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<p>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 SON<sup>AVP</sup> neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Chemogenetic activation of SON<sup>AVP</sup> 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 SON<sup>AVP</sup> neurons as a central regulator of physiological aging and a potential therapeutic target for age-related homeostatic dysfunction.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Nancy Morones,
  • Predrag Jovanovic,
  • Anna M. Sanetra,
  • Kaitlyn Jang,
  • Nareg Keshishian,
  • Zhihan C. Cui,
  • Edward Novinbakht,
  • Joshua J. Breunig,
  • Anders H. Berg,
  • Tamar Pirtskhalava,
  • Selim Chaib,
  • S. Ananth Karumanchi,
  • Tamar Tchkonia,
  • Katlin Silm,
  • James L. Kirkland,
  • Celine E. Riera

摘要

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.