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

## TL;DR

Removing p16+ cells in aging mice improves health in females more than males, especially in the liver, with benefits like better grip strength and reduced inflammation.

## Contribution

The study reveals sex-specific differences in p16+ cell accumulation and response to clearance, emphasizing the importance of considering sex in anti-aging therapies.

## Key findings

- Female mice accumulate more p16+ cells in multiple tissues, especially the liver.
- Clearing p16+ cells in females improves grip strength, skin regeneration, and liver health.
- p16+ cell removal in females shifts liver gene expression toward youthful patterns with better mitochondrial function and less inflammation.

## 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.

Aging causes accumulation of p16⁺ senescent cells that promote inflammation and dysfunction. Multi‐omics analyses reveal striking sex differences in senescent cell burden and clearance: females accumulate more p16⁺ cells, especially in the liver, and their removal rejuvenates molecular and functional profiles. Conserved mitochondrial–immune networks underlie these effects, underscoring sex as key for precision senotherapeutics.