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      “Inflammaging” as a Druggable Target: A Senescence-Associated Secretory Phenotype—Centered View of Type 2 Diabetes

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          Abstract

          Aging is a complex phenomenon driven by a variety of molecular alterations. A relevant feature of aging is chronic low-grade inflammation, termed “inflammaging.” In type 2 diabetes mellitus (T2DM), many elements of aging appear earlier or are overrepresented, including consistent inflammaging. T2DM patients have an increased death rate, associated with an incremented inflammatory score. The source of this inflammation is debated. Recently, the senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammaging in both aging and T2DM. Different pathogenic mechanisms linked to T2DM progression and complications development have been linked to senescence and SASP, that is, oxidative stress and endoplasmic reticulum (ER) stress. Here we review the latest data connecting oxidative and ER stress with the SASP in the context of aging and T2DM, with emphasis on endothelial cells (ECs) and endothelial dysfunction. Moreover, since current medical practice is insufficient to completely suppress the increased death rate of diabetic patients, we propose a SASP-centered view of T2DM as a futuristic therapeutic option, possibly opening new prospects by moving the attention from one-organ studies of diabetes complications to a wider targeting of the aging process.

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          Most cited references79

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          Cellular senescence in aging and age-related disease: from mechanisms to therapy.

          Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.
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            Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

            Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging." Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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              Inflamm-aging. An evolutionary perspective on immunosenescence.

              In this paper we extend the "network theory of aging," and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as "inflamm-aging," is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi Publishing Corporation
                1942-0900
                1942-0994
                2016
                1 June 2016
                : 2016
                : 1810327
                Affiliations
                1August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and Centre of Biomedical Investigation on Diabetes and Associated Metabolic Disorders Network (CIBERDEM), 08036 Barcelona, Spain
                2Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica delle Marche, 60126 Ancona, Italy
                3IRCCS Multimedica Group, 60126 Sesto San Giovanni, Italy
                4Center of Clinical Pathology and Innovative Therapy, Italian National Research Center on Aging (INRCA-IRCCS), 60121 Ancona, Italy
                Author notes
                *Francesco Prattichizzo: f.prattichizzo@ 123456univpm.it

                Academic Editor: Mark J. Crabtree

                Author information
                http://orcid.org/0000-0002-2959-2658
                http://orcid.org/0000-0002-4786-6747
                http://orcid.org/0000-0002-7580-1377
                http://orcid.org/0000-0002-7955-4684
                Article
                10.1155/2016/1810327
                4908264
                27340505
                c7091608-0683-49de-9f49-f939d26e8be2
                Copyright © 2016 Francesco Prattichizzo et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 February 2016
                : 9 May 2016
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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