Infection of the aero-digestive tract represents a major disease burden of the elderly, and despite recent advances in our understanding of the mucosal immune system, its immunosenescence remains poorly defined. Age-associated alterations of the intestinal and respiratory immune systems occur at distinct times and in a distinct manner. A reduction in gut-associated lymphoreticular tissues, intestinal antigen-specific IgA antibody responses and lack of oral tolerance induction are all associated with aging. By contrast, nasopharyngeal-associated lymphoreticular tissue function remains intact during aging with notable signs of immunosenescence seen only in the elderly. The distinct timing of mucosal immunosenescence seen between the gut and respiratory system suggests the nasal route of vaccination might be preferable for effective mucosal vaccines in the elderly.