Estado del arte
4.1 Algoritmos bio-inspirados en hardware
While caloric restriction has been shown to prolong survival, as first demonstrated in 1935,79 the same conclusion cannot be substantiated in humans. Much evidence and many observations link the importance of nutrition and its effects on immunity. In the hospitals of the Warsaw ghetto in 1942, Jewish physicians noted that tuberculosis was much more severe in the malnourished, the tuberculin skin test was impaired in malnourished patients with TB, and allergic diseases improved spontaneously as mal-nutrition worsened. In the two groups of British and Russian prisoners of war who had similar food rations and living and working conditions, the British group received daily food supplements from the Red Cross. There was a marked difference in the incidence of tuberculosis in the two groups, with a lower incidence in the British group, indicating the importance of nutrition on the immune response.80,81
Malnutrition is a common clinical entity found with increased prevalence in the elderly population. Malnutrition can be caused by many different etiologies: physical disability, medication-induced anorexia, anorexia of aging, restrictive diets, poor dentition, chronic medical conditions, living situations, psychosocial issues, and depression. All these factors lead to a common endpoint of malnutrition, worsening function, and frailty.
6.6.1 CELL-MEDIATED IMMUNITYIN THE MALNOURISHED
In patients with impaired nutritional status, either lower serum albumin (3.0 to 3.9 g/dl) or normal albumin but lower micronutrient status, the changes in T cell subsets (CD3+, CD8+, and CD4+) and function (decreased IL-2, IL-6 release) were marked compared to the discussed changes with aging in the healthy aged population.28,32 In addition, the immune responses of the elderly are very sensitive to nutritional influ-ences, for example, folic acid deficiency. Even in the very healthy elderly group, minor changes in folic acid level were found to result in decreased T cell subsets and lower cell-mediated immune (CMI) responses, while young adults with low folic acid levels do not exhibit a lower immune response.40 In ambulatory elderly individuals with serum albumin less than 3 g/dl, the peripheral lymphocyte count was shown to be suboptimal and CD4 T cells lower than 400/mm3, a level comparable to acute acquired immune deficiency syndrome in human immunodeficiency virus infection.82
In general, poor nutritional status exacerbates the already impaired function of the aging immune system and resembles the same pattern as those discussed in the immunosenescence section, but the degree of impairment is more marked.
Delayed cutaneous hypersensitivity (DCH) reaction declines significantly in the elderly population at risk for nutritional deficiencies of vitamins,82 and when replaced with nutritional supplement, the DCH reaction seems to improve.83 In hospitalized elderly at risk for malnutrition84,85 and in idiopathic senile anorectic elderly,86 the DCH reaction is significantly depressed. Anergy is also found to be more prevalent in nursing home residents than in geriatric clinic patients (community dwellers).87 Although elderly subjects with chronic diseases have a significantly lower DCH reaction than young controls, only a small subpopulation show some anergy to the common antigens.53 Deficiency of essential omega-3 fatty acids may also contribute to cutaneous anergy in the malnourished elderly.88
6.6.2 MACROPHAGE–T CELL INTERACTIONS: CYTOKINE PRODUCTION
Undernutrition also affects cytokine production. Macrophages release cytokines in response to stress. The decreased T cell functions in the frail elderly result in decreased cytokine release from macrophages. These cytokines modify metabolic functions and induce utilization of body reserves of nutrients, resulting in hypercat-abolic syndrome (proteolysis, osteolysis, changes in protein synthesis in the liver, decrease in insulin).40 The vicious cycle continues with further body reserve depletion under longer stress reaction, and the elderly undergo accelerated aging when under prolonged stress. The elderly recover in a more frail state and lower body reserve (lower muscle mass), and thus exemplify the importance of nutrition on frailty progression and accelerated aging. In idiopathic senile anorexia, there is increased production of several cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ,86 and this increase in proinflammatory cytokines may contribute to protein-energy malnutrition (PEM), frequently found in chronic nonmalignant disorders.89
When undernutrition reaches the PEM state, all immune responses are decreased, including macrophage cytokine synthesis. This leads to lower nutritional utilization and impaired lymphocyte activation and results in longer duration of disease and longer inflammatory response, leading to more decreases in body nutritional reserves, a more profound malnourished state,40 and eventually to death.
6.6.3 MUCOSAL IMMUNE SYSTEM IN AGING AND MALNUTRITION
Mucosal immunity is primed after birth and develops throughout life via the inter-action of microflora with the gut immune system (gastrointestinal-associated lym-phoid tissue, or GALT). Any changes in the gut with aging affect the microenviron-ment, and therefore the mucosal immune system. Mucosal defense utilizes innate and adaptive immune cells. The innate immune cells, namely, monocytes, macro-phages, NK cells, and dendritic cells, recognize the specific pathogen motif and
mount an immediate immune reaction. Available studies show mucosal immune deficits in the differentiation and migration of immunoglobulin A cells to the intes-tinal lamina propria, and the initiation or regulation of local antibody production with aging.90,91 This results in impaired secretory IgA responses, induction of anergy, and suppression or tolerance to oral antigen in the elderly. Furthermore, GALT-mediated responses are more susceptible to aging than are lymphoid tissues else-where in the body. These changes may be due to the reduced size of Peyer’s patches and decreased cytokine production and response.92
Nutritional deficiencies of vitamins and minerals pose different influences on the immune system as a whole and play an important role in growth and diseases. Micro-flora of the gut, respiratory tract, perineum, vagina, and distal urethra control the homeostasis of the mucosal immune system. Malnutrition can shift the balance of normal flora and result in increased susceptibility to infections and other derangements, for example, coagulopathy and Clostridium difficile colitis. Studies have found some benefits of probiotic bacteria effective against antibiotic-associated diarrhea, such as C. difficile colitis. Probiotic lactobacilli can decrease tumor risk by neutralizing car-cinogens and producing antitumor factors and by replacing microflora that produce carcinogens and tumor promoters.93–97 Moreover, lactobacilli can be used to increase a weak systemic immune response, even in an HIV-positive host.93,98
The route of nutrition delivery may greatly affect the mucosal immunity of the intestine, liver, and lungs. It has been hypothesized that there is an immunologic link between the gastrointestinal tract and respiratory tract via a common mucosal immune system. Results from experimental and clinical studies in animals and humans support the hypothesis that immune cells sensitized in the Peyer’s patches of the intestine can migrate to other intestinal and extraintestinal sites and induce specific mucosal immune responses at these sites. In animal models, mice fed parenterally were found to have marked reduction of B and T lymphocytes in the intestinal lamina propria and a significant shift of the CD4:CD8, ratio resulting in decreased cytokines, specifically IL-4 and IL-10, which are important for B cell switching to sIgA-producing plasma cells, and decreased IgA production. When mice immunized with a respiratory virus were then fed parenterally, 50% of the animals lost protection against the virus and had continued viral shedding 40 hours after rechallenge; all animals fed via the gastrointestinal tract cleared the virus.
However, immunologic memory was restored with enteral refeeding.99,100 In human trials, patients postoperatively were randomized to start enteral feeding vs. parenteral nutrition; the enteral group was found to have significantly lower incidence of pneumonia and trending to lower incidence of intra-abdominal abscess.101–103
Glutamine is an amino acid recognized for its role in modulating the immune changes with parenteral nutrition. Adding glutamine to the parenteral preparation improves intestinal lymphocyte number, preserves IL-4 function, increases intestinal and respiratory tract IgA levels, and may partially reverse the impaired antiviral and antibacterial immune response due to parenteral feeding.100
6.7 IMMUNE RECONSTITUTION AND ENHANCEMENT