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Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second‐generation fluorogenic substrate for β‐galactosidase and multi‐parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence‐associated β‐galactosidase (SA‐βGal) activity with advancing donor age. The greatest age‐associated increases were observed in CD8+ T‐cell populations, in which the fraction of cells with high SA‐βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA‐βGal activity, but not those with low SA‐βGal activity, were found to exhibit features of telomere dysfunction‐induced senescence and p16‐mediated senescence, were impaired in their ability to proliferate, developed in various T‐cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age. Senescent CD8+ T cells in peripheral blood can be detected, quantified, and isolated using a fluorogenic and self‐immobilizing substrate of senescence‐associated β‐galactosidase. Characterization of CD8+ T cells with high SA‐βGal activity isolated from healthy donors in their 20s and 60s revealed a significantly greater abundance of SA‐βGal expressing CD8+ T cells with a unique transcriptional signature and features telomere dysfunction‐induced senescence and p16‐mediated senescence in older humans.

Senescence is a cellular state in which cells undergo persistent cell cycle arrest in response to nonlethal stress. In the treatment of cancer, senescence induction is a potent method of suppressing tumour cell proliferation. In spite of this, senescent cancer cells and adjacent nontransformed cells of the tumour microenvironment can remain metabolically active, resulting in paradoxical secretion of pro‐inflammatory factors, collectively termed the senescence‐associated secretory phenotype (SASP). The SASP plays a critical role in tumorigenesis, affecting numerous processes including invasion, metastasis, epithelial‐to‐mesenchymal transition (EMT) induction, therapy resistance and immunosuppression. With increasing evidence, it is becoming clear that cell type, tissue of origin and the primary cellular stressor are key determinants in how the SASP will influence tumour development and progression, including whether it will be pro‐ or antitumorigenic. In this review, we will focus on recent evidence regarding therapy‐induced senescence (TIS) from anticancer agents, including chemotherapy, radiation, immunotherapy, and targeted therapies, and how each therapy can trigger the SASP, which in turn influences treatment efficacy. We will also discuss novel pharmacological manipulation of senescent cancer cells and the SASP, which offers an exciting and contemporary approach to cancer therapeutics. With future research, these adjuvant options may help to mitigate many of the negative side effects and protumorigenic roles that are currently associated with TIS in cancer. In response to therapy or other stimuli, cancer cells can undergo cellular senescence, a stress response leading to cell cycle arrest. An unintended consequence of cellular senescence is a perturbed, pro‐inflammatory cancer cell secretome, the senescence‐associated secretory phenotype (SASP). Here, we explore the role of SASP in promoting tumorigenesis and treatment resistance, with particular focus on mechanisms of therapy‐induced senescence (TIS).

Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age‐related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anticancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. “One‐two punch” therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. “One‐two punch” represents an emerging and promising new strategy in cancer treatment. Future challenges of “one‐two punch” approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy. Conventional cancer therapies induce senescence. While senescence contributes to therapy outcome, accumulation of senescent cells can promote cancer progression, metastasis and therapy resistance. One‐two punch approaches aim to combine cancer therapies with senolytics to remove senescent tumour cells. Here, we review senescence in the context of cancer and discuss future challenges of senotherapies for cancer treatment.

Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications. Obesity induces the formation of senescent cells, which contribute to inflammation, insulin resistance, and organ dysfunction. Senescent cell clearance may be an effective strategy for alleviating important elements of obesity‐related metabolic dysfunction.

In contrast to the well-recognized replicative and stress-induced premature senescence of normal somatic cells, mechanisms and clinical implications of senescence of cancer cells are still elusive and uncertain from patient-oriented perspective. Moreover, recent years provided multiple pieces of evidence that cancer cells may undergo senescence not only in response to chemotherapy or ionizing radiation (the so-called therapy-induced senescence) but also spontaneously, without any external insults. Since the molecular nature of the latter process is poorly recognized, the significance of spontaneously senescent cancer cells for tumor progression, therapy effectiveness, and patient survival is purely speculative. In this review, we summarize the most up-to-date research regarding therapy-induced and spontaneous senescence of cancer cells, by delineating the most important discoveries regarding the occurrence of these phenomena in vivo and in vitro. This review provides data collected from studies on various cancer cell models, and the narration is presented from the broader perspective of the most critical findings regarding the senescence of normal somatic cells.

