Senescent cells induce vascular MHC II to recruit CD4+ T cells and drive inflammation in aging adipose tissue

Abstract Adipose tissue exhibits pronounced inflammation during aging, yet the mechanisms sustaining this chronic state are not well understood. By creating an atlas integrating histology, single-nucleus transcriptomics and flow cytometry across the murine lifespan, we find that age-associated inflammation is distinct from the obesity-like inflammatory profile observed at mid-life. Specifically, age-associated inflammation is characterized by a potent interferon-gamma (IFNγ) response signature and the accumulation of T cells. We demonstrate that senescent cells act as an upstream trigger, indirectly initiating an IFNγ response that upregulates vascular MHC II to promote extravasation of CD4+ T cells into the aging tissue. These recruited T cells then act as a critical source of IFNγ, thereby perpetuating a positive feedback loop that maintains chronic immune infiltration and tissue inflammation. These results provide a multi-modal view of adipose aging and identify a mechanism that sustains its age-associated inflammation. Competing Interest Statement All authors are employees of Calico Life Sciences, LLC at the time of this study.