Aging drives senescence in visceral adipose to a greater extent than obesity, instigating multicellular common signaling patterns that impair organ function and drive inflammation

Abstract Obesity accelerates key hallmarks of biological aging in visceral adipose tissue (VAT), yet age-associated changes in cellular senescence against a background of sustained elevated adiposity remain poorly understood. To investigate these changes, we examined human omental VAT from younger (18-35 years), middle-aged (36-51 years), and older adults (52-75 years) with comparable BMI (40 {+/-}5 kg/m2) using a cross-sectional design. We integrated bulk and single- nucleus RNA sequencing (snRNA-seq), Visium HD spatial transcriptomics, and three complementary computational approaches for senescent cell (SnC) identification. VAT from older adults exhibited increased expression of senescence-associated markers, including CDKN2A (p16INK4a) and CDKN1A (p21CIP1), as well as enhanced fibro-inflammatory and tissue-remodeling programs. snRNA-seq revealed a non-linear age-associated pattern, with relatively modest differences between younger and middle-aged adults and more pronounced senescence- associated changes in older adults. SnCs were increased primarily in adipose stem/progenitor cells and mesothelium, which also emerged as major intercellular communication hubs. CellChat analyses identified SnCs of multiple lineages converging on shared outgoing signaling programs, implicating inflammatory, extracellular matrix-remodeling, and adipogenic regulatory pathways, including IL-1, IL-6, TGF-{beta}, and WNT signaling. These predicted interactions were accompanied by transcriptional programs involving HIF1A, NF-{kappa}B, SMADs, PRRX1, and TP53 in SnCs, as well as consistent upregulation of KDM6B a histone demethylase activating gene expression. Collectively, our findings suggest that aging drives the senescence program to a greater extent than obesity, potentiating tissue dysfunction through coordinated intercellular signaling mechanisms.