Aging is characterized by the deterioration of tissue structure and function. In skin, environmental factors, for example, ultraviolet radiation (UVR), can accelerate the effects of aging such as decline in barrier function and subsequent loss of hydration. Water homeostasis is vital for all cellular functions and it is known that organic osmolyte transport is critical to this process. Therefore, we hypothesized that as we age, these tightly controlled physiological mechanisms become disrupted, possibly due to loss of transporter expression. We investigated this in vivo, using human skin samples from photoprotected and photoexposed sites of young and aged volunteers.We show a reduction in keratinocyte cell size with age and a downregulation of osmolyte transporters SMIT and TAUT with both chronic and acute UVR exposure.Single-cell live imaging demonstrated that aged keratinocytes lack efficient cell volume recovery mechanisms possessed by young keratinocytes following physiological stress. However, addition of exogenous taurine significantly rescued cell volume; this was corroborated by a reduction in TAUT mRNA and protein in aged, as compared to young, keratinocytes. Collectively, these novel data demonstrate that human epidermal keratinocytes possess osmolyte-mediated cell volume regulatory mechanisms, which may be compromised in aging. Therefore, this suggests that organic osmolytes-especially taurine-play a critical role in cutaneous age-related xerosis and highlights a fundamental mechanism, vital to our understanding of the pathophysiology of skin aging. K E Y W O R D Saging, cell volume, human skin, osmolytes

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Suprabasin (SBSN) is a secreted protein expressed in stratified squamous epithelium, and its expression is upregulated with keratinocyte differentiation. The main organ expressing SBSN is the skin, but also the esophagus and forestomach, where metals can be absorbed. By proteome analysis of stratum corneum, we found that the amount of SBSN was lower in atopic dermatitis (AD) patients. Moreover, plasma SBSN was lower in AD, especially intrinsic AD. Here, we addressed the dual roles of SBSN in the skin barrier and the upper digestive tract by using SBSN-deficient mice (CRISPR/Cas9-generated C57BL/6N). By Western blotting and immunohistochemistry, SBSN was completely knocked down in SBSN-/-mice. Toluidine blue dye assay exhibited delay in the development of the skin barrier in KO embryos, while the barrier function against Lucifer yellow dye in newborns was comparable between KO and wild-type mice. Cornified envelope fragility was seen in KO newborns. Electron microscopic observation revealed thin stratum corneum and immature keratohyline granules in 8-weekold KO mice. However, mature KO mice did not show alterations in phenotype, TEWL, or OVA epicutaneous immunization, suggesting that SBSN deficiency leads to a temporary phenotype at embryo, but compensatory mechanisms dominate after birth. Since metals are absorbed in the upper digestive tract and metal allergy (nickel, cobalt and chrome) is frequently seen in intrinsic AD, continuous nickel-containing water supply was performed in 6-8-week-old mice. At 2 weeks, KO mice had a significantly higher level of serum nickel than did wild-type mice. These results suggest that SBSN has dual roles for the skin barrier and the upper digestive tract, and its deficiency may mimic intrinsic AD.

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