 |
|
|
| Edited
by:
R.H. Straub, University Medical Center, Department of Internal Medicine I, Laboratory of Neuroendocrinoimmunology, Regensburg, Germany E. Mocchegiani, Immunology Center, Research Department INRCA, Ancona, Italy Published
by: Elsevier Science
Description:
Audience: Neurologists, psychologists, psychiatrists, immunologists, endocrinologists, physiologists, practising clinicians, veterinarians, animal scientists. Contents: I.
Introduction.
II. Ageing of the immune system Immunosenescence.
Zinc-binding
proteins (metallothionein and alpha-2 macroglobulin) as potential biological
markers of immunosenescence.
Neutrophil
ageing and immunosenescence.
Apoptosis
and ageing.
MHC-unrestricted
cytotoxicity in ageing.
Major
histocompatibility complex polymorphisms and ageing.
III. Ageing of the endocrine system Neuroplascticity
in the human hypothalamus during ageing.
Ageing
and the adrenal cortex.
Hormonal
changes in ageing men.
Ageing
and the endocrine circadian system.
Melatonin
rhythms, melatonin supplementation and sleep in old age.
IV. Ageing of the nervous system Age-related
changes of the human autonomic nervous system.
Age-related
alterations in autonomic nervous innervation.
Modulating
effects of nutrition on brain ageing.
Ageing-related
role of nitric oxide in the brain.
V. Links between one global system and another global system during the ageing process Introduction
Pasticity
of neuroendocrine-thymus interactions during ontogeny and ageing: Role
of zinc.
Adverse
glucocorticoid actions and their relevance to brain ageing.
Neuroendocrine
- immune aspects of osteoporosis during the ageing process.
VI. The ageing process and chronic inflammatory diseases Neuroendocrine
immune mechanisms of accelerated ageing in patients with chronic inflammatory
diseases.
Thyroid
autoimmunity and ageing.
The
clinical importance of proinflammatory cytokines in elderly populations.
VII. Conclusions Possible
new anti-ageing strategies related to neuroendocrine immune interactions.
Concluding
remarks and future directions.
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| Concluding
Remarks and Future Directions
ISTVAN BERCZI1 and ANDOR SZENTIVANYI2 1 Department of Immunology, Faculty of Medicine, The University of Manitoba, Winnipeg, MB Canada, R3E 0W3, and 2Department of Internal Medicine, Faculty of Medicine, The University of South Florida, Tampa, Florida 33612, USA ABSTRACT It is indicated by this volume that normal age related changes in the neuroimmune regulatory network are highly relevant to “successful”, or healthy ageing. Abnormal regulation is associated with age related diseases. Clinical observations provide compelling evidence for the relevance of Neuroimmune Biolgy (NIB) to practical Medicine. Thus the Science of NIB provides novel perspectives for the investigation of highly complex biological processes, such as ageing and lead to original observations that allows for better understanding of higher organisms in their entire complexity. The future is very challenging both scientifically and from the moral standpoint. 1. INRODUCTION Ageing is one of the unresolved problems in Biology. However, the rule is abundantly clear: we all must be born in order to exist and eventually must die. Without this iron-fisted law of Mother Nature the evolution of the species would have been difficult if not impossible. Further, the proper balance of the Plant and Animal Kingdoms would have been endangered. Clearly, immortality could be considered as the cancer of the evolutionary process and of normal biological ecosystems. By now it is firmly established that programmed cell death (apoptosis) is part of normal embryonic and post-partum development as well as it is fundamental to the regulation of various systems in the body, including the immune system. Immune killer cells use apoptosis as efficient weapons for the elimination of infected and cancerous target cells. Clearly all of our cells possess the genetic machinery for apoptosis and there are multiple receptors that are capable of committing various somatic cells to the suicide pathway [1-3]. One may pose the question: if all of our cells can be induced to die, are we also programmed to die? Common sense would give us a Yes answer. In other words, under normal conditions ageing may be a maturation process, which will proceed smoothly, without major life-threatening problems. This is often termed as “successful” ageing. However, it seems that in most people ageing is associated with major abnormalities, including of those of the Neuroimmune Regulatory System and consequently, diseases prevail during aging. The chapters in this book lend support to this hypothesis. 