Translational research in ageing Immunological pathogenesis of main age-related diseases and frailty: Role of immunosenescence P.O. Lang b, *, W.A. Mitchell a , A. Lapenna a , D. Pitts a , R. Aspinall a a Translational medicine, Cranfield Health, Cranfield University, Cranfield, United Kingdom b University hospitals and Medical school of Geneva, Department of rehabilitation and geriatrics, Geneva, Switzerland 1. Introduction Nowadays, it is well known that adults present an increased susceptibility to develop diseases such as Alzheimer’s disease, infectious diseases, cancer, and osteoporosis with advancing age. As ageing is also associated with various changes in immune parameters, therefore many authors have postulated that these age-related diseases could be explained, at least in part, by an overall deregulation in immune system response [1–7]. Immunosenescence is the term usually used to describe this acquired dysfunctional immunity with ageing population. Immu- nosenescence is characterised not only by a simple deterioration of the functionality of the immune system, but also by a complex modification of several components. As a result, some immune parameters tend to diminish with ageing while some other remains constant or increase. The immune system is generally divided into an innate part, consisting mainly of monocytes, natural killer (NK), and dendritic cells (DC), and an adaptive part, represented by T and B-cells [1]. The age-related changes affecting both parts of the immune system are summarised in Table 1. It is still controversial whether these changes occur as part of a pathological or the normal physiological ageing process [8]. For example, diminished T-cell proliferation, IL-2 production, antigen recognition, a shift in T-cell subpopulation type, and cytokine production were found to be present in a healthy elderly population. Although the exact causes of immunosenescence are not clear, it is becoming accepted that the multifactorial nature of immunosenescence in the healthy elderly population correlates with certain universally observed processes, including thymic involution, chronic antigenic stimulation (predominantly attrib- utable to persistent infections – see below), signal transduction changes in immune cells, and protein-energy malnutrition [8]. The two current hallmarks of immunosenescence are immune risk profile (IRP) and Inflamm-Ageing. IRP, identified from healthy octogenarians and nonagenarians in OCTO and NONA studies, characteristically displays (i) high levels of CD8+ and low levels of CD4+ T-cells (inverted CD4+/CD8+ ratio), (ii) an increase in the numbers of dysfunctional terminally differentiated T-cells that previously were exposed to antigens (memory and effectors cells), and (iii) the depletion number of cells being able to recognise and combat new antigens (naı ¨ve cells) [9]. The second hallmark, Inflamm-Aging, results from an shift from a helper CD4+ T-cells (TH) 1-like cytokine response (Interleukin – IL-2, Tumour necrosis factor – TNFg) to a TH2-like response (IL-4, IL-6, IL-10) with advancing age, and furthermore an increase in levels of pro- inflammatory cytokines (IL-6, TNFa, IL-1b, IL-18, IL-8, IL-12). Inflamm-Aging contributes to the deregulation of the cell- mediated immune response [6]. Indeed, the function of the immune system depends on a subtle and well-tuned network of humoral mediators, collectively called cytokines. Responsible for differentiation, proliferation and survival of lymphoid cells, they include colony stimulating factors, and cytokines such as interferon (IFN) and TNFs. These molecules constitute a complex European Geriatric Medicine 1 (2010) 112–121 ARTICLE INFO Article history: Received 1 December 2009 Accepted 20 January 2010 Available online 24 February 2010 Keywords: Ageing Immunosenescence Frailty Age-related diseases Pathogenesis ABSTRACT Nowadays, it is well known that with advancing age individuals are at an increased susceptibility to develop diseases such as Alzheimer’s disease, infectious diseases, cancer, and osteoporosis. Ageing is associated with various changes in immune parameters; therefore many authors have postulated that these age-related diseases could be explained, at least in part, by an overall deregulation of the function of the immune system. Immunosenescence is the term usually used to describe the acquired dysfunctional immunity within the ageing population affecting both innate and adaptive immunity. The present review examines the close involvement of the immunosenescence in the pathogenesis of these main age-related clinical outcomes, insulin resistance and the frailty process. ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. * Corresponding author at: Translational medicine, Cranfield Health, Vincent Building, Cranfield University, College Road, Bedfordshire, MKL43 0AL, England. E-mail address: p.o.lang@cranfield.ac.uk (P.O. Lang). 1878-7649/$ – see front matter ß 2010 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved. doi:10.1016/j.eurger.2010.01.010 © 2013 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 24/07/2013 par Lang Pierre Olivier (202682)