The discovery centers on the way transcription factors control enhancers, regulatory regions of DNA that act as molecular switches for nearby genes. Enhancers do not usually encode proteins themselves. Instead, they recruit combinations of transcription factors and cofactors that determine when and how strongly a gene is expressed. In healthy epidermis, BMAL1 and YAP occupy enhancer regions linked to epidermal identity, helping skin cells preserve their specialized state. BMAL1, or brain and muscle ARNT-like 1, is widely recognized for coordinating daily cycles of gene expression through its partnership with other clock proteins. YAP, by contrast, is a major effector of the Hippo signaling pathway and responds to mechanical forces, cell density and tissue architecture. Its activity can influence proliferation, differentiation and regeneration. The study indicates that these two proteins form a functional partnership in epidermal cells, connecting circadian biology with tissue mechanics and gene regulation.

The researchers found that aging changes the consequences of this partnership. In older epidermis, BMAL1 and YAP showed enhanced binding at enhancer regions associated with inflammation. This altered occupancy was linked to stronger transcription of inflammatory target genes, suggesting that the aging process rewires existing regulatory circuitry rather than simply activating an entirely new pathway. The same molecular partners that help preserve epidermal identity in younger tissue can therefore become associated with a damaging inflammatory program later in life. Such enhancer rewiring provides a possible explanation for the persistence of low-grade inflammation, sometimes called inflammaging. Instead of a brief response that resolves after injury or infection, inflammatory transcription can remain elevated, contributing to tissue dysfunction and impaired homeostasis. The findings place chromatin regulation at the center of this transition, showing how changes in the use of regulatory DNA may convert normal maintenance mechanisms into drivers of chronic inflammation.

This mechanism is especially significant because it separates BMAL1’s inflammatory role from its canonical function in the circadian clock. The study describes BMAL1 activity in the epidermis that operates independently of its role in daily rhythmic gene expression. In other words, BMAL1 is not acting only as a biological timekeeper. It also serves as a context-dependent transcriptional partner whose effects depend on the factors bound alongside it and the enhancer landscape of the cell. YAP appears to provide a critical connection to the physical state of the tissue. Because YAP responds to mechanical inputs such as changes in cell packing, matrix stiffness and tissue tension, it can translate the altered architecture of aged skin into changes in gene activity. When YAP and BMAL1 bind together at selected enhancers, they may stabilize or intensify the recruitment of transcriptional machinery, increasing the production of genes that shape epidermal behavior and inflammatory signaling.

The study also identifies an interaction with NF-κB, one of the best-known regulators of inflammation. NF-κB acts as a central transcriptional hub for genes involved in immune responses, cytokine production and stress signaling. The researchers report that the inflammatory program associated with BMAL1–YAP cooperation is partially coregulated by NF-κB. This suggests that aging epidermis may experience a convergence of several regulatory systems: BMAL1–YAP enhancer occupancy provides one layer of control, while NF-κB reinforces the inflammatory output. Such cooperation could make the response more persistent than activation of any single factor alone. It may also help explain why inflammatory signals in aged skin are difficult to shut down. Once enhancer regions become preferentially occupied by multiple transcriptional regulators, the resulting chromatin state may favor continued expression even after the original stimulus has weakened.

A further finding links the process to interleukin-17, or IL-17, a cytokine associated with inflammatory immune responses at barrier tissues. In aged skin, pro-inflammatory IL-17 signaling activated YAP through a mechanism that did not depend on the conventional Hippo pathway. Under many conditions, Hippo pathway activity controls whether YAP remains inactive in the cytoplasm or enters the nucleus, where it can influence transcription. The observation that IL-17 can activate YAP independently of this pathway indicates that inflammatory cytokines may directly reroute YAP activity through alternative signaling mechanisms. This provides an important connection between immune-derived signals and the mechanical or transcriptional state of epidermal cells. It also suggests a feed-forward model: age-related inflammation increases IL-17 signaling, IL-17 activates YAP, and YAP then cooperates with BMAL1 at inflammatory enhancers to strengthen the transcriptional response.

The consequences of this molecular circuit could extend across several features of aging skin. Persistent activation of inflammatory genes can disrupt epidermal differentiation, weaken barrier integrity and alter the behavior of stem and progenitor cells responsible for renewal. Chronic inflammation is also frequently associated with elevated oxidative stress and the accumulation of DNA damage, both of which can further impair tissue function. When the skin is injured, an inflammatory response is necessary to initiate repair, but prolonged or poorly resolved signaling can interfere with the later stages of regeneration. The BMAL1–YAP mechanism described in the study may therefore help connect inflammation with inefficient wound healing and loss of tissue homeostasis. Because the work was conducted in the murine epidermis, it does not yet establish that the same regulatory circuit operates identically in human skin. Nevertheless, the conservation of many signaling pathways and transcriptional mechanisms makes the findings relevant to questions about human aging and chronic inflammatory skin disorders.

The discovery points toward several possible therapeutic strategies, although none can yet be considered validated treatments. Interfering with inappropriate YAP activation, modulating BMAL1’s enhancer-associated functions or reducing excessive IL-17 signaling could theoretically weaken the inflammatory circuit while preserving the proteins’ normal roles in tissue maintenance. Targeting enhancer activity rather than broadly suppressing inflammation may offer greater precision, since BMAL1, YAP and NF-κB each regulate many genes required for healthy cellular function. However, such approaches would need to distinguish harmful age-associated activity from beneficial responses involved in barrier repair, regeneration and defense against pathogens. The study also raises the possibility that restoring the regulatory balance of aged epidermal cells may be more effective than blocking a single inflammatory molecule. Understanding how chromatin accessibility, mechanical signals and cytokine pathways interact will be essential for designing interventions that calm chronic inflammation without compromising skin resilience.

By revealing a noncircadian BMAL1–YAP program in aged epidermis, the research expands the biological meaning of both proteins. BMAL1 is shown not merely as a component of the cellular clock, and YAP not merely as a sensor of tissue mechanics, but as members of a flexible regulatory network whose effects change with age and inflammatory context. The work offers a molecular explanation for how aging can transform normal enhancer activity into a persistent inflammatory state. It also illustrates why the biology of aging cannot be reduced to one damaged pathway: tissue decline emerges from the interaction of chromatin architecture, immune signaling, mechanical stress and cell identity. If future studies confirm that this mechanism is conserved in human skin, the BMAL1–YAP axis could become a promising target for strategies designed to restore epidermal balance, improve repair and limit the chronic inflammation that accompanies aging.

Subject of Research: Noncircadian BMAL1–YAP cooperation and enhancer rewiring in age-related inflammation of the epidermis.

Article Title: Noncircadian BMAL1–YAP activity amplifies persistent inflammation in aged epidermis

Article References: Bonjoch, J., Solá, P., García-Mulero, S. et al. “Noncircadian BMAL1–YAP activity amplifies persistent inflammation in aged epidermis.” Nature Aging (2026). https://doi.org/10.1038/s43587-026-01192-1

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s43587-026-01192-1

Keywords: Aging, epidermis, chronic inflammation, BMAL1, YAP, NF-κB, IL-17, enhancers, chromatin regulation, skin homeostasis, wound healing, inflammaging

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