2. AGING OF THE IMMUNE SYSTEM 2.1 Immunosenescence. The currently accepted wisdom is that as we age, we get sicker and sicker, and then we die. Early immunological studies support very well this common belief. Nearly all immune parameters have been shown to decline with ageing, especially when male subjects were examined. However, most clinical experiments are done in hospitals, where only sick people are available for study. Some recent data indicate that healthy old people have healthy immune -, endocrine - and nervous systems. Nevertheless, the Immune System shows age-related changes, but it may be regarded as maturation, rather then a disastrous break down. Thus thymus involution is possible because the thymus has less and less work to do with our immunological adaptation to our external and internal environment. This hypothesis is supported by the fact that antigen presentation does not decline, if anything it is improving with age. So are memory T lymphocytes. Few immunological phenomena carry the same significance than antigen presentation and immunological memory [4-6]. The above parameters are fundamental pre-requisites of maintaining an effective immune defense. So, if older people are better than in some aspects of immunity than are younger individuals, should they be examined with the expectation that they are deficient? Should not we consider the possibility that a process of immune maturation takes place during aging that under normal conditions is capable of maintaining good health and survival? Should one consider the possibility of ripen old age without disease? Studies of healthy old people in order to learn more about health, disease, the immune system and ageing represent a new dimension of research in ageing [7-9] Apparently
now there is evidence for the relationship between the oligoclonal expansion
of lymphocytes with age and endogenous viruses (e.g. Herpes, Cytomegalovirus
and Epstein-Barr virus) [10-13].
2.2 Metallothioneins as potential biological markers of immunosenescence. The zinc-zinc-binding protein system regulates the activity of key hormones, cytokines and enzymes in the body. Moreover, this system is affected by stress and the zinc binding proteins are known as acute phase proteins (APP). Apparently Zn is essential for the normal function of the adaptive immune system as it controls the activity of key hormones, such as growth hormone (GH) and of cytokines, as well as enzymes. Indeed, the over-expression of zinc binding proteins during the acute phase response (APR) may play an essential role in the conversion of the immune system from the adaptive mode of reactivity to the boosting of natural immune host defense [16,17] Because there is a drift during aging from prevalent adaptive immune reactions towards natural immune mechanisms and to frequent APRs, it comes natural that zinc-binding proteins show elevations with aging [15] However, memory T cells are all right in old age, in spite of Zn deficiency. Moreover, these changes are not inevitable as centenarians were found to have normal Zn and binding protein values [18] It is also noteworthy that liver regeneration was not affected in old mice with high MT and Zn levels in this organ[19]. This observation indicates that cell proliferation per se may not be deleteriously affected by the zinc homeostatic regulatory system. 2.3 Neutrophil ageing and immunosenescence Neutrophil numbers are not lowered with age [20] and there is normal neutophilia to infectioin [21]. Adhesion molecules are normal or may even be increased [22,23] and bactericid innate recognition is all right [24] Contradictory observations were made for neutrophil extravasation, chemotaxis and superoxide production. Neutrophil reaction was reduced to GCSF but not to GMCSF. Significant reduction was found in phagocytosis and cytotoxicity was declined towards bacteria and yeast [25] However, it is not clear, how much of this functional impairment is due to the ageing of neutrophils and to what extent is it the consequence of glucocorticoid excess, which is characteristic of ageing animals and man [15,26,27]. Hypopituitary patients show excess mortality due to respiratory disease [28] which gives further emphasis to the relevance of age related neuroendocrine alterations to immune abnormlities. 2.4 Apoptosis and aging Apoptotic (APO) phenomena are increased in ageing [29]. Tumor necrosis factor (TNF) is also increased, as well as tumor necrosis factor receptor-I (TNFR-I), which mediates APO on various target cells. In contrast, TNFR-II, which conveys other actions of TNF, is decreased [30,31,]. Effector memory T cells (e.g. CD28+) are increased during ageing and these cells are susceptible to apoptosis [32]. However some subsets of memory T cells may be APO resistant [33]. Replicative senescence may block APO [34] Several functions of polymorfonuclear cells (e.g. killing, free radicals, chemotaxis, O3, lytic enzymes) are decreased with ageing [1,35]. Cholesterol, which is often elevated in the elderly, is important for signal transduction by membrane bound receptors [1]. It is apparent from this chapter that APO occurs more frequently in the elderly. However, it is also apparent that programmed cell death remains an important physiological regulatory mechanism for memory T cells, which show an increase, rather than a decline with ageing. 