Human aging can be considered as a dynamic process that leads to a continuous adaptation of the body to the deteriorative changes occurring lifelong. This picture is conceptualised in the remodelling theory of aging [29,30], based on experimental evidence obtained from studies on human immunosenescence and on healthy very old people (centenarians) as a model of successful aging. Specifically, these results show that the aging process affects immune responses differently; some of them decline while others remain unchanged or increase [31-33], Accordingly, a variety of immune responses and parameters are well conserved in centenarians [34^10],
Data from the literature seem to indicate that natural immunity remains preserved or less affected by aging than clonotypic and adaptive immunity. Indeed, the absolute number of cells belonging to the natural immunity compartment, such as dendritic cells (DCs), monocytes/ macrophages and granulocytes is not affected by age, while their ability to function, responsiveness, or number of precursors can change, as described in detail below.
Rapid progress in the characterisation of DCs, the most important antigen-presenting cells with a central role in initiating and modulating immune responses, has been made in recent years. DC activity appears to be well preserved during aging , even if some alterations seem to occur. For instance, one type of DC precursor, i.e., plasmacytoid DC, a rare circulating population of blood cells, seems to be decreased together with its capacity to produce IFN-a , As far as migratory capacity is concerned, it is not yet clear whether it is impaired in aged DC [43,44], while DC responsiveness to some pathogens and vaccines has been found to be unimpaired ,
Monocytes and macrophages appear to be mostly activated in aged subjects, based on the observed immunophenotype as well as on biological activity assays . Specifically, their production of cytokines, such as IL-1|3, IL-6, IL-10, and chemokines, such as RANTES and MlP-la, is up-regulated during aging [45-48], These results are very important and the central role of monocytes in the pro-inflammatory status, which can contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegenerative disorders and diabetes, will be discussed in the paragraph dedicated to the inflammatory diseases. The number of circulating neutrophil cells in the peripheral blood is not altered with age, though the proliferative response of neutrophil progenitors to G-CSF appears to be reduced [49,50], It is well known that during bacterial infection neutrophil growth is massively up-regulated by the action of proinflammatory cytokines, leading to neutrophilia. Reduced responsiveness of neutrophil progenitors to G-CSF can therefore potentially affect the ability of the elderly to increase the number of neutrophil cells during infection, leading to a higher susceptibility to infectious diseases. This fact has been observed in elderly people affected by chronic infection , and suggest that neutrophil production is modified under conditions of persistent infection. Moreover, a reduced neutrophil phagocytic capacity is found in elderly donors, together with a decreased expression of CD 16, one of the key receptors inducing phagocytosis of bacteria . This loss of membrane receptors could be a major factor contributing to reduced neutrophil function and increased susceptibility to bacterial infections in the oldest old. Nevertheless, when healthy centenarians are considered, the number of granulocytes (mainly neutrophils) has been found to be increased. Moreover, phagocytic function and production of cytokines such as IL-1 (3 and TNF-a in granulocytes from centenarians, seem to be increased, whereas the production of superoxides is decreased in comparison with that measured in middle-age subjects .
An increased number and percentage of NK cells (CD 16+, CD56+, CD57+) has been found in the elderly and even more in centenarians [36,52,53]. It has been proposed that the increased number of NK cells can be a compensatory mechanism that counteracts their decreased functionality. Such a functionality is correlated with a preserved metabolism of thyroid hormones and vitamin D [53,54]. These findings are very important, since multiple interactions are known to exist between the endocrine and immune system, and thus alterations in hormone metabolism and responsiveness occurring with age can be the cause of impairment in the NK compartment. Moreover, NK cells from healthy aged subjects and centenarians seem to have a peculiar impairment of some activation pathways such as that involving Protein Kinase C, while others such as the antibody-dependent pathway, seem to be preserved [52,53]. A decreased level of chemokine production in isolated and stimulated NK cells from nonagenarian subjects has been demonstrated . Other authors have found an increased production of IFN-y by NK cells both in middle-age subjects and centenarians .
During ageing, an increase in the proportion of T cells expressing NK markers (CD 16, CD56, CD57) has also been reported particularly in centenarians [36,52,53]. Studies on human NKT cells and aging are limited. Nevertheless, some authors have found a decreased percentage of cells bearing CD3 and Valpha24, a membrane marker for a subpopulation of human NKT cells, together with an increase of Valpha24+CD8+ cells in peripheral blood from the elderly, indicating a redistribution of this subset according to the CD4/CD8 phenotype . Moreover, unhealthy centenarians have a high level of Valpha24+ cells that produce high amounts of IFN-y . It also has been speculated that in humans an age-related shift in lymphocyte populations from canonic T and NK cells to NKT cells would be responsible for a progressive difficulty in discriminating NK from T cells of aged individuals on the basis of phenotypic markers [57-59],
The number of circulating y8 T cells is found to be reduced in old people and centenarians together with an altered pattern of cytokine production, particularly evident at the level of TNF-a production. In spite of these alterations, the level of y8 T cell cytotoxicity appears to be well preserved [60,61]
As far as the complement system is concerned, it appears well preserved in elderly subjects and centenarians. Indeed, the immunochemical levels of C3 and C4 together with serum functional haemolytic activity for classical (CH50) and alternative pathways (AP50) are found to be in the normal range ,
On the whole, natural immunity seems to be affected by age to a lesser degree than clonotypi-cal immunity. Actually, it is emerging that different cells, such as monocytes, granulocytes, NK and NKT cells can up-regulate their production of cytokines and chemokines thus inducing a pro-inflammatory status. These findings suggest that the reshaping of the organism occurring with age can be, at least in part, orchestrated by a shift in cytokine production toward a proinflammatory profile, together with other endocrine and metabolic alterations . Moreover, the progressive accumulation of clones of memory cells, together with the age-related decrease of thymic output of new T cells, leads to a progressive filling of the available immunological space with antigen-experienced, low-responder cells and to a correspondent decline in the number of virgin T cells . This renders the subjects likely more prone to a variety of infectious and non-infectious diseases, where immunity and inflammation play a major role .
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