Cellular senescence is implicated in physiological and pathological processes spanning development, wound healing, age-related decline in organ functions and cancer. Here, we discuss cell-autonomous ...and non-cell-autonomous properties of senescence in the context of tumour formation and anticancer therapy, and characterize these properties, such as reprogramming into stemness, tissue remodelling and immune crosstalk, as far more dynamic than suggested by the common view of senescence as an irreversible, static condition.
Activated oncogenes or anticancer therapies evoke senescent cell-cycle arrest in (pre-)malignant cells, thereby interrupting tumor formation or progression. Physiologically, cellular senescence ...contributes to embryonic development and tissue regeneration. These observations and the overlap of numerous gene products in senescence and stem cell signaling prompted investigations into whether epigenetic establishment of the senescent state may concomitantly reprogram the cell into a latent stem-like condition, whose functional impact becomes evident when arrested cells resume proliferation. We review here recent discoveries underscoring the unexpected senescence–stemness alliance, elucidate underlying molecular mechanisms, and discuss its fundamentally different implications in normal tissue repair – to replenish the exhausted repopulation capacity – as compared to cancer biology, where usurpation of this natural principle accounts for particularly aggressive tumor behavior.
Cellular senescence with its cell-autonomous and cell non-autonomous implications is now recognized as a key component of development, tissue regeneration, aging-related pathologies, and cancer.
The increasingly investigated biological consequences of the senescence-associated secretome are complex, spanning paracrine senescence, immune activation, and chronic inflammation.
Senescence has been viewed as a static, molecularly fixed condition, and final phase of the life-cycle of a cell, but recent advances indicate that the senescent growth arrest might not be terminal but potentially reversible.
Targeted, continuous elimination of senescent cells in aging mice resulted in reduced organ dysfunction and extended healthy lifespan.
Emerging evidence links senescent cells to stem cell properties, for example in the context of wound healing, induced reprogramming into pluripotency, and cancer.
Cellular senescence is a critical stress response program implicated in embryonic development, wound healing, aging, and immunity, and it backs up apoptosis as an ultimate cell-cycle exit mechanism. ...In analogy to replicative exhaustion of telomere-eroded cells, premature types of senescence-referring to oncogene-, therapy-, or virus-induced senescence-are widely considered irreversible growth arrest states as well. We discuss here that entry into full-featured senescence is not necessarily a permanent endpoint, but dependent on essential maintenance components, potentially transient. Unlike a binary state switch, we view senescence with its extensive epigenomic reorganization, profound cytomorphological remodeling, and distinctive metabolic rewiring rather as a journey toward a full-featured arrest condition of variable strength and depth. Senescence-underlying maintenance-essential molecular mechanisms may allow cell-cycle reentry if not continuously provided. Importantly, senescent cells that resumed proliferation fundamentally differ from those that never entered senescence, and hence would not reflect a reversion but a dynamic progression to a post-senescent state that comes with distinct functional and clinically relevant ramifications.
Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve ...healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
The cellular state of “senescence” has proven difficult to define, presenting an obstacle for progress in the field. This perspective provides a consensus on the cellular and molecular features of senescence from 26 field leaders.
The mammalian circadian clock and the cell cycle are two major biological oscillators whose coupling influences cell fate decisions. In the present study, we use a model-driven experimental approach ...to investigate the interplay between clock and cell cycle components and the dysregulatory effects of RAS on this coupled system. In particular, we focus on the Ink4a/Arf locus as one of the bridging clock-cell cycle elements. Upon perturbations by the rat sarcoma viral oncogene (RAS), differential effects on the circadian phenotype were observed in wild-type and Ink4a/Arf knock-out mouse embryonic fibroblasts (MEFs), which could be reproduced by our modelling simulations and correlated with opposing cell cycle fate decisions. Interestingly, the observed changes can be attributed to in silico phase shifts in the expression of core-clock elements. A genome-wide analysis revealed a set of differentially expressed genes that form an intricate network with the circadian system with enriched pathways involved in opposing cell cycle phenotypes. In addition, a machine learning approach complemented by cell cycle analysis classified the observed cell cycle fate decisions as dependent on Ink4a/Arf and the oncogene RAS and highlighted a putative fine-tuning role of Bmal1 as an elicitor of such processes, ultimately resulting in increased cell proliferation in the Ink4a/Arf knock-out scenario. This indicates that the dysregulation of the core-clock might work as an enhancer of RAS-mediated regulation of the cell cycle. Our combined in silico and in vitro approach highlights the important role of the circadian clock as an Ink4a/Arf-dependent modulator of oncogene-induced cell fate decisions, reinforcing its function as a tumour-suppressor and the close interplay between the clock and the cell cycle network.
