Tree Shrew as an Emerging Model for Aging Research: Characterization of Senescence and Therapeutic Interventions

ABSTRACT

Aging is characterized by progressive physiological decline and increased susceptibility to age‐related diseases. Conventional rodent models have contributed significantly to our understanding of aging, yet their translational relevance is limited by substantial evolutionary divergence from humans. Here, we introduce the tree shrew ( Tupaia belangeri chinensis ) as a novel and biologically relevant model organism for aging research. In vitro, we induced cellular senescence in tree shrew fibroblasts through ionizing radiation, doxorubicin treatment, or replicative exhaustion, all of which consistently triggered robust senescent phenotypes and a pronounced senescence‐associated secretory phenotype (SASP), accompanied by upregulation of conserved senescence biomarkers. In vivo, aged tree shrews exhibited progressive physical frailty, metabolic dysfunction, organ fibroplasia, and spontaneous tumorigenesis. Transcriptomic profiling uncovered widespread age‐related alterations across multiple tissues, prominently affecting pathways involved in chronic inflammation, extracellular matrix remodeling, and metabolic dysregulation. Further comparative transcriptomic analyses of liver and spleen tissues confirmed that tree shrews recapitulate conserved human aging transcriptional trajectories and core gene expression patterns, whereas mice displayed markedly divergent aging signatures. Notably, senolytic intervention with dasatinib and quercetin (D + Q) effectively reversed key transcriptional changes and ameliorated selected age‐related pathologies, including hepatic steatosis. Importantly, the D + Q‐induced transcriptomic responses in tree shrews exhibited markedly greater concordance with human aging signatures than did corresponding mouse datasets. Collectively, these findings establish the tree shrew as a translationally relevant aging model that bridges the gap between fundamental discovery and clinical application.