biostudies-literatureGonzalez-Hurtado EAging Biology FoundationNIDDK NIH HHSNIA NIH HHSNIAID NIH HHSFoundation for the National Institutes of HealthFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)American Federation for Aging ResearchCure Alzheimer's FundNIAMS NIH HHS1828-1843https://www.ebi.ac.uk/biostudies/studies/S-EPMC12443591biostudies-literatureUnknown5(9)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. NotNature agingNerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.PMC12443591AR070811P01 AG051459R01 AI143861P01AG051459R01 AI188824R01 AR070811R01 DK138675Shepard TMKluger YDamani-Yokota PGoldberg ELGonzalez-Hurtado ELi KQu RDixit VDGonzalez DSidorov SCamell CKhanna KMLeveau CKhairallah CMishra MArtyomov MNYeung STfalseNerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.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. Not2025-01-01T00:00:00Z2025 Sep2026-06-03T10:12:41.268Z2026-04-26T03:11:42.848ZS-EPMC124435914089790810.1038/s43587-025-00952-9