1. ¹Department of Dermatology, University of California San Francisco and Dermatology Service, Veteran's Administration Medical Center, San Francisco, California, USA
2. ²Department of Dermatology, Yonsei University Wonju College of Medicine, Wonju, Korea
3. ³Dalian Skin Disease Hospital, Liaoning, PR China

Correspondence: Dr Theodora M. Mauro, Veteran's Administration Medical Center, Dermatology Service Chief (190), 4150 Clement Street, San Francisco, California 94121, USA. E-mail: maurot@derm.ucsf.edu

Received 11 October 2006; Revised 12 March 2007; Accepted 23 March 2007; Published online 7 June 2007.

Abstract

Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that could be triggered or exacerbated by impaired epidermal permeability barrier homeostasis. This defect is linked to reduced epidermal lipid synthesis in humans and in mice of advanced age (i.e., >75 years in human or >18–24 months in mice). We now report that barrier defects in moderately aged humans (50–80 years) or analogously aged mice (12–15 months) are linked instead to defective stratum corneum (SC) acidity. In moderately aged mouse epidermis, we find that abnormal acidification, in turn, is linked to decreased Na⁺/H⁺ antiporter (NHE1) expression. Decreased NHE1 levels lead to increased SC pH, which results in defective lipid processing and delayed maturation of lamellar membranes, due to suboptimal activation of the pH-sensitive essential, lipid-processing enzyme, -glucocerebrosidase. Conversely, impaired SC integrity in moderately aged mice is due to increased pH-dependent activation of serine proteases, leading to premature degradation of corneodesmosomes. These abnormalities were normalized by exogenously acidifying the SC, suggesting a basis for the well-known acidification therapies that are widely used to treat the pathologic xerosis/eczema seen in moderately aged humans.