Aged white adipose tissue is rejuvenated in a young host through thermogenic remodeling of mature adipocytes

Abstract

Existing studies focus on endpoints, leaving unambiguous rejuvenation largely undemonstrated. To address this gap, we transplanted white adipose tissue (WAT) between young and old mice and longitudinally quantified biological age using molecular and histological approaches. Transplantation accelerated graft aging, and young WAT engrafted into old hosts acquired an aged state without rejuvenating the recipient. Conversely, old WAT engrafted into young hosts rejuvenated. Single-nucleus profiling localized rejuvenation to mature adipocytes and, within them, to chromatin, splicing, translation, and energy metabolism pathways. Rejuvenation was characterized by activation of thermogenesis and structural remodeling, and suppression of differentiation and lipid accumulation. Proteomic and metabolomic analyses supported these findings and implicated DNA repair. Histologically, rejuvenated WAT had smaller, more uniform lipid droplets, resembling young WAT. Top rejuvenation-associated genes were context-dependent modulators of lifespan in Drosophila. WAT's biological age is therefore partially reversible, and the rejuvenation program components regulate longevity.