Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate limited efficacies. Advancing our understanding of the pathogenic mechanisms of lung fibrosis will provide a future path for the cure. Cellular senescence has gained substantial interest in recent decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence-targeted signaling molecules and specific therapies to target senescent cells, known collectively as “senolytic” or “senotherapeutic” agents.     

Reactive and Senescent Astroglial Phenotypes as Hallmarks of Brain Pathologies

Astrocytes, as the most abundant glial cells in the central nervous system, are tightly integrated into neural networks and participate in numerous aspects of brain physiology and pathology. They are the main homeostatic cells in the central nervous system, and the loss of astrocyte physiological functions and/or gain of pro-inflammatory functions, due to their reactivation or cellular senescence, can have profound impacts on the surrounding microenvironment with pathological outcomes. Although the importance of astrocytes is generally recognized, and both senescence and reactive astrogliosis have been extensively reviewed independently, there are only a few comparative overviews of these complex processes. In this review, we summarize the latest data regarding astrocyte reactivation and senescence, and outline similarities and differences between these phenotypes from morphological, functional, and molecular points of view. A special focus has been given to neurodegenerative diseases, where these phenotypic alternations of astrocytes are significantly implicated. We also summarize current perspectives regarding new advances in model systems based on astrocytes as well as data pointing to these glial cells as potential therapeutic targets.     

Mechanisms Underlying Connexin Hemichannel Activation in Disease

Gap junctions and connexin hemichannels mediate intercellular and extracellular communication, respectively. While gap junctions are seen as the “good guys” by controlling homeostasis, connexin hemichannels are considered as the “bad guys”, as their activation is associated with the onset and dissemination of disease. Open connexin hemichannels indeed mediate the transport of messengers between the cytosol and extracellular environment and, by doing so, fuel inflammation and cell death in a plethora of diseases. The present mini-review discusses the mechanisms involved in the activation of connexin hemichannels during pathology.     

Mechanics Insights of Alpha-Lipoic Acid against Cardiovascular Diseases during COVID-19 Infection

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019. Since then, COVID-19 has spread rapidly worldwide and was declared a global pandemic on 20 March 2020. Cardiovascular complications are rapidly emerging as a major peril in COVID-19 in addition to respiratory disease. The mechanisms underlying the excessive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities remain only partly understood. SARS-CoV-2 infection is caused by binding of the viral surface spike (S) protein to the human angiotensin-converting enzyme 2 (ACE2), followed by the activation of the S protein by transmembrane protease serine 2 (TMPRSS2). ACE2 is expressed in the lung (mainly in type II alveolar cells), heart, blood vessels, small intestine, etc., and appears to be the predominant portal to the cellular entry of the virus. Based on current information, most people infected with SARS-CoV-2 virus have a good prognosis, while a few patients reach critical condition, especially the elderly and those with chronic underlying diseases. The “cytokine storm” observed in patients with severe COVID-19 contributes to the destruction of the endothelium, leading to “acute respiratory distress syndrome” (ARDS), multiorgan failure, and death. At the origin of the general proinflammatory state may be the SARS-CoV-2-mediated redox status in endothelial cells via the upregulation of ACE/Ang II/AT1 receptors pathway or the increased mitochondrial reactive oxygen species (mtROS) production. Furthermore, this vicious circle between oxidative stress (OS) and inflammation induces endothelial dysfunction, endothelial senescence, high risk of thrombosis and coagulopathy. The microvascular dysfunction and the formation of microthrombi in a way differentiate the SARS-CoV-2 infection from the other respiratory diseases and bring it closer to cardiovascular diseases like myocardial infarction and stroke. Due the role played by OS in the evolution of viral infection and in the development of COVID-19 complications, the use of antioxidants as adjuvant therapy seems appropriate in this new pathology. Alpha-lipoic acid (ALA) could be a promising candidate that, through its wide tissue distribution and versatile antioxidant properties, interferes with several signaling pathways. Thus, ALA improves endothelial function by restoring the endothelial nitric oxide synthase activity and presents an anti-inflammatory effect dependent or independent of its antioxidant properties. By improving mitochondrial function, it can sustain the tissues’ homeostasis in critical situation and by enhancing the reduced glutathione it could indirectly strengthen the immune system. This complex analysis could open a new therapeutic perspective for ALA in COVID-19 infection.     

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.     

Telomere Targeting Approaches in Cancer: Beyond Length Maintenance

Telomeres are crucial structures that preserve genome stability. Their progressive erosion over numerous DNA duplications determines the senescence of cells and organisms. As telomere length homeostasis is critical for cancer development, nowadays, telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere dysfunction impinges on intracellular signaling pathways, in particular DNA damage signaling and repair, affecting cancer cell survival and proliferation. This review summarizes and discusses recent findings in anticancer drug development targeting different “telosome” components.     

The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence

Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.     

Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis

Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4⁺ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28⁻ Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4⁺CD28⁻ T lymphocytes in periodontitis.     

