI; single housing) activated the stress response, augmented apneas during natural sleep, and increased the ventilatory responses to O ₂ and CO ₂ challenges. In supine anesthetized rats, obstructive apneas with O ₂ desaturations were 5 times more frequent in SI males than in controls, with no effect in females. SI-related anomalies in airway motor control contribute to the problem. SI also induced increased blood pressure and augmented fat gain, especially in males. In humans, MR analysis using genome-wide association studies of multiple stress-related neurological disorders from European cohorts (~100,000 to 1,096,458 participants) revealed significant effects of loneliness on the risk of SA, independent of adiposity. Together, these results challenge the conventional view of stress as merely a consequence of SA and instead position it as a possible cause. These results open the door to a paradigm shift, recognizing psychosocial stress as a risk factor paves the way for alternative avenues in basic mechanistic research, as well as in preventive and therapeutic strategies.