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Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
The key characteristic of MIDAS is its secretory phenotype (Hernandez-Segura, Nehme, and Demaria 2018). Various types of mitochondrial perturbations can result in a distinct senescent secretory profile referred to as the MiDAS secretome, which is different from the canonical secretory phenotype caused by SIS or OIS (Wiley et al. 2016). The senescence-associated secretory phenotype (SASP), which is also referred to as senescence messaging secretome (SMS) (Kuilman and Peeper 2009), is a hallmark of many senescent cells (Coppé et al. 2008; Rodier et al. 2009). SASP include various types of cytokines, chemokines, growth factors, and proteases that are responsible for either the harmful or beneficial effects of senescent cells (Coppé et al. 2010; Freund et al. 2010; Tchkonia et al. 2013). The SASP includes several families of soluble and insoluble factors that may act in a paracrine manner, activating cell-surface receptors, and corresponding cell signaling pathways that may lead to multiple pathologies, including cancer. Generally, SASP secretion can be grouped into these categories: soluble signaling factors, secreted proteases, and secreted insoluble proteins/extracellular matrix (ECM) components (Coppé et al. 2010).SASP factors include IL-6, IL-8, monocyte chemoattractant proteins (MCPs), macrophage inflammatory proteins (MIPs), and granulocyte/macrophage colony–stimulating factor (GM-CSF) (Adams 2009; Coppé et al. 2010; Davalos et al. 2010).
Senescent Cells as Drivers of Age-Related Diseases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cielo Mae D. Marquez, Michael C. Velarde
Senescent cells are marked by their inability to divide and by their dramatic changes in morphology and metabolic processes. Senescent cells are characterized by their enlarged cell size and flattened cytoplasm compared to the normal cell morphology in proliferating, quiescent, or terminally differentiated cells (Figure 16.1). Senescent phenotypes also include development of nuclear blebbing, increase in lysosomal mass, increased activity of the pH-dependent senescence-associated β-galactosidase (SA β-gal), downregulation of lamin B1, formation of senescence-associated heterochromatin foci (SAHF), establishment of DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), activation of p53/p21 and p16/pRb pathways, and secretion of high mobility group box 1 (HMGB1) (Figure 16.2) [19–23]. Cells that undergo senescence develop resistance to apoptosis partly due to the absence of insulin-like growth factor-binding protein 3 (IGFBP-3) within the nucleus [4]. Senescent cells also express many cytokines, chemokines, growth factors, and other proteins collectively termed as the senescence-associated secretory phenotype (SASP) [24,25].
Tumor Microenvironment, Therapeutic Resistance, and Personalized Medicine
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Cellular senescence occurs among normal cells in response to oncogenic overexpression (oncogene-induced senescence, OIS) or telomeric attrition (replicative senescence, RS), serving as a physiological checkpoint to cause cell cycle arrest and prevent carcinogenesis. Importantly, senescent cells also exhibit another visage characterized with production of a plethora of cytokines, chemokines, proteases, and growth factors, a signature termed the senescence-associated secretory phenotype (SASP) or the senescence messaging secretome (SMS) [53, 54]. Despite the cell-autonomous function of certain SASP factors such as IL-6 and IL-8 in reinforcing the senescence state, diverse SASP effectors perform as cell non-autonomous molecules that degrade basement membrane, promote cancer resistance, enhance metastatic potential, together accelerating tumorigenic progression [55, 56].
Danggui-Buxue decoction alleviated vascular senescence in mice exposed to chronic intermittent hypoxia through activating the Nrf2/HO-1 pathway
Published in Pharmaceutical Biology, 2023
Dongli Li, Jianchao Si, Yajing Guo, Bingbing Liu, Xue Chen, Kerong Qi, Shengchang Yang, Ensheng Ji
Inflammation is a primary pathological mechanism of aging-related endothelial dysfunction and artery aging. Inflammatory protein levels increase with age, including proinflammatory cytokines TNF-α, IL-6, and NF-κB (Li et al. 2020; de Oliveira Zanuso et al. 2022). The senescence-associated secretory phenotype (SASP) is a novel mechanism linking cell senescence and tissue dysfunction and is characterized by increased secretions of proinflammatory cytokines and chemokines, such as IL-6, IL-8, TNF-α, and MMP. Senescent cells in the SASP state can maintain and propagate senescence to adjacent cells through the autocrine or paracrine regulatory loop, thus causing fatal degenerative diseases and leading to persistently low levels of chronic inflammation (Hernandez-Segura et al. 2018). The proinflammatory transcription factor NF-κB and JAK/STAT pathways are involved in regulating SASP expression (Hernandez-Segura et al. 2018; Birch and Gil 2020). Nrf2 can inhibit the expression of NF-κB, TNF-α, IL-6, and other pro-inflammatory cytokines and play an anti-inflammatory role (Wu et al. 2021; Wang and He 2022). In our research, CIH enhanced the transcription and secretion of IL‐6, TNF-α, and NF-κB. DBD treatment attenuated the inflammatory response in CIH mice, indicating that DBD may contribute to antiaging effects by attenuating vascular inflammation of the aortas in CIH mice.
Immune senescence in non-small cell lung cancer management: therapeutic relevance, biomarkers, and mitigating approaches
Published in Expert Review of Anticancer Therapy, 2022
Teodora Alexa-Stratulat, Mariana Pavel-Tanasa, Vlad-Andrei Cianga, Sabina Antoniu
NSCLC remains a therapeutic challenge despite the availability of screening programs and despite the existence of many therapeutic options. One of the aspects making therapy challenging is the lack of robust predictors of response to systemic therapy. One such predictor might be represented by the immune senescence, especially when immune checkpoint inhibitors are to be considered for therapy. Therapy-induced cell senescence is also a challenging issue because up to a point this is a beneficial therapeutic outcome and beyond that point is a risk factor for tumor recurrence. Immune senescence can be assessed with the aid of biomarkers and can be reversed with senotherapeutics. This pharmacological approach includes senolytics which are able to kill senescent cells (including immune senescent cells) respectively senomorphics which are able to inhibit pathogenic SASP. There are many experimental data available for such potential therapies in the setting of NSCLC but some pieces of this senescence-related puzzle are still missing.
Immunosenescence, inflammaging, and cancer immunotherapy efficacy
Published in Expert Review of Anticancer Therapy, 2022
Julieta E Rodriguez, Marie Naigeon, Vincent Goldschmidt, Matthieu Roulleaux Dugage, Lauren Seknazi, Francois X Danlos, Stephane Champiat, Aurélien Marabelle, Jean-Marie Michot, Christophe Massard, Benjamin Besse, Roberto Ferrara, Nathalie Chaput, Capucine Baldini
As previously discussed, aging is also associated with SASP, which is a complex mechanism, characterized among others by an increased serum level of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNFα. There is a strong biological rationale indicating that SASP should be associated with poorer benefit from immune checkpoint blockade as cytokines associated with SASP rather favor tumor progression. IL-6 inhibits intratumoral T cell activation by monocyte-derived dendritic cells [49], and is associated with higher C-reactive protein levels and poorer outcome after immune checkpoint-blockade [50]. Similarly, IL-1 induces the expression of CXCL1, CXCL2, and CXCL5 by intratumor macrophages and monocytes, resulting in a recruitment of neutrophils and suppressive myeloid cells, and in an inhibition of antitumor immune response [51]. IL-8 is also associated with poorer outcome under ICB [52], notably through the recruitment of neutrophils and suppressive myeloid cells, but also by the induction of neutrophil extracellular traps that promote immune escape [53].