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<p>Age-related inflammation or ‘inflammaging’ increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38<sup>+</sup> age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169<sup>+</sup>CD11c<sup>−</sup> ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169<sup>+</sup> NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.</p>

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Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月2日

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  • Elsie Gonzalez-Hurtado,
  • Claire Leveau,
  • Keyi Li,
  • Manish Mishra,
  • Rihao Qu,
  • Emily L. Goldberg,
  • Sviatoslav Sidorov,
  • Payal Damani-Yokota,
  • Stephen T. Yeung,
  • Camille Khairallah,
  • David Gonzalez,
  • Taverlyn M. Shepard,
  • Christina Camell,
  • Maxim N. Artyomov,
  • Yuval Kluger,
  • Kamal M. Khanna,
  • Vishwa Deep Dixit

摘要

Age-related inflammation or ‘inflammaging’ increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c− ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.