Senescence-associated Secretory Phenotype Research Articles

HGG-07. INVESTIGATING THE ROLE OF SENESCENCE IN PEDIATRIC HIGH-GRADE GLIOMAS

Abstract Cellular senescence has expanded well past the original definition of just proliferative exhaustion and tumor suppression. Today, senescence is considered a “Hallmark of Cancer” and the senescence-associated secretory phenotype (SASP) secretes molecules that can promote oncogenesis, angiogenesis, and an immunosuppressive tumor microenvironment (TME). Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors with dismal outcomes and limited therapeutic options. Accumulating evidence suggests potential therapeutic vulnerabilities in targeting senescence in adult solid and brain tumors. Furthermore, senescent immune cells in the TME appear to play an important role in the initiation and progression in adult solid tumors. The role of senescence in pHGGs, however, has not been well described. Here, we show evidence of senescent glial and immune cells in pHGG tumors. Using patient-derived cell lines, we also investigate triggers of senescence and further characterize SASP in pHGGs. By understanding the role of senescence in gliomagenesis, we hope to open new approaches in treating pHGGs.

EPEN-10. INDUCING A SENESCENCE PHENOTYPE BY BROMODOMAIN INHIBITION IN HIGH-RISK EPENDYMOMA

Abstract BACKGROUND Ependymomas (EPN) constitute 10% of pediatric brain tumors. WHO classification identified 10 molecular subtypes, with ZFTA fusion-driven supratentorial tumors (ST-ZFTA) and posterior fossa group A (PFA) being amongst the most aggressive ones. Current therapeutic success relies on local treatments, emphasizing the urgent need for novel targets. Epigenetic dysregulation is a major contributor to EPN aggressiveness. Bromodomain and extra-terminal domain (BET) proteins are transcriptional mediators involved in proto-oncogene transcription, thereby representing promising targets in cancer therapy. As the BET protein BRD4 co-regulates ZFTA-RELA fusion-mediated aberrant transcription, BET inhibitors emerge as novel targeted therapy approach in ST-ZFTA. METHODS Initial assessments encompassed primary, patient-derived (n=9) cell models representing ST-ZFTA and PFA EPN. RNA sequencing of two ZFTA-RELA models was performed, using DGE and GSEA analyses to discern altered pathways following BET-inhibition. On functional level, we investigated sensitivity towards BET-inhibition using cell viability, clone- and sphere formation assays, as well as Western blot and qPCR after treatment. Additionally, anti-tumor effects in genetically engineered cerebral organoids were assessed. RESULTS First investigations showed elevated BRD2 and BRD4 levels in ST-ZFTA compared to PFA models. Accordingly, treatment with BET inhibitors resulted in reduced survival and cell cycle arrest, evidenced by cell viability and clone formation assays, along with increased p21 and cleaved PARP levels in Western blot analyses. RNA sequencing revealed altered pathways associated with cell-cycle regulation and senescence following BET inhibition, supported by downregulation of the telomerase subunit TERT and genes of the senescence-associated secretory phenotype. Additionally, BET inhibitors exhibited synergistic effects with EZH2- and PARP inhibitors primarily in ZFTA-RELA cell lines, as well as decreased tumor volumes in ZFTA-RELA-driven cerebral organoids. CONCLUSIONS Summarizing, we show drastic effects of BET-inhibition in ZFTA-RELA EPN. Subsequently, the influence of Bromodomain inhibition on stemness and senescence, particularly combined with radio- and chemotherapy will be investigated.

Looking for the philosopher's stone: Emerging approaches to target the hallmarks of aging in the skin.