Adipose Tissue Plasticity in Response to Pathophysiological Cues: A Connecting Link between Obesity and Its Associated Comorbidities

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications.     

mTOR Activity and Autophagy in Senescent Cells,a Complex Partnership

Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors.     

Direct Cell-Cell Communication via Membrane Pores,Gap Junction Channels,and Tunneling Nanotubes: Medical Relevance of Mitochondrial Exchange

The history of direct cell-cell communication has evolved in several small steps. First discovered in the 1930s in invertebrate nervous systems, it was thought at first to be an exception to the “cell theory”, restricted to invertebrates. Surprisingly, however, in the 1950s, electrical cell-cell communication was also reported in vertebrates. Once more, it was thought to be an exception restricted to excitable cells. In contrast, in the mid-1960s, two startling publications proved that virtually all cells freely exchange small neutral and charged molecules. Soon after, cell-cell communication by gap junction channels was reported. While gap junctions are the major means of cell-cell communication, in the early 1980s, evidence surfaced that some cells might also communicate via membrane pores. Questions were raised about the possible artifactual nature of the pores. However, early in this century, we learned that communication via membrane pores exists and plays a major role in medicine, as the structures involved, “tunneling nanotubes”, can rescue diseased cells by directly transferring healthy mitochondria into compromised cells and tissues. On the other hand, pathogens/cancer could also use these communication systems to amplify pathogenesis. Here, we describe the evolution of the discovery of these new communication systems and the potential therapeutic impact on several uncurable diseases.     

Cellular Senescence and Inflammaging in the Skin Microenvironment

Cellular senescence and aging result in a reduced ability to manage persistent types of inflammation. Thus, the chronic low-level inflammation associated with aging phenotype is called “inflammaging”. Inflammaging is not only related with age-associated chronic systemic diseases such as cardiovascular disease and diabetes, but also skin aging. As the largest organ of the body, skin is continuously exposed to external stressors such as UV radiation, air particulate matter, and human microbiome. In this review article, we present mechanisms for accumulation of senescence cells in different compartments of the skin based on cell types, and their association with skin resident immune cells to describe changes in cutaneous immunity during the aging process.     

The Role of PERK in Understanding Development of Neurodegenerative Diseases

Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein’s role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.     

The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.     

Recent Advances in Strategies for Imaging Detection and Intervention of Cellular Senescence

Cellular senescence is a stable cell cycle arrest state that can be triggered by a wide range of intrinsic or extrinsic stresses. Increased burden of senescent cells in various tissues is thought to contribute to aging and age-related diseases. Thus, the detection and interventions of senescent cells are critical for longevity and treatment of disease. However, the highly heterogeneous feature of senescence makes it challenging for precise detection and selective clearance of senescent cells in different age-related diseases. To address this issue, considerable efforts have been devoted to developing senescence-targeting molecular theranostic strategies, based on the potential biomarkers of cellular senescence. Herein, we review recent advances in the field of anti-senescence research and highlight the specific visualization and elimination of senescent cells. Additionally, the challenges in this emerging field are outlined.     

The Emerging Role of Extracellular Vesicles Detected in Different Biological Fluids in COPD

The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by complex cellular and molecular mechanisms, not fully elucidated so far. It involves inflammatory cells (monocytes/macrophages, neutrophils, lymphocytes), cytokines, chemokines and, probably, new players yet to be clearly identified and described. Chronic local and systemic inflammation, lung aging and cellular senescence are key pathological events in COPD development and progression over time. Extracellular vesicles (EVs), released by virtually all cells both as microvesicles and exosomes into different biological fluids, are involved in intercellular communication and, therefore, represent intriguing players in pathobiological mechanisms (including those characterizing aging and chronic diseases); moreover, the role of EVs as biomarkers in different diseases, including COPD, is rapidly gaining recognition. In this review, after recalling the essential steps of COPD pathogenesis, we summarize the current evidence on the roles of EVs collected in different biological mediums as biomarkers in COPD and as potential players in the specific mechanisms leading to disease development. We will also briefly review the data on EV as potential therapeutic targets and potential therapeutic agents.     

Extracellular Vesicles as New Players in Cellular Senescence

Cell senescence is associated with the secretion of many factors, the so-called “senescence-associated secretory phenotype”, which may alter tissue microenvironment, stimulating the organism to clean up senescent cells and replace them with newly divided ones. Therefore, although no longer dividing, these cells are still metabolically active and influence the surrounding tissue. Much attention has been recently focused not only on soluble factors released by senescent cells, but also on extracellular vesicles as conveyors of senescence signals outside the cell. Here, we give an overview of the role of extracellular vesicles in biological processes and signaling pathways related to senescence and aging.     

Lipidomics of Bioactive Lipids in Alzheimer’s and Parkinson’s Diseases: Where Are We?

Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as “bioactive lipids”. Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer’s (AD) and Parkinson’s (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.     

Cellular Senescence in Lung Fibrosis

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.     

Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases.