The role of supraoptic hypothalamic arginine vasopressin neurons in aging-associated water balance and thermoregulatory deficits in male mice

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes in male mice. Single-nucleus RNA-sequencing revealed Avp among the most upregulated neuronal transcripts with age. Aged SONAVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Chemogenetic activation of SONAVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and metabolism. Pharmacological studies demonstrated that neuroendocrine AVP signaling mediates these deficits through distinct contributions of V1A and V2 receptors. These findings identify SONAVP neurons as a central regulator of physiological aging and a potential therapeutic target for age-related homeostatic dysfunction. Aging is associated with impairments in thermoregulation, metabolism, and water balance, but the neural mechanisms underlying these deficits are poorly understood. Here, authors show that hyperactive supraoptic hypothalamic vasopressin neurons drive age-related homeostatic dysfunction in male mice, and targeting AVP signaling partially restores physiological function.