Age-Related Loss of Nerve-Linked Macrophages Drives Fat Tissue Inflammation
A specialized immune cell population near adipose nerves declines with age, fueling inflammaging and disrupting fat metabolism.
Summary
Researchers at Yale identified a population of nerve-associated macrophages (NAMs) in visceral fat tissue that decline with aging. Using single-cell RNA sequencing and intravascular labeling to distinguish true tissue-resident immune cells from circulating ones, the team mapped 13 distinct macrophage subsets across the lifespan of male and female mice. With age, NAMs—marked by CD169 expression—were depleted, while inflammatory and lipid-associated macrophage subsets expanded. Depletion of CD169+ NAMs in aged mice worsened inflammation and impaired lipolysis, suggesting these cells normally protect fat tissue from catecholamine resistance. This work establishes NAMs as critical regulators of adipose homeostasis and links their loss to the chronic low-grade inflammation characteristic of aging.
Detailed Summary
Chronic low-grade inflammation—'inflammaging'—is a hallmark of aging and a driver of age-related disease. Visceral adipose tissue (VAT) is a major source of this inflammation, and adipose tissue macrophages (ATMs) are central players. Yet until now, the precise molecular identities of distinct ATM subsets and how they change across the lifespan remained poorly understood, partly because standard isolation methods cannot distinguish true tissue-resident macrophages from circulating immune cells trapped in the tissue's dense vasculature.
This study used intravascular (iv) antibody labeling to exclude circulating myeloid cells, enabling clean isolation of genuinely tissue-resident F4/80+CD11b+ macrophages from the VAT of young (2-month) and aged (22-month) male and female mice. Bulk RNA sequencing confirmed that resident and circulating macrophage populations are transcriptionally distinct—resident cells upregulate antigen-presentation and extracellular matrix genes, while circulating cells retain transendothelial migration signatures. Single-cell RNA sequencing of nearly 15,000 resident macrophages revealed 13 biologically meaningful clusters including vascular-associated macrophages (VAMs), lipid-associated macrophages (LAMs), interferon-associated macrophages (IAMs), nerve-associated macrophages (NAMs), and a newly described CD38+ age-associated macrophage (AAM) subset that emerged only in aged animals.
The most striking age-related changes included depletion of VAMs, expansion of LAMs, and the emergence of AAMs with a pro-inflammatory transcriptional profile. Critically, CD169+CD11c− NAMs—enriched near sympathetic nerve fibers in the fat—declined substantially with age. To test NAM function, the team used CD169-DTR transgenic mice to selectively deplete CD169+ cells. Depletion in aged mice caused a marked increase in inflammatory cytokine production and impaired lipolysis in response to adrenergic stimulation, indicating catecholamine resistance. This suggests NAMs normally degrade excess catecholamines near nerve terminals, preventing overstimulation-induced desensitization and preserving fat mobilization capacity.
The study also revealed sex-specific differences in ATM composition, with some subsets showing sex-biased abundance, and demonstrated that the NAM decline is a conserved feature of aging rather than an artifact of any single experimental condition. Orthogonal validation by multiparametric flow cytometry confirmed the single-cell sequencing findings, strengthening confidence in the subcluster identities.
These findings position NAMs as a specialized, functionally critical macrophage subset that bridges neuroimmune and metabolic regulation in adipose tissue. Their age-related loss may be a key mechanism by which adipose tissue shifts from a homeostatic to an inflammatory state during aging, contributing to metabolic dysfunction and systemic inflammaging.
Key Findings
- 13 distinct resident ATM subsets identified in visceral fat, including a newly described CD38+ age-associated macrophage (AAM).
- CD169+ nerve-associated macrophages (NAMs) decline significantly with age in visceral adipose tissue.
- Depletion of CD169+ NAMs worsens inflammaging and impairs adrenergic lipolysis, indicating catecholamine resistance.
- Aging drives expansion of lipid-associated macrophages and emergence of pro-inflammatory AAMs in visceral fat.
- Intravascular labeling revealed ~75% of sorted ATMs are truly tissue-resident, transcriptionally distinct from circulating cells.
Methodology
The study used intravascular antibody labeling to separate tissue-resident from circulating macrophages in mice aged 2 and 22 months, followed by bulk and single-cell RNA sequencing of sorted F4/80+CD11b+ cells from visceral and brown adipose tissue. Functional depletion of CD169+ NAMs was performed using CD169-DTR transgenic mice, with results validated by multiparametric flow cytometry.
Study Limitations
The study was conducted entirely in mice, and translation of specific ATM subset identities and functions to human adipose tissue requires validation. The CD169-DTR depletion model is not fully NAM-specific, as CD169 is expressed on other macrophage populations. Sex-specific findings were noted but not fully mechanistically explained.
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