2.5 MHC-unrestricted cytotoxity in ageing Monocyte and macrophage numbers and cytokine production are increased in the elderly [36], and dendritic cells are unimpaired as well [37]. This assures excellent antigen presentation as well as phagocytic/cytotoxic activity by these cells. TNF alpha was not changed, whereas IFN gamma was increased in centenarians [38]. Mature NK (CD56+) cells were elevated in the elderly [39], and NK functions were not diminished with aging [40]. High NK numbers were observed in centenarians [41]. Gamma/delta T cell cytotoxicity was preserved in centenarians [42] and higher gamma-delta-T activation was observed in old individuals [43]. Bone and muscle remodeling by the immune system was maintained in the elderly [44,45] This chapter testifies that innate cytotoxic mechanisms are actually superior in elderly people when compared to young individuals. This is coupled with excellent antigen presentation and immunological memory. Moreover, immune capability of centenarians is truly remarkable. All these facts support the idea, that during successful ageing an immune disaster is not inevitable, on the contrary, it is possible to suggest that the immune system keeps adapting to age related changes in order to optimally fulfill its normal functions. 2.6 MHC Polymorphism and ageing Caruso and colleagues conclude that there is no statistically significant relationship between MHC-polymorphism and successful ageing [46] [Candore et al. 2004]. However, one must not forget that MHC polymorphism and immunological diversity play a major role in survival at the time of major epidemics. 3. AGEING OF THE ENDOCRINE SYSTEM 3.1 Neuroplascticity in the Human Hypothalamus During Ageing Hofman and Swaab [47] provides an accout of hypothalamic changes during ageing. They point out that each group of cells (e.g. nuclei) in the hypothalamus has have their own sex-specific pattern of ageing. Some nuclei become less active, others become more active with age. Steroid hormones play a key role in neuroplasticity and ageing. This story is very similar to what was said about the ageing immune system. Both positive and negative changes occur, which implies regulation rather then simple deterioration during ageing. Current evidence indicates that the hypothalamus is the ultimate immunoregulator [48] [Berczi and Szentivanyi 2003c] and it is fudamental for the regulation of all other organs and tissues in higher organisms, as is obvious from this volume. On this basis one may suggest that the process of ageing also is under hypothalamic control. Clearly this part of the central nervous sytem is involved in setting of biological rhythms and adaptive variations. The lifespan of the organism may be suggested as the ultimate rhythm to regulate. Elderly animals and humans are typically characterized by the loss of rhythmicity of physiological parameters and by the inability to adapt to environmental challenges, as repeatedly pointed out in this volume. 3.2 The role of growth hormone signaling in the control of ageing Growth hormone plasma levels gradually decline during adult life. It is apparent from the relevant literature that role of GH changes in different stages of life. Excess GH during adulthood in animals and man shortens their lifespan. Tradeoffs must exist between growth, reproduction and longevity. Low GH levels may have a role in protecting the organism from cancer and other age-related diseases. Subnormal GH levels affect body composition, muscle and brain function, and are suspected of contributing to the deterioration of quality of life in the elderly. However, the risks and benefits of anti-ageing therapy with GH are not well understood and the concept of GH replacement during “somatopause” is controversial [49] It seems very intriguing that GH has an influence on lifespan. Being an anabolic hormone, excess GH must promote metabolic processes that are deleterious for longevity. Growth hormone is the member of the growth and lactogenic hormone (GLH) family, which include multiple isoforms of GH, prolactin (PRL) and placental lactogenic hormones (PL). These hormones have overlapping functions and are of fundamental importance in governing the growth, development and bodily functions of higher animals for their life-cycle. On the basis of the immunological effects of GLH hormones it was postulated that they function as competence hormones for the immune system, and likely for all other tissues and organs in higher animals [50, 51] Because of overlapping functions between GH and PRL, GH or PRL deficiency alone rarely causes severe problems due to compensation by the other hormone, if it is present at normal levels. However, joint and complete deficiency has not been adequately demonstrated to date [52]. Our experiments in hypophysectomized rats indicated that animals lacking both hormones die of bone marrow and immune failure and of cachexia within 6 weeks [53]. These observations indicate that PRL alone is capable of maintaining vital bodily functions in hypophysectomized rats. Redundancy exists within the GLH family and these hormones are indispensable for the growth, development and functional maintenance of the body throughout the entire lifespan of higher animals [50-53]. Consequently, it is reasonable to suggest that GLH, rather than GH alone, should be viewed as functional unit, when it comes to the assessment of biological functions and of the impact on health and longevity. 