Senescence and epigenetic alterations are two important hallmarks of cellular aging. During aging, cells subjected to stress undergo many cycles of damage and repair before finally entering either apoptosis or senescence, a permanent state of cell cycle arrest. The first biomarkers of senescence to be identified were increased ß-galactosidase activity and induction of p16INK4a. Another feature of senescent cells is the senescence-associated secretory phenotype (SASP), a complex secretome containing more than 80 pro-inflammatory factors including metalloproteinases, growth factors, chemokines and cytokines. The secretome is regulated through a dynamic process involving a self-amplifying autocrine feedback loop and activation of the immune system. Senescent cells play positive and negative roles depending on the composition of their SASP and may participate in various processes including wound healing and tumour suppression, as well as cell regeneration, embryogenesis, tumorigenesis, inflammation and finally aging. The SASP is also a biomarker of age, biological aging and age-related diseases. Recent advances in anti-age research have shown that senescence can be now prevented or delayed by clearing the senescent cells or mitigating the effects of SASP factors, which can be achieved by a healthy lifestyle (exercise and diet), and senolytics and senomorphics, respectively. An alternative is tissue rejuvenation, which can be achieved by stimulating aged stem cells and reprogramming deprogrammed aged cells. These non-clinical findings will open up new avenues of clinical research into the development of treatments capable of preventing or treating age-related pathologies in humans.

Metabolic shifts during coffee consumption refresh the immune response: insight from comprehensive multiomics analysis.

Coffee, a widely consumed beverage, has shown benefits for human health but lacks sufficient basic and clinical evidence to fully understand its impacts and mechanisms. Here, we conducted a cross-sectional observational study of coffee consumption and a 1-month clinical trial in humans. We found that coffee consumption significantly reshaped the immune system and metabolism, including reduced levels of inflammatory factors and a reduced frequency of senescent T cells. The frequency of senescent T cells and the levels of the senescence-associated secretory phenotype were lower in both long-term coffee consumers and new coffee consumers than in coffee nondrinking subjects, suggesting that coffee has anti-immunosenescence effects. Moreover, coffee consumption downregulated the activities of the The Janus kinase/signal transduction and activator of transcription (JAK/STAT) and mitogen-activated protein kinases (MAPK) signaling pathways and reduced systemic proinflammatory cytokine levels. Mechanistically, coffee-associated metabolites, such as 1-methylxanthine, 3-methylxanthine, paraxanthine, and ceramide, reduced the frequency of senescent CD4+CD57+ T cells in vitro. Finally, in vivo, coffee intake alleviated inflammation and immunosenescence in imiquimod-induced psoriasis-like mice. Our results provide novel evidence of the anti-inflammatory and anti-immunosenescence effects of coffee, suggesting that coffee consumption could be considered a healthy habit.

Treatment of Rheumatoid Arthritis Based on the Inherent Bioactivity of Black Phosphorus Nanosheets.

Rheumatoid arthritis (RA) is an autoimmune disease that affects the living quality of patients, especially the elderly population. RA-related morbidity and mortality increase significantly with age, while current clinical drugs for RA are far from satisfactory and may have serious side effects. Therefore, the development of new drugs with higher biosafety and efficacy is demanding. Black phosphorus nanosheets (BPNSs) have been widely studied because of their excellent biocompatibility. Here, we focus on the inherent bioactivity of BPNSs, report the potential of BPNSs as a therapeutic drug for RA and elucidate the underlying therapeutic mechanism. We find that BPNSs inhibit autophagy at an early stage via the AMPK-mTOR pathway, switch the energy metabolic pathway to oxidative phosphorylation, increase intracellular ATP levels, suppress apoptosis, reduce inflammation and oxidative stress, and down-regulate senescence-associated secretory phenotype (SASP)-related genes in rheumatoid arthritis synovial fibroblasts (RA-SFs). Further, BPNSs induce the apoptosis of macrophages and promote their transition from the M1 to the M2 phenotype by regulating related cytokines. Significantly, the administration of BPNSs can alleviate key pathological features of RA in mice, revealing great therapeutic potential. This study provides a novel option for treating RA, with BPNSs emerging as a promising therapeutic candidate.

Molecular Signatures of Senescence in Periodontitis: Clinical Insights.

