Highlights d Activation of MnPO GABAergic neurons increased NREM sleep d Activation of VLPO glutamatergic neurons caused a robust increase in wakefulness d Activating these same preoptic neurons did not alter anesthetic state transitions d Neurons controlling sleep-wake states do not necessarily mediate general anesthesia

Loneliness, or perceived social isolation, is a leading predictor of all-cause mortality and is increasingly considered a public health epidemic afflicting significant portions of the general population. Chronic loneliness is itself associated with two of the most pressing public health epidemics currently facing the globe: the rise of mental illness and metabolic health disorders. Here, we highlight the epidemiological associations between loneliness and mental and metabolic health disorders and argue that loneliness contributes to the etiology of these conditions by acting as a chronic stressor that leads to neuroendocrine dysregulation and downstream immunometabolic consequences that manifest in disease. Specifically, we describe how loneliness can lead to overactivation of the hypothalamic-pituitary-adrenal axis and ultimately cause mitochondrial dysfunction, which is implicated in mental and metabolic disease. These conditions can, in turn, lead to further social isolation and propel a vicious cycle of chronic illness. Finally, we outline interventions and policy recommendations that can reduce loneliness at both the individual and community levels. Given its role in the etiology of the most prevalent chronic diseases of our time, focusing resources on alleviating loneliness is a vitally important and cost-effective public health strategy.

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