Aging redirects two skin regulators toward inflammatory genes in mice

What happened

A study published August 19 in *Nature Aging* reports that two cellular regulators, BMAL1 and YAP, change how they cooperate in aged mouse epidermis. Instead of acting mainly at genomic regions associated with normal epidermal identity, the proteins showed increased activity at enhancers controlling inflammation-related genes.

The researchers propose that this altered cooperation helps sustain low-grade inflammation in aging skin. They also found that the inflammatory signal IL-17 can activate YAP through a route that does not depend on the canonical Hippo signaling pathway, connecting immune activity in the skin’s deeper layers with gene regulation in epidermal cells.

The finding matters because persistent inflammation accompanies declining barrier function, slower wound healing and other features of skin aging. It also offers a detailed example of how aging can repurpose existing regulatory machinery rather than merely reducing or eliminating its activity. The study does not show that targeting BMAL1 or YAP improves skin function, slows organism-wide aging or produces a safe intervention in people.

How the mechanism was studied

The work was primarily a mechanistic study of mouse epidermis. Researchers compared adult and aged tissue across multiple times of day, using gene-expression profiling to distinguish persistent inflammatory activity from ordinary circadian variation. Chromatin immunoprecipitation sequencing mapped where BMAL1, YAP and selected chromatin marks were located across the genome. Imaging and biochemical measurements assessed YAP activation and the proximity of the two regulators inside epidermal nuclei.

The resulting data indicated that inflammation-related genes were elevated throughout the day in aged epidermis rather than appearing as a simple shift in daily rhythm. BMAL1 and YAP increasingly occupied overlapping enhancer regions associated with inflammatory genes, some of which were also regulated by NF-κB.

The researchers further examined causality by removing BMAL1 from the epidermis. Loss of BMAL1 reduced YAP binding at shared genomic targets and changed expression of the associated genes. Experiments involving IL-17 signaling supported the proposed upstream connection: blocking IL-17 in aged mice reduced YAP-associated activity and expression of selected inflammatory genes.

Mechanical changes were also investigated because YAP responds to the physical properties of surrounding tissue. A collagen-XIV-deficient mouse model altered skin stiffness but did not reproduce the full aged inflammatory program, suggesting that stiffness alone was insufficient to explain the findings.

Human evidence remains indirect

The study supplemented its mouse experiments with analyses of previously collected human skin datasets, including bulk tissue from the GTEx project and published single-cell keratinocyte data. Those comparisons found age-associated inflammatory patterns consistent with portions of the mouse results.

That is useful corroboration, but it is not a prospective human experiment and does not establish that the complete BMAL1–YAP mechanism operates identically in people. Human skin varies with sun exposure, anatomical site, disease, medication use and environmental history, factors that public datasets cannot uniformly control.

What remains unanswered

The principal endpoints were gene expression, chromatin occupancy, protein localization and pathway activity. The new study did not demonstrate improved wound healing, stronger barrier function, reduced infection risk or another clinical outcome after selectively modifying the BMAL1–YAP interaction.

Target selection may also be difficult. BMAL1 is a core circadian regulator, while YAP participates in tissue growth, repair and cell-state control. Broadly suppressing either protein could disrupt functions that healthy skin needs. The authors identify safe regulation of the pathway without compromising epidermal function as a next research question.

Several sequencing comparisons used small numbers of biological replicates, and the evidence comes predominantly from mice. The practical conclusion is therefore narrow: aging appears to redirect an established epidermal regulatory partnership toward persistent inflammatory gene activity. Whether that mechanism can be modified safely, and whether doing so improves meaningful health outcomes, remains untested.