**4. Epithelial Barrier and Digestive Function Impairment**

In the elderly, the integrity of the gut epithelial barrier is compromised, contributing to the chronic subclinical inflammatory state. Furthermore, the leaky epithelial barrier promotes Th2-immune responses by allowing allergens to penetrate into tissues where they are processed by dendritic cells and macrophages and presented to T cells [39]. Allergen-exposed epithelial cells produce cytokines, including thymic stromal lymphopoietin, which drive Th2 immune responses [40]. Impaired gut permeability therefore contributes to FA development. Derangement of the intestinal barrier integrity associated with aging may arise after gastroenteric mucosa damage [41]. The decreased digestive capacity of the stomach in the elderly, mainly caused by atrophic gastritis, is an additional risk factor for FAs. Gastric atrophy is frequent in the elderly, and depends on underlying diseases, alcohol abuse, or the chronic consumption of drugs, such as proton pump inhibitors or antacids. Long-term use of glucocorticoids determines a variety of serious side effects, including gastrointestinal effects [42]. Chronic alcohol abuse notoriously enhances the gastric mucosa permeability, induces atrophic gastritis,

and decreases the gastric secretory capacity [43,44]. The consequent hypoacidity prevents cleavage of the inactive pro-enzyme pepsinogen and the activation of its protease function in the gastric lumen, thus food proteins remain undigested and transit to the intestine. Such intact food proteins can cross the gut mucosa and enter the blood stream, eliciting the production of IgE antibodies. After a consecutive ingestion of the same food protein, the allergen can crosslink IgE on effector cells, namely mast cells, and trigger the release of mediators, including histamine and leukotrienes, which are the elicitors of local and systemic allergic reactions, whose clinical severity is also partly determined by allergen dosage and integrity [45]. Therefore, a physiologically low gastric pH, by allowing an optimal protein digestibility and preventing the sensitizing and eliciting capacity of the allergen, represents an important protective factor against FAs [14].

Food allergens are mostly structurally stable proteins that usually present a greater risk of causing systemic reactions. When digestion is compromised, labile food proteins can also persist partially undigested along the gastrointestinal tract and become food allergens [46]. The gastric protease propepsin is activated only for pH values below 3.0. Furthermore, only acidic chymus entering the duodenum can induce the release of pancreatic enzymes. Thus, because of the decrease in gastric acidity in the elderly population, protein digestion is compromised and harmless proteins are transformed into potentially dangerous allergens [47]. The therapy with proton pump inhibitors in the elderly, through these mechanisms, could thus facilitate the sensitization to food allergens or lower the trigger threshold of the allergic reaction if a FA is already present [48].

Also, age-related changes in organs and systems different from the gut can exert an important role in the development of FAs in the elderly. The skin is one of the main targets of an allergic reaction to food, as well as an important site of primary sensitization. As a result of chronological and environmental factors, the aged skin is characterized by atrophy and dehydration [49]. The progressive loss of structural integrity leads to an impaired immune response and skin barrier function, increased reactive oxygen species and extracellular matrix component, and vascular impairment [50]. Although T-cell-mediated immunity appears decreased, elderly patients can develop contact dermatitis, as well as sensitize themselves through the skin to food allergens [3].