Most of the elderly population is afflicted by periodontal diseases, creating a health burden worldwide. Cellular senescence is one of the hallmarks of aging and associated with several chronic comorbidities. Senescent cells produce a variety of deleterious secretions, collectively termed the senescence-associated secretory phenotype (SASP). This disrupts neighboring cells, leading to further senescence propagation and inciting chronic inflammation, known as "inflammaging." Detrimental repercussions within the tissue microenvironment can trigger senescence at a younger age, accelerate biological aging, and drive the initiation or progression of diseases. Here, we investigated the biological signatures of senescence in healthy and diseased gingival tissues by assessing the levels of key senescence markers (p16, lipofuscin, and β-galactosidase) and inflammatory mediators (interleukin [IL]-1β, IL-6, IL-8, matrix metalloproteinase [MMP]-1, MMP-3, and tumor necrosis factor-α). Our results showed significantly increased senescence features including p16, lipofuscin, and β-galactosidase in both epithelial and connective tissues of periodontitis patients compared with healthy sites in all age groups, indicating that an inflammatory microenvironment can trigger senescence-like alterations in younger diseased gingival tissues as well. Subsequent analyses using double staining with specific cell markers noted the enrichment of β-galactosidase in fibroblasts and macrophages. Concurrently, inflammatory mediators consistent with SASP were increased in the gingival biopsies obtained from periodontitis lesions. Together, our findings provide the first clinical report revealing susceptibility to elevated senescence and inflammatory milieu consistent with senescence secretome in gingival tissues, thus introducing senescence as one of the drivers of pathological events in the oral mucosa and a novel strategy for targeted interventions.

Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis.

In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. In this narrative review, we aimed to give a comprehensive overview of recent studies dealing with the cellular and molecular mechanisms underlying SSc defective angiogenesis and the related endothelial cell dysfunctions, mainly the endothelial-to-mesenchymal transition process. We also discussed potential novel vascular treatment strategies able to restore the angiogenic process and reduce the endothelial-to-mesenchymal transition in this complex disease.

Egr1 regulates regenerative senescence and cardiac repair.

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.

Luteoloside mitigates premature age-related macular degeneration by suppressing p53-p21-Rb1 axis: Insights from transcriptomic analysis, serum metabolomics and gut microbiota analysis

Transcriptomics of dry age-related macular degeneration (AMD) patients with premature aging revealed the upregulated pathways involved in glycerolipid metabolism, tyrosine metabolism, and pentose and glucuronate interconversion. To investigate natural strategies for modulating these implicated pathways, we examined the impact and underlying mechanism of luteoloside on premature AMD using a stress-induced premature senescence (SIPS)-associated AMD animal model in middle-aged mice that mimicked the dysregulated pathways observed in dry AMD patients with premature aging. Luteoloside supplementation resulted in a significant reduction in serum levels of the pro-inflammatory cytokine IL-1β and lipofuscin, along with increased serum activity of the antioxidant enzyme superoxide dismutase (SOD) and elevated levels of pigment epithelium-derived factor (PEDF), and preserved retinal thickness and structure in AMD mice. Furthermore, luteoloside supplementation effectively reversed the abnormal serum levels of metabolites, particularly by reducing harmful lysophosphatidylcholine (LysoPC) and increasing beneficial 4-guanidinobutanoic acid. In addition to its impact on metabolites, luteoloside modulated the composition of gut microbiota, promoting the enrichment of beneficial bacterial populations, including Lactobacillus, while reducing the abundance of harmful bacterial populations, including Bacteroides. Overall, our findings highlight the potential of luteoloside supplementation in regulating the dysregulated intestinal microbiota and metabolites in premature AMD, thereby reducing ocular levels of senescence-associated secretory phenotype (SASP) factors through the suppression of the p53-p21-retinoblastoma protein 1 (Rb1) axis.

Primary oocytes with cellular senescence features are involved in ovarian aging in mice

In mammalian females, quiescent primordial follicles serve as the ovarian reserve and sustain normal ovarian function and egg production via folliculogenesis. The loss of primordial follicles causes ovarian aging. Cellular senescence, characterized by cell cycle arrest and production of the senescence-associated secretory phenotype (SASP), is associated with tissue aging. In the present study, we report that some quiescent primary oocytes in primordial follicles become senescent in adult mouse ovaries. The senescent primary oocytes share senescence markers characterized in senescent somatic cells. The senescent primary oocytes were observed in young adult mouse ovaries, remained at approximately 15% of the total primary oocytes during ovarian aging from 6 to 12 months, and accumulated in aged ovaries. Administration of a senolytic drug ABT263 to 3-month-old mice reduced the percentage of senescent primary oocytes and the transcription of the SASP factors in the ovary, in addition, led to increased numbers of primordial and total follicles and a higher rate of oocyte maturation. Our study provides experimental evidence that primary oocytes, a germline cell type that is arrested in meiosis, become senescent in adult mouse ovaries and that senescent cell clearance reduced primordial follicle loss and mitigated ovarian aging phenotypes.

