**5. Age-Associated Microbial Dysbiosis**

In addition to the impaired function of the local immunity and increased gastrointestinal mucosa permeability, age associated alterations of the gut microbiota may also favor FA development in the elderly.

The gut microbiota is a complex ecological system that exerts a central role in several physiological functions, and its composition changes throughout the host's life. It is sensitive to environmental influences and the host's diet, and depends on the host's genetics, gender, and the aging process per se [51].

The system of the secretory IgA plays a critical role not just for the defense against infections but also for the modulation of local immune responses through the maintenance of the intestinal microbiota. Inflammatory processes are associated with dysregulation of the homeostatic interactions between the intestinal microbiota and the aging host [52].

Intestinal microbiota exhibit significant age-associated changes in composition and diversity, as well as in functional features, mainly caused by the immune system remodeling and low-grade chronic inflammation, which respectively characterize immunosenescence and inflammaging [22].

Immunosenescence exerts a key role by modifying the host's response to microbiota, triggering inflammaging, and shifting Th1 versus Th2 responses, thus favoring tolerance dysruption and allergic reaction development [52].

Antibiotics are among the most commonly used drugs in the elderly and are often used improperly. They influence the microbiome composition and function interfering with immune homeostasis. In the geriatric age, antibiotics can further disturb the composition of the microbiota [53,54]. However, even in

the elderly, the intestinal flora can be reconstituted by probiotics, but it is not yet known how this can prevent the development of FAs [55].

#### **6. Immune Dysfunctions Due to Nutritional Deficits**

Together with the peculiar remodeling of the immune system during senescence, the compromised integrity of epithelial barriers and the sub-clinical chronic inflammatory condition commonly observed in the elderly, a central role in sensitization to food allergens is also played by the lack of micronutrients and vitamins [12].

Micronutrients and antioxidants modulate immune responses and it is suggested that their deficits favor the development of Th2 type responses. For example, deficits of iron, zinc, and vitamin D, which are very common in the elderly, may represent additional risk factors for the onset of allergic reactions during senescence [10].

Zinc is an essential trace element that plays a central role regarding the immune efficiency. Zinc intracellular homeostasis, regulated by metallothioneins and specific transporter proteins, is altered in aging, leading to its decreased availability for immune functions. A reduced zinc level, frequently observed in the elderly, could be responsible for a decreased production of Th1 cytokines, whereas this does not affect the production of Th2 cytokines, thus inducing a cytokine imbalance that promotes the development of allergic diseases [56].

Zinc deficiency contributes to thymic atrophy; immature B cell accumulation; and decreased IgM, Ig-G2a, and IgA subclasses. Stress situations, through pro-inflammatory cytokine production, including IL-6 and TNF-α, are often associated withzinc deficiency. Inflammatory cytokines, permanently increased in the geriatric population, bind zinc ions with a consequent reduced zinc bioavailability and altered immune functions. In particular, decreased levels of zinc induce a reduction of Th1 cytokines, such as IFN-γ, IL-2, and TNF-α, while Th2 cytokines, in particular IL-4, are enhanced. Through this mechanism, zinc deficiency could favor the development of FAs in the elderly [57].

Iron deficiency is also frequent in the elderly [20]. The decreased iron level induces impaired humoral responses, and in particular reduces the production of the IgG4 subclass that physiologically captures the allergens before they can bind to the IgE, thus preventing the activation of effector cells, such as mastocytes and basophils [58].

Several studies suggest that vitamin D deficiency is also very common in the elderly, supporting FA development. Immune dysregulation, in addition to an increased parathyroid hormone level and impaired bone health resulting in enhanced risk of fractures, is a serious consequence of vitamin D deficiency in the elderly [59,60]. The active metabolite of vitamin D, calcitriol, influences T lymphocytes and antigen-presenting cells to induce peripheral tolerance by inhibiting inflammatory responses and promoting regulatory T cells [61]. Vitamin D deficiency is therefore associated with an increased risk of autoimmune and atopic diseases, although the association with IgE levels is not clear [62].

#### **7. Clinical Features of FAs in the Elderly**

The variable natural history and the complexity of the possible pathogenetic mechanisms, as well as several age-associated factors, make the diagnosis and management of FAs in the elderly difficult. Nutritional abnormalities and vitamin deficiencies, as well as hormonal imbalances and inflammaging, interacting with genetics, may alter the immune responses, leading to FA development. The age-related decline of physiological functions, in addition to the immune system remodeling, which characterizes senescence, contribute to confer peculiar clinical findings to FA in the elderly [23,63].

