Schematic of experimental procedure for iv labeling of circulating cells with CD45.2 antibody (CD45.2iv) via retro-orbital delivery in 2-month-old and 22-month-old male and female mice. Credit: Nature Aging (2025). DOI: 10.1038/s43587-025-00952-9

Yale School of Medicine-led research reports that nerve-associated macrophages help maintain healthy fat over a lifespan and curb age-related inflammation.

Aging brings chronic low-grade inflammation that coincides with declining tissue function and rising disease burden. Previous studies have identified diverse adipose macrophage states and proposed roles for macrophages near vessels, nerves, and lipid-laden niches.

Building a map of niche-specific resident macrophages throughout a lifespan and direct tests of their functions in adipose metabolism and inflammation would help researchers unlock some of the mechanisms behind how and why we age.

In the study, "Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation, " published in Nature Aging, researchers used intravascular labeling to exclude circulating myeloid cells, followed by single-cell RNA sequencing, to define resident adipose tissue macrophage subsets and test their roles.

Mouse cohorts included young (two months) and aged (22 months) males and females, with analyses focused on visceral adipose tissue and brown adipose tissue. Single-cell profiling examined thousands of murine myeloid cells pooled from across sexes and ages.

Researchers used a blood tag (anti-CD45.2) to mark cells in circulation, which allowed sorting of resident murine myeloid cells (F4/80+CD11b+) from visceral fat.

Gene sequencing at bulk and single-cell scale then cataloged the resident subsets. Imaging of intact tissue with whole-mount immunofluorescence and live two-photon microscopy placed macrophages along nerves and vessels and electron microscopy captured nerve ultrastructure.

Single-cell profiling revealed resident groups that included vascular-associated macrophages, lipid-associated macrophages, interferon-associated macrophages, CD38+ age-associated macrophages with an inflammatory phenotype, and a CD169+CD11c− subset matching nerve-associated macrophages.

Aging reduced vascular-associated macrophages in males and expanded lipid-associated macrophages in both sexes, while a CD38+ population was largely absent in youth.

Nerve-associated macrophages sat on adipose nerves, extended pseudopodia, and showed features consistent with myelin handling. Removing CD169+ nerve-associated macrophages boosted inflammatory transcripts in aged visceral fat, reduced adipose triglyceride lipase and fasting hormone-sensitive lipase phosphorylation and produced body-weight loss in aged females.

Authors describe nerve-associated macrophages as specialized subsets that sit on adipose nerves. They are essential for fat breakdown and keeping inflammation in check as mice age.

Written for you by our author Justin Jackson, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

More information: Elsie Gonzalez-Hurtado et al, Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation, Nature Aging (2025). DOI: 10.1038/s43587-025-00952-9  Journal information: Nature Aging

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