The Role and Implications of Epidermal Dysfunction in the Pathogenesis of Inflammaging

Inflammaging has long been linked to the pathogenesis of various aging-associated disorders, including cardiovascular disease, obesity, type 2 diabetes, and dementia. Yet, the origins of inflammaging remain unclear. Although inflammatory dermatoses such as psoriasis and atopic dermatitis predispose to the development of certain aging-associated disorders, suggesting a pathogenic role of cutaneous inflammation in these disorders, the great majority of aged humans do not have inflammatory dermatoses. Nonetheless, recent studies point to epidermal dysfunction as contributing to inflammaging, even in otherwise normal aged humans. Chronologically aged skin exhibits reduced stratum corneum hydration levels, delayed permeability barrier recovery, and an elevated stratum corneum pH, all of which can provoke and exacerbate cutaneous inflammation. Owing to the prolonged release of proinflammatory cytokines (including TNFα, IL-1β, and IL-6) from the epidermis into the circulation in response to these functional abnormalities, cutaneous inflammation can lead to extracutaneous inflammation, resulting in the downstream development of inflammaging and its accompanying disorders. In support of this concept, topical therapies that improve epidermal function can mitigate some aging-associated disorders, such as mild cognitive impairment. In this perspective, we discuss the link between epidermal dysfunction and inflammaging and highlight the potential management of inflammaging-associated sequelae by enhancing epidermal functions.