3.3 Ageing and the adrenal cortex Ageing in healthy people is associated with the gradual decrease of adrenal dehydroepiandrosterone (DHEA) secretion. This leads to a relative glucocorticoid excess during ageing. At present, there is no clear indication that DHEA therapy would work in the elderly [54] DHEA functions as a steroid hormone precursor, and its decline leads to androgen and estrogen deficiency, whereas glucocorticoid levels are not changed or may even be elevated during ageing. Whether or not these changes represent adaptation to the changing internal milieu characteristic of ageing, or may function as an important link between immune-, endocrine- and neuronal-senescence, remains to be determined. In woman a major trigger of changes in steroid hormone secretion is menopause. It is abundantly clear that steroid hormones are major regulators in the body that includes the immune system and that altered levels do have far reaching consequences [3, 55] 3.4 Hormonal changes in ageing men A number of age-related changes in men can ultimately lead to androgen deficiency. Some of the symptoms and disorders frequently seen in elderly men (e.g. loss of body mass, sexual dysfunction, osteoporosis, depression) have been linked to low androgen levels. Up to one third of men beyond the age of 60 have low serum testosterone levels. Androgen supplementation for these men is controversial at this time [56].. Circadian changes of testosterone are lost in man during ageing [57,58]. There is little doubt that testosterone declines with age, even wen levels do not get subnormal in elderly man. A more serious problem may be the loss of the ability for adaptive changes. This is indicated by the loss of the circadian rhythm. Testosterone declines during trauma and inflammatory disease, and exerts a major effect on the immune system, which has a bearing on mortality [3]. Therefore, this hormone has a much wider biological potential than originally anticipated, and this should be taken into consideration in future investigations. 3.5 Ageing of the neuroendocrine circadian system Changes do occur in the neuroendocrine circadian system. The most frequent observation is the reduction of circadian amplitude during ageing. With the reduction of melatonin the information on time and seasons is decreased. This leads to reduced adaptability, the loss of seasonal adjustments and more susceptibility to climatic change and in general to stress [59] Adrenal cortisol is maintained, whereas DHEA abruptly declines during ageing. The circadian rhythm of ACTH decreases or is abolished in aged rats. In man melatonin decreases during the sixties and seventies, but later it levels off. Many factors influence the hypothalamus-pituitary-thyroid axis. It is inhibited by sleep deprivation, iodine deficiency. Fasting suppresses TSH levels, which may be restored by leptin. Geographical changes and climatic changes, such as cold increase T4 levels, but not in the elderly [59]. The circadian rhythm of prolactin continues in the elderly. High levels are secreted during REM sleep. Nursing over-rules this regulation. Numerous medications stimulate PRL secretion (e.g. psychoactive drugs). In sexually mature woman, cycling PRL is increased. Stress also increases PRL serum levels [59]. Catecholamines drop with age and beta-adrenergic receptors are impaired. However dopamine (DOP) cells increase in the substancia nigra up to age 60. Sympathetic nervous responses to stress increase with age. Norepinephrine production and release is up and blood pressure is elevated, which may be decreased by bromocriptine. Urinary catecholamine levels are higher in hypertension. Melatonin antagonizes these changes [59]. There is no doubt that the neuroendocrine system plays a major role in adaptation to environmental factors and to stressors. The diurnal rhythm of hormones is related to the rhythm of daytime activity, energy spending and catabolism and night-time regeneration and anabolism. The loss of circadian rhythm of various hormones impairs adaptability as well as proper regeneration and maintenance of good health. It is remarkable that PRL levels and rhythms are maintained in the elderly. Indeed, PRL is required to maintain vital bodily functions. Animal experiments showed, that if this hormone is lost, it has fatal consequences [53]. Therefore, GH may decline with age because PRL is able to maintain all the vital functions GH would do, without the deleterious effects that elevated GH levels may produce [49]. 3.6 Melatonin rhythms, melatonin supplementation and sleep in old age After 80 years of age, there are no rhythms of melatonin secretion and there is no diurnal periodicity. Rhythms are regulated by noradrenaline, which is increased. However, melatonin did not decline in extremely healthy people. At present there is no clear evidence for the benefit of melatonin treatment [60,61]. As already pointed out, the lack of biological rhythms leads to the loss of adaptation and impair the daily regeneration of the body. These are very significant problems of most elderly people. 4. AGEING OF THE NERVOUS SYTEM 4.1 Age-related changes of the human autonomic nervous system Ageing is accompanied by significant structural and functional modifications of the cardiovascular system. Cardiovagal modulation is decreased with increasing age indicated by a decrease of cardiovagally mediated indices of heart rate variability. Sympathetic outflow to the heart is elevated, however, it is not well transformed into an enhanced end-organ response because of a decrease of alpha - and beta -adrenergic receptor potency. Orthostatic dysregulation is common in the elderly for several reasons; one major point is that the baroreflexes are impaired with increasing age [62]. 4.2 Age-related alterations in autonomic nervous innervation The thymus is innervated, alpha - and beta adrenergic receptors are present and there is evidence for the neural regulation of T cell subsets. Of the neuropeptides substance P, calcitonin gene related peptide, meth-enkephalin, vasoactive intestinal peptide, cholecystokinin, neurotensin, intreleukin-1, C-reactive protein and arginine vasopressin are present in thymic nerves. Noradrenalin (NE) is diminished in spleen of old rats in all compartments. There is peripheral neuropathy suggesting metabolic insults. Heightened sympathetic activity is present in the remaining nerves. NE treatment depletes NE nerves in the rat. Bacterial lipopolysaccharide (LPS) has no effect, but IL-2 releases NE. L-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, partially restores NA in 21 month-old rats. Natural killer cell activity, Concanavalin-A and IL-2 responses are increased by such treatment. Immune changes in aged humans and animals are variable. Sympathetic nerves may stimulate immunity and inhibit B cells and the TH1 response. The effect is variable, depending on the circumstances. Compensatory mechanisms operate in order to achieve “fine tuning” of the immune system. T cell memory is increased with ageing and this requires adjustments [63-71]. This chapter sums up very well the facts and dilemmas of ageing and neural regulation of the immune system. Yes, there are definite signs of deterioration and malfunction, but neither the regulatory influence of sympathetic nerves, nor the age related deterioration of immune function is etched in stone. One reason for this must be that no differentiation is made between ageing with disease and healthy ageing. As for the fine-tuning of the immune system by the autonomic nerves system, this must be viewed as an important mechanism for the adaptive modulation of immune function. However, it seems certain that T cell memory is maintained, no matter what age-related changes are present. 4.3 Ageing and the neuroendocrine system of the gut Everything declines in the gut with ageing, somatostatin is decreased and so is gastrin, more so in males than in females. Endocrine cells are all right in the large intestine. Serotonin is increased in the small intestine, so are peptide YY and enteroglucagon . In BALB/c/nunu mice, which do not have thymuses, endocrine cells are increased in the gastrointestinal tract with age. In general gastrointestinal nerve cells decrease in man and in the guinea pig with ageing, but not in the mouse [72-74]. Here again the general rule is decline, but the mouse is exception and in thymus-less nude mice actually there is an increase of gastrointestinal nerve cells with age. Does this signify the existence of as yet unsuspected influence of the thymus or of T cells on gastrointestinal innervation? Future studies are to decide this question. 