Furthermore, despite the normal or increased number of mast cells in the skin of aged subjects with an allergy and a sufficient positive response to prick tests with specific allergens, elderly show weaker cutaneous responses and less intense pomfoid reactions to histamine control [64]. Therefore, since the positive reactions to skin test for an allergy could be partially reduced in the elderly, creating possible risk of false negative skin test, a specific IgE search to diagnose FA is commonly used in older patients [65].

Frailty, comorbidity, and multi-drug intake are conditions commonly found in the elderly and must be taken into account in the management of aged people affected by FAs. Immunologic reactions to foods can be confused with symptoms of other common age-related diseases or be masked by the use of various drugs. Consequently, the characteristic symptoms of FAs often go unnoticed and this contributes to underestimating FA prevalence in old age [7]. Dryness and hyperkeratosis, with consequent itching and increased risk of skin infections, are dermatologic manifestations that often mimic and/or mask the symptoms of an allergy. Cutaneous symptoms, such as atopic dermatitis and urticaria, could also represent manifestations of FAs in the elderly [25]. However, in addition to FAs, even drugs and systemic diseases, mainly hematologic and immune dysfunctions, can also induce urticaria in the elderly. Underlying diseases must, therefore, always be suspected, especially when a new diagnosis of chronic urticaria is made in an elderly person [66,67]. Although aged individuals can respond to immunotherapy for a respiratory allergy, as well as to biological drugs commonly used for the treatment of allergic manifestations, such as urticaria and atopic dermatitis, they are usually excluded from these kinds of therapy [68,69]. This is due to the frequent presence of age-related clinical conditions that are considered contraindications. Moreover, the common occurrence of comorbidities and multidrug intake can affect the therapeutic response and promote the onset of side effects. However, immunotherapy and biologic drugs could also significantly improve the quality of life in the elderly, reducing symptoms and drug consumption [70].

Anaphylaxis is a severe and life-threatening hypersensitivity reaction that can affect allergic patients at any age [45]. Clinical manifestations of anaphylaxis caused by food allergens are less frequent in the elderly compared to young subjects [71]. However, although less common, anaphylaxis exhibits a worst prognosis in older patients [72]. The anaphylaxis mediators released by the mast cells after the binding of the allergen to the IgE anchored to their surface induce profound functional modifications on the cardiocirculatory system, including vasospasms of coronary arteries with reduced myocardial blood flow and arhythmias [10,73]. The age-related susceptibility of the cardiovascular system to mast-cell-derived mediators and underlying comorbidities, such as coronary diseases, contribute to the increased mortality and frequent cardiovascular involvement during anaphylaxis in aged people [74]. In patients with multimorbidities, multidrug prescriptions are important cofactors complicating anaphylactic events in the elderly [75]. Cardiovascular drugs, increasingly prescribed to the elderly, strongly contribute to thegreater probability of a fatal outcome. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, commonly used to treat congestive heart failure and hypertension, may in fact contribute to aggravate the impairment of compensatory mechanisms typical of the elderly [76]. Several other drugs may interfere with allergic effector cells of FAs. Nonsteroidal anti-inflammatory drugs, taken for chronic osteoarticular pain, are relevant cofactors in urticaria and anaphylaxis in aged subjects [67]. Tricyclic antidepressants, monoamine oxidase inhibitor, and neuroleptics may increase the cardiac risk of epinephrine administration. All these different drugs could cause hypotension, accelerate and increase exposure to allergens, and mask the symptoms of a possible allergic reaction. Although the advanced age doesnot represent an absolute contraindication to self-injectable adrenaline prescription in those at higher risk of anaphylaxis, impaired neuro-motor coordination, frequent hypomobility, and the common coexistence of osteo-muscular and arthrosic hand pathologies compromise the ability to use auto-injectors, suggesting caution in this prescription [77].

The intake of antiulcer drugs is common in the elderly to cure gastritis, gastroesophageal reflux, gastric ulcers, or in association withcorticosteroids and non-steroidal painkillers to minimize their gastrolesive effects. Gastric hypoacidity and increased permeability of the upper gastrointestinal tract also occur as a result of therapy with acid-suppressive drugs, facilitating the onset of an FA, as well as eosinophilic esophagitis. Elderly patients treated with proton pump inhibitors or H2-receptor blockers are at higher risk for sensitization because dietary proteins both remain incompletely digested and can cross the mucosal barrier more easily due to the increased permeability, thus becoming allergenic [8,49].