The transcription factor PAX5 activates human LINE1 retrotransposons to induce cellular senescence

As a hallmark of senescent cells, the derepression of Long Interspersed Elements 1 (LINE1) transcription results in accumulated LINE1 cDNA, which triggers the secretion of the senescence-associated secretory phenotype (SASP) and paracrine senescence in a cGAS-STING pathway-dependent manner. However, transcription factors that govern senescence-associated LINE1 reactivation remain ill-defined. Here, we predict several transcription factors that bind to human LINE1 elements to regulate their transcription by analyzing the conserved binding motifs in the 5’-untranslated regions (UTR) of the commonly upregulated LINE1 elements in different types of senescent cells. Further analysis reveals that PAX5 directly binds to LINE1 5’-UTR and the binding is enhanced in senescent cells. The enrichment of PAX5 at the 5’-UTR promotes cellular senescence and SASP by activating LINE1. We also demonstrate that the longevity gene SIRT6 suppresses PAX5 transcription by directly binding to the PAX5 promoter, and overexpressing PAX5 abrogates the suppressive effect of SIRT6 on stress-dependent cellular senescence. Our work suggests that PAX5 could serve as a potential target for drug development aiming to suppress LINE1 activation and treat senescence-associated diseases.

Chronic inflammation with microglia senescence at basal forebrain: impact on cholinergic deficit in Alzheimer's brain haemodynamics.

Cholinergic innervation in the brain is involved in modulating neurovascular function including cerebral blood flow haemodynamics in response to neuronal activity. Cholinergic deficit is associated with pathophysiology in Alzheimer's disease, albeit the aetiology remains to be clarified. In the current study, neocortex cerebral blood flow response to acetylcholine was evaluated by Laser-Doppler Flowmetry (LDF) in 3xTgAD Alzheimer's disease model) and wild-type mice of two age groups. The peak of cerebral blood flow to acetylcholine (i.v.) from baseline levels (% ΔrCBF) was higher in young 3xTgAD versus in wild-type mice (48.35; 95% CI:27.03-69.67 versus 22.70; CI:15.5-29.91, P < 0.05); this was reversed in old 3xTgAD mice (21.44; CI:2.52-40.35 versus 23.25; CI:23.25-39). Choline acetyltransferase protein was reduced in neocortex, while cerebrovascular reactivity to acetylcholine was preserved in young 3×TgAD mice. This suggests endogenous acetylcholine deficit and possible cholinergic denervation from selected cholinergic nuclei within the basal forebrain. The early deposition of tauopathy moieties (mutant hTau and pTau181) and its coincidence in cholinergic cell clusters (occasionaly), were observed at the basal forebrain of 3xTgAD mice including substantia innominate, nucleus Basalis of Meynert and nucleus of horizontal limb diagonal band of Broca. A prominent feature was microglia interacting tauopathy and demonstrated a variety of morphology changes particularly when located in proximity to tauopathy. The microglia ramified phenotype was reduced as evaluated by the ramification index and Fractal analysis. Increased microglia senescence, identified as SASP (senescence-associated secretory phenotype), was colocalization with p16Ink4ɑ, a marker of irreversible cell-cycle arrest in old 3xTgAD versus wild-type mice (P = 0.001). The p16Ink4ɑ was also observed in neuronal cells bearing tauopathy within the basal forebrain of 3xTgAD mice. TNF-ɑ, the pro-inflammatory cytokine elevated persistently in microglia (Pearson's correlation coefficient = 0.62) and the loss of cholinergic cells in vulnerable basal forebrain environment, was indicated by image analysis in 3xTgAD mice, which linked to the cholinergic deficits in neocortex rCBF haemodynamics. Our study revealed the early change of CBF haemodynamics to acetylcholine in 3xTgAD model. As a major effector of brain innate immune activation, microglia SASP with age-related disease progression is indicative of immune cell senescence, which contributes to chronic inflammation and cholinergic deficits at the basal forebrain. Targeting neuroinflammation and senescence may mitigate cholinergic pathophysiology in Alzheimer's disease.

