Dissecting Spatiotemporal Heterogeneity of Senescence Markers p16/p21 Across Tissues During Type 2 Diabetes Progression

This study investigates p16/p21 senescence marker heterogeneity in diabetes-related tissues using the p21-3MR mouse model, focusing on p16 and p21 as senescence markers. Type 2 diabetes, a common age-related disease, impacts multiple organs; the study examines the heterogeneous distribution of senescence markers in tissues including the pancreas, kidney, heart, adipose tissue, femur, spleen, thymus, liver, and lungs. The results reveal significant spatiotemporal heterogeneity in p16/p21 co-expression patterns across different organs during diabetes progression, with varying responses to senescent cell clearance treatments. Specifically, the combination of dasatinib and quercetin demonstrated superior reduction in p16/p21 dual-positive cells in several tissues compared to p21 intervention alone, while p21 intervention showed distinct effects on marker expression in adipose tissue and bone marrow. Immune organs displayed heterogeneity in p16-associated immunosenescence, and the liver and lungs showed greater p16/p21 expression in vascular niches. This is the first study to use the p21-3MR model to explore p16/p21 marker heterogeneity and differential clearance efficacy of senolytic treatments in diabetic tissues. The findings highlight the need for tissue-specific senolytic strategies, particularly targeting adipocytes and metabolic disorders. Future research should focus on understanding the mechanisms of p21high cell persistence, offering insights for more senescence-targeted treatments.