**1. Introduction**

Food allergies (FAs) are becoming a relevant public health concern, affecting over 200 million people worldwide and its prevalence is increasing, mainly in developed countries [1]. FAs are characterized by a wide spectrum of manifestations affecting several organs, ranging from mild to severe and life-threatening reactions [2,3]. The diagnosis of a food allergy is complex because different immunologic mechanisms (IgE-mediated, cell-mediated, or mixed) may play a role. As in most immune-mediated diseases, the variability of clinical expression, as well as its growing prevalence, is determined by genotypic, epigenetic, and environmental factors [4–6].

FAs are much more common in children than in adults. Most FAs start in early childhood and usually disappear in adulthood. For this reason, FAs are often considered an almost exclusively pediatric disease. However, although its prevalence is greatest in young children, the occurrence of FA reactions is becoming frequent in the elderly [7,8]. Most studies on epidemiology, immunopathogenesis, and clinical manifestations of FAs have been conducted on children or adolescents rather than in elderly people. However, the demographic distribution of the world population is rapidly changing, with the proportion of older people on the rise and a significant percentage of them haveallergic diseases [9,10]. Parallel to these demographic changes, we can therefore expect that FAs, already increasing in the general population, will also increase in the elderly [11].

It is estimated that the current prevalence of allergic diseases in the elderly reaches 10% but this data is underestimated and also destined to increase [12]. An increasing proportion of children with a FA reaches adulthood and old age, and in some of them, the persistence of the allergic problem occurs. Furthermore, FAs can develop in adulthood and the first symptoms can occur even in elderly subjects [13]. However, to date, there is still not much attention given to FAs in aged people, and symptoms related to FAs, such as vomiting, dyspepsia, diarrhea, pruritus, and skin and respiratory manifestations, often remain undiagnosed in the elderly [14].

Besides the lack of epidemiological data, very little is known about the peculiar immunopathogenetic aspects and the clinical presentation of FAs in old people [15].

The aim of this review is to analyze the pathophysiological mechanisms underlying food allergy in the elderly, emphasizing the most peculiar aspects in this segment of the population, which form the basis of possible intervention measures.

#### **2. Immune System Remodeling in the Elderly**

The genetic background controls immunity and inflammation, and influences both the aging process and the development of allergies. Several underlying mechanisms of FAs in the elderly are now recognized, the first of which is immunosensecence, i.e., the peculiar age-related remodeling of the immune system. During senescence, both innate and adaptive immune reactions are deeply changed, favoring the development of FAs [16].

In the elderly, there is an imbalance of lymphocyte sub-populations, characterized by a decrease of naive lymphocytes with an accumulation of memory and senescent lymphocytes. Dysfunctions of immune regulatory cells, thymus involution, hematopoietic stem cell malfunctioning, dysregulation of apoptotic processes, a stress response, and mitochondrial function all contribute to the remodeling of the immune system in the elderly [17]. How the balance between the Th1 and Th2 branches is influenced by the aging process is still a controversial matter. Peripheral T cells from aged subjects are activated, exhibiting higher HLA-DR and CD69 expressions, as well as the increased production of inflammatory cytokines, including IL-1β, IL-6, IL-17, IL-31, and TNFα [18]. Immune responses are skewed toward a proallergenic Th2 profile. In particular, the increased IL-4, IL-5, and other Th2 cytokine production observed in aged subjects suggests a Th2 dominance in the elderly [19]. Such immune profile is the main substrate of the allergic reaction [20]. Moreover, certain Th1 cytokines that are increased in the elderly, such as IL-17, may also contribute to the progression of allergic inflammation. The age-related derangement of the cytokine profile may therefore influence the development of FAs in the elderly [21].

Increased inflammatory cytokines and antigen-presenting cell dysfunction contribute to allergic sensitization and inflammation in the aging. Dendritic cells, the mainstarter of the adaptive responses, exhibit altered costimulatory molecule expression in frail elderly subjects, conditioning dysfunctional antigen processing and presentation, which can elicit allergic responses [22].

Concerning effector cells of allergic reactions, most studies report a reduction in eosinophil degranulation in response to IL-5 stimulation and a decreased mast cell function notwithstanding a normal number of mast cells in the tissues [23].

A compromised T helper function and defects of the isotype switching leading to impaired immunologic memory and lower response to vaccines have been observed in the elderly [24]. Conversely, the IgE isotype is less compromised by aging [25]. In particular, immunosenescence does not influence IgE levels in aged patients with atopy, suggesting the persistence of allergy propensity into advanced age [14,26].

#### **3. The Mucosal Immune System in Aging**

Senescence affects not only the systemic immunity but also the local immune responses, especially on the gastrointestinal mucosa. The induction of mucosal tolerance is of paramount importance in mounting protective responses against new dietary antigens, therefore preventing FAs [3]. The gastrointestinal tract is the largest immunologic system with a relevant amount of lymphocytes that are both scattered and aggregated in lymphatic structures (Peyer's patches). This gut immune system exerts a key role in FA development, in particular in the elderly, when the thymic function has almost disappeared [27]. Age-related changes affecting the local immune responses contribute variously to the development of FAs. Mucosal tolerance induction is impaired in the elderly, whereas the effector phase of the allergic reaction is substantially maintained [28]. The mechanism of tolerance to food allergens is an active and ongoing process, and the age-related derangement of regulatory functions mediated by interactions of specific cell types promotes allergic sensitization [29,30]. Changes responsible for the breaking of oral tolerance take place in the gut associated lymphoid tissue. The oral tolerance is generally established in childhood and persists even over 65, unless new unknown allergens are introduced. Usually, new dietary protein intake may induce de novo sensitization in the elderly, whereas oral tolerance established in childhood and young age is generally maintained [31].

Inflammaging, the condition of chronic inflammation that drives senescence [32], increases the tight junction permeability through the effects of proinflammatory cytokines [33]. The epithelial cells in the gastrointestinal tract are themselves responsible for both the production of large amounts of cytokines and the reduction of the proteins of the tight junctions and occludens zonula, leading to an increased gut permeability [34]. This decreased barrier effect results in a rupture of the mechanism of tolerance, which predisposes patients to FAs. The presence of inflammatory cytokines, such as IFN-γ, IL-6, and IL-1β, in the gut mucosa is an important factor in this process [35].

The presence of opsonizing secretory IgA antibodies against food antigens is a central mechanism of mucosal immunity by reducing the attachment, penetration, and invasion of antigens across the mucosal wall. Secretory IgA supplied through breastfeeding protect newborns against harmful antigen penetration, leading to transient tolerance/immunity against oral allergens. This mucosal first-line defense mechanism deteriorates with age and orally induced antigen-specific IgA responses weaken [36]. The immunosenescence itself is associated with a significant reduction in IgA levels in the aged mucosa due to the decreased production by B cells and plasma cells [37]. The reduced IgA levels can reflect both an impaired migration of IgA-secreting plasma cells and their numerical reduction [23]. The decreased production of hyaluronic acid and mucus in the elderly also leads to a reduction in the mechanical protection and transport of antibacterial and defensive proteins to the mucosal surface, including IgA. Moreover, differences in the IgA repertoire between young and old subjects have been described, a difference that probably conditions a decreased efficacy of the IgA mediated defenses in the elderly [38]. IgA deficiency in the elderly is related to the development of FAs and intolerances.