Regulation of cell function and identity by cellular senescence.

During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.

Depletion of SASP senescent cardiomyocytes with senolytic drugs confers therapeutic effects in doxorubicin-related cardiotoxicity.

Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox-induced cardiotoxicity, but whether diminishing thesesenescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence-associated secretory phenotype (SASP) that affects healthy non-senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl-2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ-H2A.X was used to assess the SASP in the Dox-treated heart. To explore the molecular mechanisms involved, the Bcl-2 inhibitor ABT-199 was employed to eliminate SASP senescent cardiomyocytes. We show that the cardiomyocytes acquire a SASP during Dox treatment. The senescent cardiomyocytes upregulated Bcl-2, although treatment of mice with ABT-199 selectively eliminated SASP senescent cardiomyocytes involved in Dox-induced cardiotoxicity, thus leading to partial alleviation of Dox-induced cardiotoxicity. Moreover, we concluded that SASP factors secreted by senescent cardiomyocytes induced by Dox renders otherwise healthy cardiomyocytes senescent through exosome delivery. Our findings suggest that SASP senescent cardiomyocytes are a significant component of the pathogenesis of Dox-dependent cardiotoxicity and indicate that targeting the clearance of SASP senescent cardiomyocytes could be a new therapeutic approach for Dox-induced cardiac injury.

The miR-30-5p/TIA-1 axis directs cellular senescence by regulating mitochondrial dynamics

Senescent cells exhibit a diverse spectrum of changes in their morphology, proliferative capacity, senescence-associated secretory phenotype (SASP) production, and mitochondrial homeostasis. These cells often manifest with elongated mitochondria, a hallmark of cellular senescence. However, the precise regulatory mechanisms orchestrating this phenomenon remain predominantly unexplored. In this study, we provide compelling evidence for decreases in TIA-1, a pivotal regulator of mitochondrial dynamics, in models of both replicative senescence and ionizing radiation (IR)-induced senescence. The downregulation of TIA-1 was determined to trigger mitochondrial elongation and enhance the expression of senescence-associated β-galactosidase, a marker of cellular senescence, in human foreskin fibroblast HS27 cells and human keratinocyte HaCaT cells. Conversely, the overexpression of TIA-1 mitigated IR-induced cellular senescence. Notably, we identified the miR-30-5p family as a novel factor regulating TIA-1 expression. Augmented expression of the miR-30-5p family was responsible for driving mitochondrial elongation and promoting cellular senescence in response to IR. Taken together, our findings underscore the significance of the miR-30-5p/TIA-1 axis in governing mitochondrial dynamics and cellular senescence.

METTL3 Promotes Nucleus Pulposus Cell Senescence in Intervertebral Disc Degeneration by Regulating TLR2 m6A Methylation and Gut Microbiota.

Nucleus pulposus cell (NPC) senescence in intervertebral disc (IVD) tissue is the major pathological cause of intervertebral disc degeneration (IDD). N6-methyladenosine (m6A) methylation and gut microbiota play important roles in the progression of IDD. This study investigated whether methyltransferase-like 3 (METTL3) regulates TLR2 m6A modification and gut microbiota to influence NPC senescence. An IDD rat model was established by lumbar IVD puncture and NPCs were challenged with IL-1β to mimic IVD injury. IDD rats and IL-1β-exposed NPCs were treated with METTL3-interfering lentivirus and the TLR2 agonist Pam3CSK4. Compositional changes in the rat gut microbiota were analyzed and fecal microbiota transplantation procedures were used. NPC senescence, cell cycle, and the expression of senescence-associated secretory phenotype (SASP) factors were assessed. The m6A enrichment of TLR2 and the binding of IGF2BP1 to TLR2 mRNA were examined. METTL3 and TLR2 were highly expressed in IDD rats. METTL3 silencing attenuated senescent phenotypes and reduced secretion of SASP factors. Pam3CSK4 reversed the beneficial effects of METTL3 silencing on NPC senescence and IVD injury. METTL3 stabilized TLR2 mRNA in an IGF2BP1-dependent manner. METTL3 silencing restored specific gut microbiota levels in IDD rats, which was further reversed by administration of Pam3CSK4. Fecal microbiota from METTL3 silenced IDD rats altered the pathological phenotypes of IDD rats. These results demonstrate the beneficial effects of METTL3 silencing on NPC senescence and amelioration of IVD injury, involving modulation of TLR2 m6A modification and gut microbiota. These findings support METTL3 silencing as a potential therapeutic target for IDD.

