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      Targeting accelerated pulmonary ageing to treat chronic obstructive pulmonary disease‐induced neuropathological comorbidities


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          Chronic obstructive pulmonary disease (COPD) is a major incurable health burden, ranking as the third leading cause of death worldwide, mainly driven by cigarette smoking. COPD is characterised by persistent airway inflammation, lung function decline and premature ageing with the presence of pulmonary senescent cells. This review proposes that cellular senescence, a state of stable cell cycle arrest linked to ageing, induced by inflammation and oxidative stress in COPD, extends beyond the lungs and affects the systemic circulation. This pulmonary senescent profile will reach other organs via extracellular vesicles contributing to brain inflammation and damage, and increasing the risk of neurological comorbidities, such as stroke, cerebral small vessel disease and Alzheimer's disease. The review explores the role of cellular senescence in COPD‐associated brain conditions and investigates the relationship between cellular senescence and circadian rhythm in COPD. Additionally, it discusses potential therapies, including senomorphic and senolytic treatments, as novel strategies to halt or improve the progression of COPD.

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          The Hallmarks of Aging

          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Cellular Senescence: Defining a Path Forward

            Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
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              The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

              The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

                Author and article information

                Br J Pharmacol
                Br J Pharmacol
                British Journal of Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                15 November 2023
                January 2024
                15 November 2023
                : 181
                : 1 ( doiID: 10.1111/bph.v181.1 )
                : 3-20
                [ 1 ] Centre for Respiratory Science and Health, School of Health & Biomedical Sciences RMIT University Melbourne Victoria Australia
                Author notes
                [*] [* ] Correspondence

                Professor Ross Vlahos, PhD, Respiratory Research Group, Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, PO Box 71, Bundoora, Victoria 3083, Australia.

                Email: ross.vlahos@ 123456rmit.edu.au

                Author information
                © 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 06 September 2023
                : 26 July 2023
                : 27 September 2023
                Page count
                Figures: 2, Tables: 1, Pages: 18, Words: 19003
                Funded by: RMIT University , doi 10.13039/501100001780;
                Funded by: National Health and Medical Research Council of Australia
                Award ID: ID1139843
                Funded by: Lung Foundation Australia/Boehringer Ingelheim Postdoctoral Research Fellowship
                Review Article
                Review Article
                Custom metadata
                January 2024
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.9 mode:remove_FC converted:20.03.2024

                Pharmacology & Pharmaceutical medicine
                accelerated ageing,cellular senescence,chronic obstructive pulmonary disease,circadian rhythm,neurodegeneration


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