4.4 Nutrition and brain ageing Ageing is characterized by the loss of capacity to maintain homeostasis. During dietary caloric restriction more synapses are present in the brain with larger transmission area. Vitamin E deficiency leads to less and larger synapses. Synapses enlarge in order to compensate for the decreased numbers. Ageing is accelerated under these conditions. Alcohol impairs synaptic potential by disturbing lipid metabolism [75,76] Brain ageing may be thought of as a particular condition in which specific pathological changes are found without clinically evident manifestations, because nerve cell alterations are continuously counteracted by compensating reactions. As a consequence, deterioration of function occurs when the number of neurons and of their connections decrease below a critical reserve level and coping with environmental stimulations becomes difficult [77,78]. There is no doubt that optimal nutrition is fundamental to good health. Over-nutrition is just as damaging as is under-nutrition. Food does not only pose “oxidative damage”, but always contain multiple carcinogenic and other harmful substances. Toxic substances are also produced during the process of digestion. These insults must be adequately handled by the defence systems of the body in order to survive and to maintain good health. Clearly, understanding and practising proper nutrition is one of the key concerns of ageing and of public health today. 4.5 Ageing-related role of nitric oxide in the brain This review points out the possible functional link between age-dependent decrease in neural nitric oxide synthase (nNOS) activity and increase in inducible NOS (iNOS) expression in the brain. Evidence is presented for the existence of infections in the brain, which is one of the hallmarks of ageing, and apparently trigger “spontaneous” iNOS expression. The future treatment of aged people is also described, which takes into consideration these facts [79].. The problem of persistent infections is not resolved at the present time. Most scientists tend to regard them as harmful, yet they were observed to afford protection to the host on repeated occasions. For instance it is well known about the herpes simplex virus persists within the CNS in most people and that it becomes readily activated in certain individuals in response to various stressors [80]. In the overwhelming majority of the cases there is a harmless self-resolving infectious lesion, which heals spontaneously, and hardly can be classified as dangerous. Actually there is a real possibility that the cytokines generated during this benevolent immune activation are quite beneficial to the individual. Recent observations revealed, that inflammation itself has protective value for the nerves system, possibly via T cell derived nerve growth factor [81]. Moreover, the lipopolysaccharide endotoxin of intestinal gram negative bacteria, which are absorbed from the gut during trauma and shock, functions as a powerful immune activator. Clearly, LPS functions to activate the innate immune system in stressful conditions, and therefore, it may be considered as one of the remedies for self-medication in emergency situations [82]. Persistent neurotrop viruses may in fact fulfill a similar mission. It is very well established that iNOS is an important weapon against infectious agents, and may be used as such in the ageing brain. It is also clear that LPS, iNOS and excessive activation of persistent viruses may have harmful effects. These questions await further clarification. 5. LINKS BETWEEN ONE GLOBAL SYSTEM AND ANOTHER GLOBAL SYSTEM DURING THE AGEING PROCESS 5.1 Plasticity of neuro-endocrine-thymus interactions during the ontogeny of aging: the role of zinc Current evidence strongly suggests that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions. The disruption of these interactions in old age is responsible for age-associated immune-neuroendocrine dysfunctions. Thymic reconstitution may be achieved by GH, thyroid hormones, and LHRH, which act on specific hormone receptors on thymocytes and on thymic epithelial cells. Melatonin may also act through specific receptors on T-cells. Zinc finger proteins are important because they regulate gene expression for hormone receptors. However, the effect of zinc is multifaceted. Zinc-dependent thymic hormone is required for intrathymic T-cell differentiation and maturation as well as for the homing of stem cells into the thymus. Therefore, the role of zinc is crucial in neuroendocrine-thymus interactions and for the maintenance of thymus function (e.g. by GH, thyroid hormones or melatonin) and for improving adaptive immunocompetence during ageing [83] The traditional view that thymic involution is responsible for immune deterioration during agEing may now be challenged. As is obvious from this volume, memory T lymphocytes increase with age. This means that memory cells are being accumulated gradually towards most, if not all, of the environmental pathogens. Therefore, there is little if any need for naïve T cells freshly released by the thymus. However, the thymus can be re-activated again, even at advanced age [84,85]. This suggests, that thymic involution may be a physiological phenomenon, at least in part, during successful agEing. Thymic involution may also occur under pathophysiological conditions, during the acute phase response (APR), or febrile illness, which is initiated by the immune system in response to infection or to other forms of traumatic injury. Cells of the monocyte/macrophage lineage