K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins

The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.

Bidirectional Two-Sample Mendelian Randomization Study of Immunoglobulin G N-Glycosylation and Senescence-Associated Secretory Phenotype.

Observational studies revealed changes in Immunoglobulin G (IgG) N-glycosylation during the aging process. However, it lacks causal insights and remains unclear in which direction causal relationships exist. The two-sample bidirectional Mendelian randomization (MR) design was adopted to explore causal associations between IgG N-glycans and the senescence-associated secretory phenotype (SASP). Inverse variance weighted (IVW) and Wald ratio methods were used as the main analyses, supplemented by sensitivity analyses. Forward MR analyses revealed causal associations between the glycan peak (GP) and SASP, including GP6 (odds ratio [OR] = 0.428, 95% confidence interval [CI] = 0.189-0.969) and GP17 (OR = 0.709, 95%CI = 0.504-0.995) with growth/differentiation factor 15 (GDF15), GP19 with an advanced glycosylation end-product-specific receptor (RAGE) (OR = 2.142, 95% CI = 1.384-3.316), and GP15 with matrix metalloproteinase 2 (MMP2) (OR = 1.136, 95% CI =1.008-1.282). The reverse MR indicated that genetic liability to RAGE was associated with increased levels of GP17 (OR = 1.125, 95% CI = 1.003-1.261) and GP24 (OR = 1.222, 95% CI = 1.046-1.428), while pulmonary and activation-regulated chemokines (PARC) exhibited causal associations with GP10 (OR = 1.269, 95% CI = 1.048-1.537) and GP15 (OR = 1.297, 95% CI = 1.072-1.570). The findings provided suggested evidence on the bidirectional causality between IgG N-glycans and SASP, which might reveal potential regulatory mechanisms.

Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants.

This comprehensive review navigates the complex relationship between cellular aging, senescence, and cancer, unraveling the determinants of cellular fate. Beginning with an overview of cellular aging's significance in cancer, the review explores processes, changes, and molecular pathways influencing senescence. The review explores senescence as a dual mechanism in cancer, acting as a suppressor and contributor, focusing on its impact on therapy response. This review highlights opportunities for cancer therapies that target cellular senescence. The review further examines the senescence-associated secretory phenotype and strategies to modulate cellular aging to influence tumor behavior. Additionally, the review highlights the mechanisms of senescence escape in aging and cancer cells, emphasizing their impact on cancer prognosis and resistance to therapy. The article addresses current advances, unexplored aspects, and future perspectives in understanding cellular aging and senescence in cancer.

Apoptosis signal-regulating kinase 1 promotes inflammation in senescence and aging

Cellular senescence is a stress-induced, permanent cell cycle arrest involved in tumor suppression and aging. Senescent cells secrete bioactive molecules such as pro-inflammatory cytokines and chemokines. This senescence-associated secretory phenotype (SASP) has been implicated in immune-mediated elimination of senescent cells and age-associated chronic inflammation. However, the mechanisms regulating the SASP are incompletely understood. Here, we show that the stress-responsive kinase apoptosis signal-regulating kinase 1 (ASK1) promotes inflammation in senescence and aging. ASK1 is activated during senescence and increases the expression of pro-inflammatory cytokines and chemokines by activating p38, a kinase critical for the SASP. ASK1-deficient mice show impaired elimination of oncogene-induced senescent cells and an increased rate of tumorigenesis. Furthermore, ASK1 deficiency prevents age-associated p38 activation and inflammation and attenuates glomerulosclerosis. Our results suggest that ASK1 is a driver of the SASP and age-associated chronic inflammation and represents a potential therapeutic target for age-related diseases.