# Intrinsic changes in cell differentiation and identity drive impaired wound healing in aged female murine skin

## TL;DR

This study shows that aging in female mice leads to impaired wound healing due to changes in skin cell behavior and increased inflammation.

## Contribution

The paper reveals cell-intrinsic changes in aged skin that persist after injury and contribute to poor healing.

## Key findings

- Aged skin shows increased basal inflammation and altered signaling affecting keratinocyte differentiation and fibroblast identity.
- Wound fibroblasts in aged mice express more senescence-related genes and show defective macrophage function.
- Intercellular signaling is impaired in aged wounds, leading to an enhanced inflammatory signature.

## Abstract

Cellular and molecular mechanisms that drive a perturbed wound microenvironment and impaired healing in aged skin have not been fully delineated. To obtain a comprehensive understanding of cell-intrinsic changes acquired during ageing that impact early responses to injury, we performed single-cell RNA sequencing in young and aged intact female murine skin and wounds 3 days post-injury. We observed that substantial changes in the mean proportional distribution and transcriptomic state of skin resident subpopulations in aged, but not young, tissues accompany a global increase in basal inflammation. This is driven by an altered signalling environment leading to impaired keratinocyte differentiation, loss of fibroblast identity and defective macrophage function. Further, we show that ageing-induced changes in skin resident cells persist after injury, resulting in increased expression of senescence-related genes in wound fibroblasts and aberrant monocyte-to-macrophage transitioning coupled to an enhanced inflammatory signature and defective intercellular signalling in comparison to wounds in young mice. In summary, our data highlights a contribution of both cell-intrinsic changes and an altered tissue microenvironment to poor wound healing responses in aged mice.

The online version contains supplementary material available at 10.1007/s10522-025-10340-w.