release massive amounts of IL-1, IL-6 and TNF-alpha into the circulation, which in turn trigger profound neuroendocrine and metabolic changes. The hypothalamus-pituitary-adrenal axis is activated, the thymus undergoes a profound involution, due to the apoptotic effect of glucocorticoids and of TNF, and to the relative deficiency of growth and lactogenic hormones, which is coupled with zinc deficiency. The biological significance of APR is that it is capable of switching over the immune system from the adaptive mode of reactivity to the amplification of natural immune mechanisms. APR is a highly coordinated emergency defense reaction, which mobilizes all the resources of the body in the interest of survival. Many individuals exhibit signs of low-grade APR during ageing [15,17]. Therefore, thymic involution may not be the primary cause for immunodeficiency in the aged, but age-related diseases, which may be the consequence of immunodeficiency, would accelerate thymic involution. Hence, thymic involution is also associated with pathological conditions. Would the improvement of thymic function lead to health benefit in the elderly? Current indications are that it would indeed do so. 5.2 Adverse glucocorticoid actions and their relevance to brain ageing This chapter discusses the concepts of stress and of homeostasis. It is presented that the HPA axis becomes gradually more active with aging. Glucocorticoids affect the CNS, immunocompetence, and inflammation. Although a fair amount of information is available, the biological significance of the observations is not always clear [86,87]. 5.3 Neuroendocrine immune aspects of osteoporosis during the ageing process Age related alterations of gonadal and thyroid hormones and of vitamin D leads to loss of bone mass. Alpha melanocyte stimulating hormone is a novel bone regulator as is leptin. Serum osteoprotegrin is increased with age [88-91]. One may remark here that osteoclasts belong to the monocyte/macrophage family of myeloid cells and they respond to immune-derived cytokines, especially to IL-6. IL-6 has a stimulatory effect on osteoclasts, which leads to accelerated bone resorption. Estrogens suppress IL-6 production. Estrogen deficiency develops abruptly in females after the menopause and to a lesser extent also in males, due to androgen deficiency. This will lead to increased secretion of IL-6 and consequently to accelerated bone loss [55]. 6. THE AGEING PROCESS AND CHRONIC INFLAMMATORY DISEASE 6.1. Neuroendocrine immune mechanisms of accelerated ageing in patients with chronic inflammatory diseases Straub and colleagues consider the deleterious effects of chronic inflammatory disease, which accelerates ageing. Indeed inflammatory disease is characterized by immune activation and cytokine release, which invariably elicit neuroendocrine and metabolic alterations as correctly pointed out by the authors. Changes in glucocorticoids, androgens, estrogens and vitamin D and the altered metabolism affect immune function, the nervous system and bone metabolism. It is concluded that more information is required before a rational approach may be adapted for therapy [92] Although there is little doubt that chronic inflammation has an enormous thaw on the patient, one should keep in mind that inflammation is a defense reaction, which should protect the host. Is this possible in chronic inflammation? Recent observations in experimental autoimmune encephalitis of rats, a chronic inflammatory disease with relapses, demonstrated that indeed, inflammation has protective value [81]. 6.2 Thyroid autoimmunity and ageing Thyroid autoantibodies and subclinical hypothyroidism increase with ageing. However, thyroid autoantibodies are rare in centenarians and in other highly selected aged populations. This suggests that thyroid autoimmunity is not the consequence of the ageing process itself, but rather, an expression of age-associated disease. Thyroid autoimmunity and/or thyroid dysfunction may have an etiological role in several age-associated diseases, although the precise mechanisms involved remain to be elucidated [93]. This chapter clearly demonstrates that successful ageing is not characterized by autoimmune reactions, whereas autoimmunity itself may be the cause of age-associated diseases. Indeed, it is highly desirable to keep these findings in mind when trying to investigate the problem of ageing. Even if most people age with disease, the goal should be to achieve successful, healthy ageing, whenever possible. 