The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting SnCs using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

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The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene‐induced stress. Many senescent cells (SnCs) develop a senescent‐associated secretory phenotype (SASP) comprising pro‐inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up‐regulate senescent cell anti‐apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age‐related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre‐clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.

Abstract-We have found that 15-hydroxyeicosatetraenoic acid (15-HETE) induced by hypoxia was an important mediator in the regulation of hypoxic pulmonary hypertension, including the pulmonary vasoconstriction and remodeling. However, the underlying mechanisms of the remodeling induced by 15-HETE are poorly understood. In this study, we performed immunohistochemistry, pulmonary artery endothelial cells migration and tube formation, pulmonary artery smooth muscle cells bromodeoxyuridine incorporation, and cell cycle analysis to determine the role of 15-HETE in hypoxia-induced pulmonary vascular remodeling. We found that hypoxia induced pulmonary vascular medial hypertrophy and intimal endothelial cells migration and angiogenesis, which were mediated by 15-HETE. Moreover, 15-HETE regulated the cell cycle progression and made more smooth muscle cells from the G 0 /G 1 phase to the G 2 /MϩS phase and enhanced the microtubule formation in cell nucleus. In addition, we found that the Rho-kinase pathway was involved in 15-HETE-induced endothelial cells tube formation and migration and smooth muscle cell proliferation. Together, these results show that 15-HETE mediates hypoxia-induced pulmonary vascular remodeling and stimulates angiogenesis via the Rho-kinase pathway. (Hypertension. 2011;58:679-688.) • Online Data Supplement Key Words: pulmonary hypertension Ⅲ pulmonary vascular remodeling Ⅲ angiogenesis Ⅲ 15-hydroxyeicosatetraenoic acid Ⅲ ROCK P ulmonary hypertension (PH) is a refractory disease commonly associated with the high morbidity and mortality of adult and pediatric patients with various lung and heart diseases. 1,2 The mechanisms by which the pulmonary arteries in the pulmonary circulation narrow include pulmonary vasoconstriction, pulmonary vascular remodeling, and thrombosis in situ. 3,4 Vascular remodeling involves all 3 layers of the vascular wall and is complicated by the finding that cellular heterogeneity exists within the compartment of the pulmonary arterial wall. 3,5 However, the specific role and the interaction between each cell are poorly understood. Generally, pulmonary vascular remodeling includes endothelial angiogenesis, smooth muscle cell proliferation and hypertrophy, adventitial fibroblast proliferation, myofibroblast differentiation, and extracellular matrix deposition. Hypoxia is considered as the predominant factor in the pathogenesis of pulmonary hypertension (PH). 1,6 During the early period of hypoxic exposure, angiogenesis in the mature pulmonary circulation is a potentially beneficial adaptation for gas exchange. 6 The lung vascular homeostasis involves maintaining an ideal number of capillaries per unit of lung volume. However, the sustained chronic hypoxia leads to disorder of the process and excess angiogenesis, which would impose more pressure on the proximal pulmonary artery and complicate the course of PH, suggesting that excess angiogenesis is a crucial player in the pathogenesis of PH. 7 Rho-kinase (ROCK), a downstream target of the GTPase RhoA, has been involved in many p...