COVID-19 and cellular senescence Schmitt, Clemens A; Tchkonia, Tamar; Niedernhofer, Laura J ...
Nature reviews. Immunology,
04/2023, Volume:
23, Issue:
4
Journal Article
Peer reviewed
Open access
The clinical severity of coronavirus disease 2019 (COVID-19) is largely determined by host factors. Recent advances point to cellular senescence, an ageing-related switch in cellular state, as a ...critical regulator of SARS-CoV-2-evoked hyperinflammation. SARS-CoV-2, like other viruses, can induce senescence and exacerbates the senescence-associated secretory phenotype (SASP), which is comprised largely of pro-inflammatory, extracellular matrix-degrading, complement-activating and pro-coagulatory factors secreted by senescent cells. These effects are enhanced in elderly individuals who have an increased proportion of pre-existing senescent cells in their tissues. SASP factors can contribute to a 'cytokine storm', tissue-destructive immune cell infiltration, endothelialitis (endotheliitis), fibrosis and microthrombosis. SASP-driven spreading of cellular senescence uncouples tissue injury from direct SARS-CoV-2-inflicted cellular damage in a paracrine fashion and can further amplify the SASP by increasing the burden of senescent cells. Preclinical and early clinical studies indicate that targeted elimination of senescent cells may offer a novel therapeutic opportunity to attenuate clinical deterioration in COVID-19 and improve resilience following infection with SARS-CoV-2 or other pathogens.
Cellular senescence serves as a barrier to tumor development and a principle effector of anti-cancer therapy, but the largely pro-inflammatory senescence-associated secretory phenotype (SASP) may ...drive tumor promotion and contribute to age-related pathologies. In this issue of Cancer Cell, Georgilis et al. present SASP-deprived senescence as a potential therapeutic perspective.
Cellular senescence serves as a barrier to tumor development and a principle effector of anti-cancer therapy, but the largely pro-inflammatory senescence-associated secretory phenotype (SASP) may drive tumor promotion and contribute to age-related pathologies. In this issue of Cancer Cell, Georgilis et al. present SASP-deprived senescence as a potential therapeutic perspective.
Cellular senescence, an irreversible cell-cycle arrest, reflects a safeguard program that limits the proliferative capacity of the cell exposed to endogenous or exogenous stress signals. A number of ...recent studies have clarified that an acutely inducible form of cellular senescence may act in response to oncogenic activation as a natural barrier to interrupt tumorigenesis at a premalignant level. Paralleling the increasing insights into premature senescence as a tumor suppressor mechanism, a growing line of evidence identifies cellular senescence as a critical effector program in response to DNA damaging chemotherapeutic agents. This review discusses molecular pathways to stress-induced senescence, the interference of a terminal arrest condition with clinical outcome, and the critical overlap between premature senescence and apoptosis as both tumor suppressive and drug-responsive cellular programs.
Primary immune thrombocytopenia (ITP) in adult patients typically presents as a repeatedly relapsing disease in need of multiple lines of therapy. Here we report the clinical courses of two patients, ...an 82-year-old female and a 54-year-old male, with primary ITP after multiple relapses and exhausted standard therapies, which we treated with the myeloma-licensed anti-CD38 monoclonal antibody daratumumab in an off-label setting. Daratumumab is known to target preferentially plasmablasts, short-lived plasma cells and long-lived plasma cells, with the latter being the major source of antiplatelet autoantibodies. Noteworthy, rituximab, a CD20 antibody, targets earlier steps in B-cell ontogenesis, thereby indirectly decreasing plasmablasts and short-lived plasma cells, but to a lesser extent long-lived plasma cells, which tend to persist after rituximab treatment. Several single-patient reports and case series have demonstrated successful treatment with daratumumab in ITP, autoimmune thrombocytopenia in Evans syndrome as well as other cytopenias or pure red cell aplasia after allogeneic stem cell transplantation or in congenital diseases, systemic lupus erythematodes and cold agglutinin disease. Our first patient with isolated primary ITP rapidly and lastingly responded to daratumumab plus tapered steroids, with platelet counts above 50 × 109/L within weeks and subsequently even stably within the normal range. Despite no objective response observed in the second patient, a lasting clinical stabilization was achieved. As the underlying mode of action, we hypothesize here daratumumab to effectively target long-lived plasma cells as the source of ITP-mediating autoantibodies, and suggest broader clinical evaluation of daratumumab in this potential indication.
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16
..., p21
and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
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