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The capability to cope with infectious agents and cancer cells resides not only in adaptive immune responses against specific antigens, mediated by T and B lymphocytes clonally distributed, but also in natural immune reactions. These innate defence mechanisms include chemotaxis, phagocytosis, natural cytotoxicity, cell interactions, and soluble mediators or cytokines. However, specific and natural immune mechanisms are always closely linked and interconnected, providing the primary defense against pathogens. The Authors discuss the main changes observed with advancing age in granulocytes and natural killer (NK) cell activity, in the expression and function of adhesion molecules, and in the pattern of cytokine production. Since phagocytic function is the primary mechanism through which the immune system eliminates most extracellular pathogenic microorganisms, analysis of this function is of clinical importance. Neutrophils from aged subjects often exhibit a diminished phagocytic capacity, as well as a depressed respiratory burst, notwithstanding an activated state. The activity of NK cells during aging has been studied extensively and different results have been reported. The most consistent data indicate an increase in cells with high NK activity with advancing age. Cells from healthy centenarians can efficiently kill target cells. This finding seems to suggest that innate immunity and in particular NK cell activity, is not heavily deteriorated with age. Conversely, a low NK activity is a predictor of impending morbidity. Immunosenescence is associated with increased expression of several cell adhesion molecules (CAM) resulting in an augmented capacity to adhere. Finally, also the cytokine network, responsible for differentiation, proliferation, and survival of lymphoid cells, undergoes complex changes with age. The main findings are a Th1 to Th2 cytokine production shift and an increased production of proinflammatory cytokines, which could explain many aspects of age-associated pathological events, such as atherosclerosis and osteoporosis.

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.-In the gastrointestinal tract, tachykinin NK1 receptors are widely distributed in a number of neuronal and nonneuronal cells involved in the control of gut motor activity. In particular, in the rabbit isolated distal colon, which is a suitable model system to investigate the contribution of tachykinins as noncholinergic excitatory transmitters, the influence of NK1 receptors in the regulation of peristalsis is not known. The selective NK1-receptor antagonists SR-140333 (0.3 and 1 nM) and MEN-10930 (0.3-10 nM) significantly enhanced the velocity of rabbit colonic propulsion to submaximal stimulation. The prokinetic effect of SR-140333 was prevented by N -nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, indicating that NK1 receptors located on nitrergic innervation exert a functional inhibitory restraint on the circular muscle and probably on descending excitatory and inhibitory pathways during propulsion. Conversely, the selective NK1-receptor agonist septide (3-10 nM) significantly inhibited colonic propulsion. In the presence of L-NNA, the inhibitory effect of septide was reverted into a prokinetic effect, which is probably mediated by the activation of postjunctional excitatory NK1 receptors. myenteric neurons; excitatory pathways; inhibitory pathways IN THE MAMMALIAN GASTROINTESTINAL tract, the tachykinins (TKs), substance P (SP) and neurokinin A (NKA) are cotransmitters in several functional classes of myenteric neurons and are concomitantly released in response to depolarizing stimuli (see Ref. 14 for review). In particular, TKs and ACh are coexpressed by certain intrinsic primary afferent (sensory) neurons (IPANs) and by many ascending interneurons and motoneurons, which are part of the circuits regulating excitatory peristaltic reflexes (4, 10, 28). Conversely, descending pathways do not contain TKs (i.e., cholinergic/noncholinergic descending interneurons and inhibitory motoneurons), although TK receptors are expressed in a portion of these neurons (4,5). This makes it difficult to explain the contribution of NK 1 , NK 2 , and NK 3 receptors to the development of descending inhibitory reflexes (18,19,44).Of the three tachykinin receptors, NK 1 receptors show a higher distribution in the intestine, because they are expressed by a number of neuronal and nonneuronal cells involved in gut motor activity. In the myenteric plexus of the guinea pig ileum, NK 1 -receptor immunoreactivity (NK 1 r-IR) is present in a large population of neurons containing nitric oxide (NO) synthase (NOS), a marker of inhibitory neurons to the muscle and in a small portion of IPANs, descending nitrergic interneurons, and excitatory neurons to the circular muscle (27,34). In the rat ileum, NK 1 r-IR occurs in cell bodies and in the proximal processes of IPANs and myenteric interneurons (31, 41). In nonneuronal cells, NK 1 r-IR is present in the interstitial cells of Cajal (ICC) and smooth muscle cells of the rat and guinea pig small and large intestine (22,34,39,41). Therefore, tachykinergic NK 1 transmission to the ...

