Barcelona researchers have identified a molecular mechanism that may help explain why ageing skin develops a persistent, low-grade inflammatory state. The study, led by Guiomar Solanas, now at the Institut de Recerca Sant Joan de Déu, Pediatric Cancer Center Barcelona, and Salvador Aznar Benitah of the Institute for Research in Biomedicine (IRB Barcelona), shows that two proteins involved in maintaining the function of epidermal cells can change their behaviour over time. Rather than supporting tissue stability alone, BMAL1 and YAP begin to cooperate in activating inflammatory genes. The findings, reported in Nature Aging, were obtained primarily through experiments in mice and reinforced by analyses of human skin data. They offer a molecular explanation for how age-related changes in the skin’s physical environment and immune signals can become locked into a self-reinforcing cycle of inflammation.
The epidermis is more than a passive outer covering. It is a continuously renewing tissue that forms a barrier against microbes, chemicals, dehydration and mechanical damage. Its cells must coordinate proliferation, differentiation, adhesion and repair to maintain this barrier throughout life. With age, however, the epidermis becomes less efficient at regenerating and healing wounds. The skin also develops a chronic inflammatory background often described as “inflammaging.” Unlike the intense, short-lived inflammation caused by an infection or injury, inflammaging is persistent and relatively subtle. Over time, it can interfere with tissue maintenance and contribute to functional decline. The new study suggests that the problem is not simply an excess of inflammatory signals, but also a change in the way epidermal cells interpret and amplify those signals.
At the centre of the mechanism are BMAL1 and YAP, two proteins with apparently different biological identities. BMAL1 is widely known as a core component of the circadian clock, the molecular timing system that helps cells coordinate activities across the 24-hour day. YAP, or yes-associated protein, is part of the Hippo signalling pathway and helps cells respond to mechanical forces, tissue architecture and changes in their surroundings. In the epidermis, the researchers found that BMAL1 and YAP work together independently of daily circadian rhythms. In adult skin, this partnership helps preserve epidermal identity and supports the proper operation of skin cells. Their interaction therefore represents a form of transcriptional control: the proteins influence which genes are switched on by occupying regulatory regions of DNA.
Ageing appears to redirect this cellular machinery. As skin becomes physically stiffer and inflammatory signals accumulate, BMAL1 and YAP increasingly concentrate at regulatory regions associated with inflammation. These regions function as genomic control points, including enhancers and promoters that determine the activity of nearby genes. By occupying them together, the two proteins can increase the transcription of inflammatory programmes in epidermal cells. The result is not merely a response to inflammation arriving from elsewhere in the tissue. The epidermis itself becomes an active amplifier, converting environmental and immune cues into a stronger and more sustained genetic response. This shift helps explain how mechanisms that normally preserve tissue homeostasis can acquire a damaging role during ageing.
The study also connects this pathway to interleukin-17, or IL-17, a cytokine previously implicated by the same laboratory in age-related skin deterioration. IL-17 is produced by immune cells located in the dermis, the layer beneath the epidermis, and acts as a communication signal between the immune system and skin cells. In their earlier work, published in 2023, the researchers reported that temporarily blocking IL-17 in mice reduced persistent inflammation and delayed some features associated with skin ageing. The new findings trace the signal further downstream. According to the experiments, IL-17 contributes to the activation of YAP in epidermal cells, linking an immune-derived message to changes in the transcriptional machinery of the skin’s outer layer.
When the researchers blocked IL-17 in aged mice, activity associated with YAP declined, as did the expression of the inflammatory genes examined in the study. This result supports a model in which immune cells in the dermis release IL-17, epidermal cells respond by activating YAP, and YAP then works with BMAL1 at inflammatory gene-control regions. Age-related changes in tissue stiffness may reinforce the same response by increasing mechanical signals that favour YAP activity. Together, these inputs could create a feedback loop: inflammation alters the cellular environment, the altered environment activates transcriptional regulators, and those regulators drive genes that sustain inflammation. Such a loop would help account for the persistence of inflammaging even when no acute injury or infection is present.
The findings are significant because they place mechanical biology, circadian proteins and immune signalling within a single framework for skin ageing. BMAL1’s involvement is particularly notable because its best-known role is regulating daily biological rhythms. In this context, however, the protein’s partnership with YAP appears to operate outside the timing function traditionally associated with the circadian clock. The work suggests that proteins can retain their molecular identity while participating in different regulatory tasks depending on the age and condition of a tissue. It also highlights the importance of chromatin context—the organisation and accessibility of DNA—in determining whether a protein supports normal cell function or promotes disease-associated gene expression.
The researchers supported their mouse experiments with analyses of human skin data, strengthening the relevance of the mechanism to human ageing while not proving that the pathway operates identically in every person. Most of the experimental evidence came from aged mouse skin, where the investigators could manipulate IL-17 and observe changes in YAP-associated activity and inflammatory gene expression. Human data provided an additional indication that the molecular relationships identified in mice are present in human tissue. As with any preclinical study, further research will be required to determine how strongly the pathway contributes to age-related skin changes in people, how it varies between individuals, and whether it is involved in specific disorders such as chronic inflammatory skin diseases or skin cancer.
The discovery also raises an important therapeutic challenge. Suppressing inflammation in ageing skin might appear beneficial, but IL-17, YAP and BMAL1 all perform essential functions. IL-17 contributes to host defence, YAP helps tissues respond to mechanical conditions and injury, and BMAL1 is central to cellular timing and physiological regulation. Blocking these pathways broadly could therefore impair wound healing, barrier maintenance or protection against infection. The most promising future strategies may need to target the age-dependent interaction between the proteins, their recruitment to inflammatory regions of DNA, or the abnormal combination of immune and mechanical signals that activates them. Any intervention would need to reduce chronic amplification without disabling the normal repair and defence programmes of the epidermis.
“Our results show that, during ageing, mechanisms that normally maintain epidermal homeostasis change function and begin to amplify inflammation,” says Salvador Aznar Benitah, an ICREA researcher and head of the Stem Cells and Cancer laboratory at IRB Barcelona. First author Júlia Bonjoch describes the work as the next step after the laboratory’s 2023 identification of IL-17 as a key signal in skin ageing: “Now we have discovered how epidermal cells respond to that signal and amplify inflammation.” Researchers from the Max Planck Institute for Molecular Biomedicine in Münster, Germany, also contributed to the study. Funders included the European Research Council, the Government of Spain, the Generalitat de Catalunya, Fundació La Marató de TV3, the Fondation Bettencourt Schueller, the Spanish Association Against Cancer and Worldwide Cancer Research.
News Publication Date: 19 August 2026
Web References: https://doi.org/10.1038/s43587-026-01192-1
References: Nature Aging, DOI: 10.1038/s43587-026-01192-1
Keywords: skin ageing, chronic inflammation, inflammaging, epidermis, BMAL1, YAP, IL-17, circadian clock, Hippo signalling pathway, skin regeneration, tissue stiffness, epidermal homeostasis, molecular biology, immunology
Tags: age-related skin regeneration declineaging skinchronic skin inflammationepidermal cell function and aginggene activity changes in aged skinimmune signaling in skin aginginflammaging and skin healthinflammation in skin agingmolecular mechanisms of skin agingrole of BMAL1 and YAP in skinskin barrier deterioration with age
