Multiomics reveals a resilient subcutaneous adipose tissue phenotype in extreme human longevity

Extreme human longevity is associated with preserved adipose tissue function, but the cellular and epigenetic mechanisms underlying this resilience remain poorly understood. To address this, we constructed an integrated multiomics atlas of subcutaneous adipose tissue from 140 long-lived individuals and 70 controls by combining histology, bulk RNA sequencing, single-nucleus RNA sequencing, spatial transcriptomics, and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq). Our analysis reveals a coordinated adipose phenotype in long-lived individuals characterized by reduced fibrosis, attenuated senescence and inflammatory signaling, and preserved vascular and adipogenic features. Single-nucleus profiling identifies distinct Adip_1 and Adip_2 adipocyte states and demonstrates greater progression toward the metabolically active Adip_2 state in long-lived individuals, consistent with preserved adipogenic differentiation. Spatial transcriptomics further reveals attenuated senescence-associated and inflammatory niches and reduced fibro-inflammatory remodeling in long-lived adipose tissue. We additionally establish a transcriptome-based adipose biological-age signature that identifies reduced age acceleration in long-lived individuals and a longevity-associated molecular program enriched for SIRT3, PRKAA1, PPARG, UCP1, SIRT1, NFE2L2, NOS3, GPX1, ADIPOQ, SOD2, and FOXO3. Finally, scATAC-seq reveals a distinct regulatory landscape, with preferential accessibility of PPARG, CEBPA, SREBF1, NFE2L2, KLF4, FOXO1, and NRF1 motifs in long-lived individuals, contrasting with increased accessibility of TP53, JUN, NFKB1, STAT3, EGR1, RELA, and ATF3 inflammatory and stress-associated motifs in controls. Together, these findings define a multi-layered adipose tissue phenotype associated with extreme human longevity and identify coordinated metabolic, antioxidant, adipogenic, and anti-inflammatory regulatory programs that may underlie resilience to age-associated adipose dysfunction.