Changes in BMAL1, YAP protein interactions drive inflammation in aging skin

BMAL1 (green) and YAP1 (red) in the adult (top) and aged (bottom) epidermis. Cell nuclei appear in blue. Image courtesy the Institute for Research in Biomedicine, Barcelona

A new study describes a molecular mechanism that helps explain the drivers of persistent low-grade inflammation that impairs skin regeneration as humans age. Findings show that during aging, two proteins, BMAL1 and YAP, change how they work together and increase the activity of inflammatory genes in the epidermis. The work was published in the journal Nature Aging.

The study was led by Dr. Guiomar Solanas, now at the Institut de Recerca Sant Joan de Déu, Pediatric Cancer Center Barcelona, and Dr. Salvador Aznar Benitah, head of the Stem Cells and Cancer laboratory at the Institute for Research in Biomedicine, Barcelona.

“Our results show that, during aging, mechanisms that normally maintain epidermal homeostasis change function and begin to amplify inflammation,” said Dr. Benitah, in a press release.

BMAL1 is known for being part of the circadian clock, which coordinates numerous processes in the body throughout the day. YAP helps cells adapt to physical changes in their environment. The study reveals that both proteins collaborate in the epidermis independently of daily rhythms. In adult skin, this collaboration helps preserve the identity and proper function of skin cells.

The investigators found that with age, changes in skin stiffness and increased inflammatory signals cause both proteins to concentrate in regions of DNA that control inflammatory genes and increase their activity.

The finding builds on a study from the same laboratory, published in 2023. In that work, the team identified IL-17 as a key inflammatory signal in skin aging. In mice, temporarily blocking this protein reduced persistent inflammation and delayed some features associated with skin aging.

The new research shows what happens inside epidermal cells when they receive this signal, which originates from immune cells in the dermis. According to the experiments, IL-17 contributes to YAP activation. When the team blocked IL-17 in aged mice, YAP-associated activity and the expression of the inflammatory genes studied also decreased.

“In 2023, we identified IL-17 as a key signal in skin aging. Now we have discovered how epidermal cells respond to that signal and amplify inflammation,” said Júlia Bonjoch, first author of the study.

The finding clarifies how aging and inflammation are connected in the skin. The next step is to explore whether this mechanism can be safely regulated without compromising essential epidermal functions.