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Immunosupportive therapies in aging - pdf attached
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Authors: Tamas Fulop, Anis Larbi, Katsuiku Hirokawa, Eugenio Mocchegiani, Bruno Lesourd, et al
Published Date May 2007 , Volume 2007:2(1)
Journal: Clinical Interventions in Aging
Our results suggest that HIV-1 infection induces an accelerated aging (senescence) of T lymphocytes, which is associated with the clinical progression to AIDS and death - (01/13/09)
JAIDS Jan 7 2009
HAART Does Not Reverse Premature T-Cell Aging Caused by HIV - (02/27/09)
Expression of CD28, CTLA-4 and perforin by CD4 lymphocytes remain dysregulated in HIV-infected patients with previous severe immunodeficiency, despite increased CD4 T-cell counts and control of HIV viraemia by HAART...
CROI: Immune Senescence, Activation and Abnormal T cell Homeostasis Despite Effective HAART, A Hallmark of Early Aging in HIV Disease - (03/03/09) Best CROI Poster Award by NATAP
Causes of Accelerated Aging in HIV: HIV Induces Aging of T-Cells - (02/10/09)
hallmark of immunosenescence is the overwhelming decrease in T cell function with aging.....So we must ask whether immunosenescence is subject to modulation and whether effective immunosupportive therapies exist.....the fi eld urgently needs to agree upon a set of biomarkers of immunosenescence to be applied preferably in careful longitudinal studies.....considering the alterations and the putative causes of immunosenescence, we would suggest that three major objectives are emerging: decrease the antigenic load either acute or chronic, but especially the latter, with the concomitant restoration of changes in T cell subpopulations; immunorestoration of the thymic environment to increase the naïve cell output; maintain or enhance T cell function (activation) of remaining intact cells.....no well-established therapy benefi cially impacting on the very complex nature of immunosenescence is yet known due to the absence of knowledge of the real primum movens. Nonetheless, we will start with those which could have a general preventive effect, and continue with those which are more specifi c for a given alteration......the use of IL-7 has been explored. IL-7 is a cytokine playing a crucial role in the development and maintenance of the peripheral T cell pool. Thymus IL-7 content decreases with age, leading to decreased thymic output of naïve cells. This was the rationale for treatment strategies administering IL-7, which induced some degree of thymic rejuvenation in mice (Aspinall 2006). There are currently many unresolved questions on IL-7 therapy before it could be used in elderly humans, fi rst and foremost being the lymphoma genesis seen in mice. This could be overcome by more effi cient targeting of the cytokine to the thymus, rather than systemically using high doses. Thus, the advance of gene therapy designing vectors specifi c for the thymus would be a major breakthrough in the thymus rejuvenation trials....Some means to intervene in compensating for immune dysregulation which could be applied in the elderly without ethical or regulatory problems do already exist. These include balanced nutrition in macro and micronutrients, including foods such as vegetables and fruit, functional foods such as probiotic-containing yoghurt, sustained moderate aerobic exercise regimens"
"This proinflammatory status was also linked to the frailty syndrome of elderly subjects (Schmaltz et al 2005). This suggests that the decreased T cell functions are correlated with a decreased longevity probably via the occurrence of life threatening diseases such as infections and cancer.....The chronic infl ammation is a result of the persistence of the pathogen combined with muscular attrition......data obtained from experimental animals and from human studies indicate that appropriate nutrition is a powerful but in principle very safe immunorestorative means to modulate immunosenescence......exercise has been proposed as a potential means to modulate dysregulated immune responses with aging.....The benefi cial effects of exercise have been noted for T cell function, antibody production, and macrophage responses.....The rejuvenation of a functional thymus is likely to be
another necessity for maintaining or restoring effective immunity with ageing.....some sort of proinfl ammatory cytokine blocking antibodies
or soluble receptors could also be benefi cial for the elderly.....
"The incidence of infections, cancers, and chronic infl ammatory diseases such as atherosclerosis and neurodegenerative diseases increases with age.....The hallmark of immunosenescence is the overwhelming decrease in T cell function with aging.....Paralleling thymic involution, a change in peripheral T cell subpopulations is found in aging (Effros 2004).....the clinical consequences of the decreased immune response with aging seem quite clear. These are mainly the increased incidence and severity of infections, and possibly also cancers and autoimmune disorders (Meyer 2005). Many elderly subjects actually die from infections even if the cause of death given by the attending physician is very different. The hallmark of immunosenescence is the overwhelming decrease in T cell function with aging.....
