The Role of Supraoptic Hypothalamic Arginine Vasopressin Neurons in Aging-Associated Water Balance and Thermoregulatory Deficits.
Publication Year:
2025
PubMed ID:
41279797
Funding Grants:
Public Summary:
As we age, our bodies struggle to regulate temperature, metabolism, and hydration, and scientists have now traced this decline to a specific group of overactive brain cells. Researchers discovered that cells in the brain's control center (the hypothalamus) that produce a hormone called AVP become unusually enlarged and hyperactive in older age. When scientists artificially activated these specific cells in young mice, the animals quickly developed "older" traits, including lower body temperatures, sluggish metabolisms, and reduced thirst. Conversely, blocking this hormone's activity in older mice successfully restored their proper water balance and improved their metabolism and temperature regulation. Interestingly, standard anti-aging drugs designed to clear out damaged cells in the rest of the body did not fix this specific issue, proving that this is a unique aging process driven directly by the brain. This breakthrough suggests that creating targeted therapies to calm these overactive brain cells could help reverse age-related declines in how our bodies manage essential water and energy.
Scientific Abstract:
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. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SON(AVP) neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SON(AVP) 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 systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SON(AVP) neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.