Aging is the inevitable, irreversible decline in function on the cellular and organ level leading to increased incidence of the most frequent diseases such as cancer and cardiovascular disease, that occurs over time. whereas the molecular mechanisms of senescence remain largely unknown. Here we identified that a novel long noncoding RNA, Morrbid was significantly decreased in different organs of aged mice, such as heart, liver, spleen, lung, kidney and brain. Interestingly, the telomeres length of Morrbid KO mice were significantly shorted than the WT mice at the same age. We also found that Morrbid was steeply decreased in a natural mouse cardiac myocyte senescence model. The senescence of mouse cardiac myocytes was effectively attenuated by Morrbid over-expression shown by the decreased β-galactosidase staining, increased telomere activity, decreased production of ROS and decreased cell apoptosis, but was enhanced by Morrbid knockdown. The results suggest that Morrbid is a critical regulator in senescence and could be used as a novel diagnostic biomarker for it, and a new therapeutic target for diverse diseases.

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose‐encapsulated nanoparticles within these cells. Here, we show that galacto‐conjugation of the BCL‐2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav‐Gal), that can be preferentially activated by SA‐β‐gal activity in a wide range of cell types. Nav‐Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav‐Gal enhances the cytotoxicity of standard senescence‐inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav‐Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto‐conjugation reduces Navitoclax‐induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities. We have developed a galactose‐conjugated derivative of Navitoclax (Nav‐Gal) with a broad‐spectrum senolytic activity. We show that Nav‐Gal efficiently kills chemotherapy‐induced senescent cells in xenografts and orthotopic in vivo models of NSCLC, resulting in impaired tumour progression. Importantly, our prodrug prevents Navitoclax‐induced platelet apoptosis in human samples and murine models. In summary, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.

ABSTRACT Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age‐related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context‐dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro‐tumorigenic and pro‐aging effects. Just as the term “cancer cell” encompasses a wide spectrum of cells, the term “senescent cell” should also be regarded as an umbrella term that includes cells with heterogeneous molecular profiles. In this review, we provide an updated overview of the molecular mechanisms underlying distinct senescent cell subtypes induced by various stimuli, including plasma membrane damage, a previously unappreciated trigger of senescence. We also highlight the necessity of subtype‐specific detection and therapeutic strategies—analogous to precision medicine in oncology.

Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome‐wide in two primary cell lines. We integrated ChIP‐seq and Hi‐C with graph theory to uncover clustering of HMGB1‐marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross‐Linking and Immuno‐Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA‐binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP‐relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell‐autonomous and paracrine senescence. Synopsis Mammalian cell senescence entry is marked by the nuclear loss of HMGB1. Genome‐wide analyses show that HMGB1 binds both chromatin and mRNAs in proliferating cells, and its loss underlies topological and splicing changes inducing the senescent transcriptional program. Senescence entry by mammalian cells is marked by the nuclear depletion of HMGB1. HMGB1 shows dual specificity binding to a subset of topological boundaries on chromatin and to hundreds of mRNAs. TAD clusters enriched for HMGB1 spatially co‐associate in proliferating cell nuclei. HMGB1 loss leads to transcriptional changes necessary for senescence establishment. Graphical Abstract Mammalian cell senescence entry is marked by the nuclear loss of HMGB1. Genome‐wide analyses show that HMGB1 binds both chromatin and mRNAs in proliferating cells, and its loss underlies topological and splicing changes inducing the senescent transcriptional program.

The skin, being the barrier organ of the body, is constitutively exposed to various stimuli impacting its morphology and function. Senescent cells have been found to accumulate with age and may contribute to age-related skin changes and pathologies. Natural polyphenols exert many health benefits, including ameliorative effects on skin aging. By affecting molecular pathways of senescence, polyphenols are able to prevent or delay the senescence formation and, consequently, avoid or ameliorate aging and age-associated pathologies of the skin. This review aims to provide an overview of the current state of knowledge in skin aging and cellular senescence, and to summarize the recent in vitro studies related to the anti-senescent mechanisms of natural polyphenols carried out on keratinocytes, melanocytes and fibroblasts. Aged skin in the context of the COVID-19 pandemic will be also discussed.