6.3 The clinical importance of proinflammatory cytokines in elderly populations Low-grade increases in plasma level of inflammatory mediators are characteristic of age-associated pathology, including cardiovascular diseases, dementia and sarcopenia. Inflammatory cytokines, such as TNF and IL-6, act as independent predictors of high mortality risk. It is suggested that systemic low-grade inflammation provide a common link between ageing, body composition, and life style factors on one hand and age-related diseases and mortality on the other [94]. The senile immune system is clinically relevant. It is likely that TNF and IL-6 trigger age associated pathology. Cardiovascular disease and dementia are prevalent in the elderly. TNF is associated with dementia in the very old (>80 years of age) and IL-6 may play a role in thromboembolic complications and cardiovascular disease in middle-aged people. Monocytes are in a pre-activated state in the elderly. Some of the possible reasons for the development of disease are: continuous antigenic load, stressors, “inflam-ageing” and dys-regulated acute phase response [94,95]. TNF and IL-6 promoter polymorphism may play an important role in disease development [96,97]. Body fat directly correlates with TNF [98] and with leptin [99] Endocrinosenescence contributes to immunosenescence. The loss of sex hormones leads to immunosuppression and to a low grade inflammatory milieu in the elderly [100] The results presented in Figure 4 of this chapter support the idea of a proinflammatory milieu in the elderly. Peripheral blood cells from young individuals produced more TNF after in vitro stimulation by LPS than did cells from old people, yet the blood level of TNF in the elderly was significantly higher after LPS treatment. Infections, especially Chlamydia and bacteriuria are frequent in the elderly [101,102]. This chapter is an excellent demonstration of the relevance of Neuroimmune Biology to Clinical Practice. Physicians have always been concerned with the patient’s well being, and for that they had to understand how the body works. This chapter presents information from the area of Molecular Biology, Immunology, Microbiology, Endocrinology, Neurology, Food Science, Pathology, Gerontology, all of which are integrated into a modern version of Clinical Medicine. The pathophysiological mechanisms that are discussed in the context of age-related diseases are compelling and are testable for further confirmation. Indeed, this is what should be the ultimate mission of Neuroimmune Biology, to understand the biology of man and of higher animals in their entire complexity, and to apply the newly found knowledge to the benefit of all. 7. CONCLUSIONS 7.1 New anti ageing strategies related to neuroendocrine immune interactions This
chapter demonstrates that the agents/methods used for the prolongation
of life span influence growth hormone, prolactin, zinc or apoptosis. The
new agents act on one of these basic factors in aging [103]
7.2 The future Much of the global problems of our times come from the fact that man aspires to bypass and overrule the laws of Mother Nature. Ageing is no exception, the quest is on for longer and healthier life, and in actual fact significant increases are seen in the mean life-span globally, with the Western world in the lead. Some countries are much overpopulated, and in others the percentage of elderly people is steadily increasing. This poses ever-increasing problems on Society and on future generations. Global overpopulation is already threatening us with catastrophe, so why push our luck any further? Why study ageing at all? Well, for most people ageing means diseases, often suffering from lengthy and debilitating conditions. Nobody will argue against studying and preventing age related diseases. Better health and better quality of life for all people are noble causes and is highly desirable to pursue. One may also argue that healthy people would be productive longer, so the burden posed on Society would decrease. The scientific value of understanding the ageing process is immense from the point of view of understanding our biology, but also for gaining better insights to the pathobiology of diseases. This volume sheds light on many aspect of the problem of ageing. The most important message is that the Neuroimmune Regulatory Network plays a fundamental role in the ageing process. Indeed, this book is living testimony for the validity and significance of Neuroimmune Biology to aging. NIB provides for a comprehensive way of viewing and investigating biological problems, such as ageing. For the first time ageing is looked upon from the special perspectives of NIB, the science of systemic regulation of higher organisms. Already there is compelling evidence that this science is highly relevant to Clinical Medicine. Is it possible to achieve immortality? It is now clear that most if not all of the biological processes, which decline during ageing, are reversible. This would suggest that it would be feasible to achieve immortality in macro-organisms. Ageing seems to be genetically programmed. However some aspects of ageing may be related to the very fundamental properties of matter and energy that dominate our world. So far we have not achieved a clear understanding of the rules governing the fundamental forces of our universe.
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