Integrative Omics Reveal Female‐Specific Benefits of p16 ⁺ Cell Clearance in Aging Mice

Abstract Aging is marked by the accumulation of cells expressing the cyclin‐dependent kinase inhibitor p16Ink4a. These p16⁺ cells, largely senescent, contribute to inflammation and tissue dysfunction. While eliminating p16⁺ cells improves healthspan, sex‐specific differences in their burden and clearance remain unclear. Through combined transcriptomic, proteomic, and functional analyses, we reveal distinct sex‐dependent dynamics of p16⁺ cells during aging. Female mice accumulate significantly more p16⁺ cells across multiple tissues, particularly in the liver. In the p16‐3MR model, selective ablation of these cells enhances grip strength, promotes skin regeneration, and reduces liver damage exclusively in females. Multi‐omics profiling shows that p16⁺ cell removal shifts female liver expression toward youthful, health‐associated profiles, marked by improved mitochondrial activity and reduced inflammatory signaling—molecular patterns resembling those induced by longevity interventions such as calorie restriction, rapamycin, and acarbose. Integrative analysis of our and independent datasets identifies a conserved transcriptional network involving Srm, Cd36, and Lrrfip1, suggesting shared mitochondrial–immune regulatory mechanisms. Overall, our findings establish p16⁺ cells as critical yet heterogeneous drivers of tissue aging, uncover sex‐specific differences in their abundance and senolytic responsiveness, and support the development of precision senotherapeutics that consider sex as a key biological variable in aging and rejuvenation.