Profound and complex changes in the immune response occur during the aging process. Immunosenescence is reflected by a sum of disregulations of the immune system and its interaction with other systems. Many of the changes would appear to implicate age-related deficiencies of the immune responses. The term immunosenescence designates therefore a sort of deterioration of the immune function which is believed to manifest itself in the increased susceptibility to cancer, autoimmune disease, and infectious disease. Evidence has been accumulating from several studies which suggest an association between immune function and individual longevity. However, there are observations, especially in very old healthy people, that several immune functions are unexpectedly well preserved and substantially comparable to those observed in young subjects. These findings raise the question of whether the alterations that can be observed in the immune parameters of the elderly are a cause or a result of underlying disease processes. Moreover, studies on centenarians revealed a remodeling of the immune system rather than a deterioration, suggesting that the changes observed during immunosenescence do not correspond to immunodeficiency. The underlying mechanisms of these events are however still unclear. The purpose of the present review is to assess the status of research on the immunobiology of aging. In this first section, we focus attention on the B cell biology of aging. In clinical practice, the changes in humoral immune responsiveness and antibody-mediated defense mechanisms could greatly influence the incidence and outcome of bacterial infections and autoimmune diseases as well as the response to vaccines.

Numerous changes occur in the immune system with advancing age, probably contributing to the decreased immunoresponsiveness in the elderly. These changes are often associated with important clinical manifestations such as increased susceptibility to infection and cancer frequently observed in the elderly population. Although both cellular and humoral immune responses are modified with advancing age, much of the decrease in immunoresponsiveness seen in elderly populations is associated with changes in T cell responses. The loss of effective immune activity is largely due to alterations within the T cell compartment which occur, in part, as a result of thymic involution. Substantial changes in both the functional and phenotypic profiles of T cells have been reported with advancing age. In fact, two prominent features of immunosenescence are altered T cell phenotype and reduced T cell response. One of the most consistent changes noted in T cells with advancing age is the decrease in the proportion of naive T cells with a concomitant increase in T cells with an activated/memory phenotype. In addition, there is evidence that the T cell population from aged individuals is hyporesponsive. The observed functional changes include decreased responsiveness to T cell receptor stimulation, impaired T cell proliferative capacity, a decline in the frequency of CD4+ T cells producing IL-2 and a decreased expression in IL-2 receptors. These latter findings probably explain the loss of proliferative capability of T cells from aged individuals. There is also evidence of a decrease in the early events of signal transduction, decreased activation-induced intracellular phosphorylation, and decreased cellular proliferative response to T cell receptor stimulation. The present review analyzes the main changes of the T cell compartment characterizing immunosenescence and discusses the possible mechanisms underlying these disregulations and their clinical implications.

Loss of the cell proliferative capability and involution of tissues and organs are among the most important phenomena that characterize the aging process. Some of the aged-linked immune dysfunctions could be partly due to a dysregulation of apoptotic processes and to a lower responsiveness of aged lymphoid cells to activation and proliferation signals. The main changes in proliferative activity and cell death during aging and their impact on the process of immunosenescence are discussed. In fact, a very important function that has been suggested to deteriorate with age and to play a major role in the aging process is the capability of cells from aged subjects to respond to mitogenic stimuli and, consequently, to undergo cell proliferation. However, the cellular activation processes are very complex and the proliferative responses can follow different interconnected signal transduction pathways, and only some of them appear to be modified during age. Moreover, cell growth, immunosenescence, and longevity are strictly interconnected and deeply related to programmed cell death or apoptosis. The cellular equilibrium between cell survival and proliferation, on the one hand, and programmed cell death, on the other hand, seems to be unbalanced with advancing age, although in each type of immune cell it could be differentially modulated, resulting in a variety of clinicopathological consequences. Thus, cell proliferation and cell death are two physiologically active phenomena closely linked and regulated and a failure of these mechanisms determines profound dysregulations of cell homeostasis with major consequences in immune functioning and the onset of autoimmune diseases and cancer, whose incidence appears to be increased in the elderly.