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• W2923604003 abstract "EditorialSenescence in the LungSenescence in the lung: is this getting old?Rory E. Morty and Y. S. PrakashRory E. MortyDepartment of Internal Medicine, Justus-Liebig-Universität Gießen, Giessen, GermanyDepartment of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany and Y. S. PrakashDepartment of Anesthesiology, Mayo Clinic, Rochester, MinnesotaDepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MinnesotaPublished Online:01 May 2019https://doi.org/10.1152/ajplung.00081.2019This is the final version - click for previous versionMoreSectionsPDF (104 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat With the proportion of individuals in the United States >65 yr reaching ~25% by 2050 (22, 58), the effects of aging on any organ system are of increasing clinical and research importance in the context of healthy aging and longevity. With age itself a risk factor for several chronic medical conditions, an understanding of the mechanisms at the intersection of aging biology and disease susceptibility also becomes important. In this regard, the lung is a critical organ, given increasing morbidity and mortality attributable to chronic lung diseases in the elderly. For example, chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and shows increasing prevalence particularly in the elderly, who also happen to be at highest risk, while there is increasing evidence that hallmarks of aging are also present prominently in COPD (9, 39, 44). In genetically susceptible aging individuals, environmental risk factors lead to pulmonary fibrosis (PF), manifesting primarily in the middle-aged and especially in the elderly (27, 35, 43, 49). Many hallmarks of aging also occur prematurely in PF (3, 36, 40, 49, 55). Furthermore, there is increasing recognition that asthma is also increasing in the elderly (AIE) with ~7% prevalence, associated with higher rates of airway hyperreactivity, more severe presentation, resistance to standard therapy, and greater morbidity and mortality (8, 20, 23, 48, 55–57). Older patients are also at significantly higher risk of developing acute respiratory distress syndrome (ARDS) compared with younger patients (28) while pulmonary hypertension (PH), which is increasingly recognized in the elderly, is associated with greater morbidity and mortality (45). Interestingly, with improved care, longer survival of patients with cystic fibrosis has necessitated an understanding of the links between aging and CF (16, 51). However, across these chronic lung diseases, diagnosis and management are complicated by a paucity of information regarding normal aging-related structural and functional changes, the influence of genetics, and the likely myriad of mechanisms that contribute to aging-related changes in the lung (36, 50, 52, 62). Added are interactions with life events such as puberty, pregnancy, and menopause, comorbid conditions that impact the lung (e.g., inflammation and inflammatory disease, cardiovascular diseases), and environmental and iatrogenic exposures (e.g., tobacco smoke, pollution, allergens, radiation and chemotherapy in cancer), many of which are prolonged and more complex in older individuals. Furthermore, many of these same factors are also important players in lung disease pathogenesis, making it critical to separate aging-related factors from exposure effects. Indeed, it is now recognized that even early life events contribute to lifelong disease, and thus it may not be just the adult lifespan that should be explored. Despite these complex issues, certain mechanisms regulating normal versus abnormal cellular structure and function could broadly contribute to lung growth and aging, as well as to disease pathogenesis. In this regard, emerging studies highlight the importance of cellular senescence in the lung and the contribution of senescent cells in aging, and in diseases including COPD (4, 5, 7), PF (47, 59), CF (6, 18), ARDS (38), and asthma (21, 61).Cellular senescence is most commonly associated with biological aging (12, 13, 31, 53), and there has been much excitement regarding understanding and targeting of senescence pathways with a goal towards blunting their (detrimental) effects and improving the healthspan of the elderly (29, 30, 37), i.e., lifespan free from pain, disability, and dependence. Senescence occurs in response to a variety of insults across a range of cell types (12, 15, 54, 60) and may represent a normal, protective response. However, accumulation of senescent cells has been observed in vivo in relation to chronological aging (17, 26), chemotherapy and radiotherapy (46), supplemental oxygen (33, 41), and cigarette smoke (2) to name a few. Indeed, emerging data suggest that insults such as hyperoxia can induce senescence in developing lung (41), dissociating aging per se from senescence.Senescent cells have been reported in both human and animal models of pulmonary diseases (1, 4, 19, 21, 24, 25, 34, 42, 47, 59, 61, 63). What is less clear is the extent to which phenotypic changes associated with normal chronological aging or in disease states are mechanistically attributable to cellular senescence or effects of senescent cells per se, i.e., how important are senescent cells in pathophysiology? Furthermore, it is important to recognize that senescence is in fact a normal, protective, and responsive process throughout life including in the fetal state, helping to coordinate development, growth, and repair (11), and thus it becomes important to appreciate when and how senescence becomes detrimental in the context of disease per se. Beyond senescent cells, it is also becoming clear that their effects are mediated through the senescence-associated secretory profile (SASP), a set of secreted factors that influence surrounding naive cells.Thus, it is likely that on the one hand, normal physiological processes throughout life and external insults induce senescence, while conversely, senescent cells (via SASP) can induce and promote normal growth and repair or induce and promote disease, overall creating a feed-forward system [as highlighted in a recent review on cellular senescence in the lung (42)]. Accordingly, it becomes important to understand the contributions of senescence to development, aging, and disease, and if significant, the processes that lead to enhanced senescent cell burden and downstream detrimental effects. Such a task will then inform the need to determine whether current or future therapies targeting disease states should be evaluated in the context of their ability to reduce senescent cell burden [i.e., senolytic drug therapies (14, 31, 32)] or the influence of senescent cells per se. However, within this framework, we also need to understand the importance of cell type, context, and even age versus aging in the roles of senescence.The importance of identifying processes that lie at the intersection of aging biology and lung disease pathogenesis was recently recognized by the National Institute of Aging and the National Heart, Lung, and Blood Institute joint workshop entitled “The Intersection of Aging Biology and Pathobiology of Lung Diseases” (10). From the several common themes that emerged, some are notable: 1) the need for better understanding of age-related changes that develop in lungs of model organisms and humans using an interdisciplinary approach; 2) research towards identifying how molecular changes that occur with aging alter responses to stress in the lung, including senescence, unfolded protein response, mitochondrial dysfunction etc.; 3) importance of developing new models of lung diseases with age as a strong risk factor including COPD and PF. While these issues are not necessarily comprehensive, we believe that the lung community is ideally situated to highlight new scientific advances in our current understanding of these critical and timely concepts, helping to identify the role(s) and importance of senescence and the contribution of senescent cells to both normal lung aging, and lung disease pathophysiology. Thus, we encourage the readership of American Journal of Physiology–Lung Cellular and Molecular Physiology to consider this a call for exciting research in the area of senescence in the lung. Some important questions to consider within this context include the following.1) What is the senescent profile within different cell types of the lung with aging?2) When does senescence start in the lung? i.e., is cellular senescence important early in life, and does it contribute to childhood lung disease as well? How does this impact disease pathogenesis and how does disease state change with age/aging? Do different lung diseases involving senescence or senescent cell effects reflect a similar phenotype and follow similar pathways and patterns with age? Should we be thinking of senolytic therapy in age-specific fashion as well?3) How distinct are senescent cells from the native cells and what are their transcriptomic and proteomic profiles? Indeed, how do we identify and differentiate senescent cells?4) What are the key senescence pathways and what is the heterogeneity of SASP profiles within each lung cell type (including inflammatory cells)?5) Are there sex differences in lung senescence biology?6) What are the interactions between established or emerging lung disease mechanisms such as inflammation, reactive oxygen species, or mitochondria (for example), and senescence pathways?7) Certainly many of the SASP factors are cytokines highly relevant to inflammatory airway disease but compared with COPD or PF, less is known regarding senescent cell burden or the role of such cells or SASP in asthma. Thus the question becomes where senescence lies in the induction or progression of asthma, and which cells are involved: inflammatory cells versus resident airway cells including epithelium and smooth muscle.8) If senescence is part of aging biology, what are the key features of senescent cells that drive the “good” versus the “bad” in contributing to lung diseases of aging?9) What is the impact of potential senolytic drugs in lung? In this regard, if age and aging are important aspects in the burden and effects of senescent cells, how should age-specific patterning of senolytic therapy be designed, made all the more relevant recognizing the lack of elderly patients in clinical trials?We believe that basic, translational, and clinical research relevant to the above topics holds substantial potential towards understanding and evaluating beneficial versus detrimental contribution of cellular senescence, thus highlighting novel therapeutic avenues for lung diseases across the age spectrum.GRANTSThis work was supported by the Mayo Clinic Center for Biomedical Discovery and National Heart, Lung, and Blood Institute Grant R01 HL056470.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSR.M. and Y.S.P. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.REFERENCES1. 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