Clinical importance of immunosenescence: The exact consequences of immunosenescence are very difficult to assess with certitude. However, the clinical observations tend to indicate that the alteration of the immune response with aging has very serious clinical consequences (Figure 2). This deregulated immune response may be responsible for the increased incidence of infections, cancers, autoimmune disorders, chronic inflammatory diseases, as well as subsequently decreased longevity (Castle 2000; Wick et al 2000; Gavazzi and Krauze 2002; DeVeale et al 2004). A direct effect of immunosenescence on infections, cancers, and autoimmune disorders can be easily conceptualized and many experimental data seem to support this contention. The relationship between immunosenescence and the increased incidence of infections with aging can be primary. As the number of naïve CD4+ T cells decreases, the possibility of mounting an effective adaptive immune response against a new pathogen also decreases.....The relationship between immunosenescence and the chronic inflammatory processes leading to age-related diseases is more diffi cult to understand......the deregulation of cytokine production is also observed in these chronic infl ammatory conditions, ie, an increase in proinfl ammatory cytokines such as TNF-α, IL-6, and IL-1 as well as an increase of the antiinfl ammatory cytokines such as IL-10, IL-4, and IL-15, as posited by the Infl ammAging hypothesis....age-related immune deregulation associated with chronic infl ammation and the suppression of the adaptive immune response leads to these chronic inflammatory processes. The increasing prevalence of this inflammation over decades leads to the development of clinically signifi cant pathological conditions such as cardiovascular diseases, dementia, diabetes mellitus, osteoporosis, Parkinson's disease, and arthritis"
The aging process and its clinical consequences
Abstract:
The primary role of the immune system is to protect the organism against pathogens, but age-associated alterations to immunity increase the susceptibility of the elderly to infectious disease. The exact nature of these changes is still controversial, but the use of screening procedures, such as the SENIEUR protocol to exclude underlying illness, helped to better characterize the changes actually related to physiological aging rather than pathology. It is generally agreed that the most marked changes occur in the cellular immune response reflecting profound alterations in T cells. Much of this is due to thymic involution as well as changes in the proportions of T cell subpopulations resulting from antigen exposure, and altered T cell activation pathways. However, a body of data indicates that innate immune responses, including the critical bridge between innate and adaptive immunity, and antigen presenting capacity are not completely resistant to senescence processes. The consequences of all these alterations are an increased incidence of infections, as well as possibly cancers, autoimmune disorders, and chronic inflammatory diseases. The leading question is what, if anything, can we do to prevent these deleterious changes without dangerously dysregulating the precarious balance of productive immunity versus immunopathology? There are many potential new therapeutic means now available to modulate immunosenescence and many others are expected to be available shortly. One main problem in applying these experimental therapies is ethical: there is a common feeling that as ageing is not a disease; the elderly are not sick and therefore do not require adventurous therapies with unpredictable side-effects in mostly frail individuals. Animal models are not helpful in this context. In this chapter we will first briefly review what we think we know about human immunosenescence and its consequences for the health status of elderly individuals. We will then discuss possible interventions that might one day become applicable in an appropriate ethical environment.
Tamas Fulop1, Anis Larbi2, Katsuiku Hirokawa3, Eugenio Mocchegiani4, Bruno Lesourd5, Stephen Castle6, Anders Wikby7, Claudio Franceschi8, Graham Pawelec2
1Research Center on Aging, Immunology Program, Geriatric Division, Faculty of Medicine, University of Sherbrooke, Quebec, Canada; 2Tubingen Ageing and Tumour Immunology Group, Center for Medical Research, University of Tubingen Medical School, Tubingen, Germany; 3Department of Pathology and Immunology Ageing and Developmental Sciences, Tokyo-Medical and Dental University Graduate School, Tokyo, Japan; 4Immunology Center, Section Nutrition, Immunity and Ageing, Research Department, Italian National Research Centres on Ageing, INRCA, Ancona, Italy; 5Hopital Universitaire de Clermont-Ferrand, Service Soins de Suite, Route de Chateaugay BP56, F-63118 Cebazat, France; 6Geriatric Research, Education and Clinical Center (GRECC), VA Greater Los Angeles Healthcare System and Multicampus Division of Geriatric and Gerontology, Department of Medicine, UCLA, Los Angeles, CA 90073, USA; 7School of Health Sciences, Jonkoping University, Department of Natural Science and Biomedicine, Jonkoping, Sweden; 8Italian National Research Center on Aging, Department of Experimental pathology, University of Bologna, Bologna, Italy
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