Cellular Senescence Research Articles

A cause-effect relationship between uterine diseases and breast cancer: A bidirectional Mendelian randomization study

ObjectiveTo explore the cause-effect relationship between uterine diseases (UDs) and breast cancer (BC) and underlying mechanism of the cause-effect relationship, enhance understanding of the association between BC and UDs. MethodsA two-sample bidirectional Mendelian randomization (MR) analysis was conducted. We obtained summary statistics data from GWAS for BC, endometriosis, endometrial cancer (EC), uterine leiomyoma (UL), uterine polyps (UP), and cervical cancer (CC). Independent SNPs were selected as instrumental variables (IVs) for each disease. The inverse variance weighted (IVW) method was primary used for estimating the causal association between UDs and BC. To further evaluate the consistency and dependability of the results, we also utilized the weighted median, weighted mode, simple mode, and MR-Egger methods, along with sensitivity analyses. Furthermore, a supplementary analysis focusing on the variants linked to BC and UDs was conducted. This involved identifying corresponding genes and subsequently performing KEGG/GO analyses to investigate potential molecular mechanisms. ResultsThe results indicated significant associations between genetic susceptibility to endometriosis, EC, and UL with BC risk. The odds ratios (ORs) were as follows: endometriosis at 0.963 (95 % CI, 0.942–0.984; p = 7.11e-5), EC at 1.056 (95 % CI, 1.033–1.081; p = 2.39e-6), and UL at 1.027 (95 % CI, 1.006–1.048; p = 0.010). Conversely, the predisposition to BC inferred from genetic factors was markedly correlated with an elevated risk of EC indicated by an OR of 1.066 (95 % CI, 1.019–1.116; p = 0.006), and was correlated with UP risk (OR, 1.001,95 % CI, 1.000–1.002; p = 0.001).Sensitivity analyses provided weak evidence for these effects, suggesting that the study's outcomes are consistent and trustworthy. Further analysis of the genetic variants associated with BC, and these related genes are enriched in Cellular senescence, GnRH secretion, Phosphatidylinositol signaling system, and so on. ConclusionThis study corroborates the existence of a reciprocal causal relationship between BC and EC, as well as highlighting the substantial correlations between a genetic susceptibility to UL and endometriosis with BC. BC may exert their influence on EC and UP through Cellular senescence, GnRH secretion, and other pathways. These discoveries offer fresh perspectives on the genetic pathogenesis of BC and UDs, and can guide future experimental studies. Additionally, they lay down a groundwork for the development of tailored preventative and therapeutic strategies moving forward.

Abstract P162: Senolytic Treatment Attenuates Palmitic Acid-Induced Microglial Activation: Therapeutic Implications for Obesity-Induced Sympathoexcitation

Objective: Microglial dysfunction has been previously implicated in the pathogenesis of obesity-induced neuroinflammation and sympathoexcitation, both of which significantly increase the risk for cardiovascular diseases. However, the mechanisms underlying obesity-induced glial dysfunction are not clear. In the current study, we investigated the role of cellular senescence that culminates in irreversible proliferative arrest and inflammatory phenotype, in obesity-induced glial dysfunction. Methods: Human microglial cells (n=6 wells/group/expt) were treated with 35 μM palmitic acid (PA) for 24 hours to mimic an obese microenvironment. Subsequently, the cells were treated with senolytic drugs, Dasatinib (250 nM) and Quercetin (100 μM) (D+Q) for 48 hours after PA treatment. Real-time PCR, lipid profiling, and senescence-associated beta-galactosidase (SAβGAL) were performed to evaluate changes in microglia to PA and D+Q treatment. Immunofluorescence staining evaluated microglial activation and vesicular glutamate transporter (VGLUT1) expression. Results: Microglial activation was confirmed by upregulation of Iba1 and CD11b in PA-treated cells. Significant upregulation of senescence genes (p16 and p21), senescence-associated secretory phenotypes (SASPs such as TNFα, MMP3), and SAβGAL staining in the PA treatment group indicating cellular senescence. PA treatment, significantly upregulated glutamate transporters EAAT1 and EAAT2 suggesting a potential adaptive response to counteract excitotoxicity. Bodipy and Oil-Red-O (ORO) staining revealed increased lipid accumulation in PA group, indicating altered lipid metabolism. D+Q group showed a significant decrease in senescence markers (p16 and p21) and SAβGAL staining, along with a reduction in lipid markers such as perilipin 1 and 2, and decreases in activated microglial markers IBA1 and CD11b. A significant decrease in EAAT1 expression was also observed. Immunofluorescence showed a significant decrease in VGLUT1 expression in the D+Q compared to PA-treated group. Conclusions: The findings suggest that palmitic acid-induced changes in human microglial cells can contribute to oxidative stress, cellular senescence, and alterations in glutamate clearance pathway potentially leading to sympathetic overactivity in obesity. Senolytic treatment (D+Q) mitigated PA-induced lipid accumulation and inflammatory changes in the microglial cells indicating a promising therapeutic strategy for managing sympathoexcitation in obesity.

M2 macrophage-derived exosomes promote tendon-to-bone healing by alleviating cellular senescence in aged rats

To explore the potential of M2 macrophage-derived exosomes (M2-Exos) in enhancing tendon-to-bone healing in aged rats by mitigating cellular senescence of bone marrow-derived stem cells (BMSCs). In vitro, effects of M2-Exos on alleviating cellular senescence and improving chondrogenic potential of senescent BMSCs were evaluated. Twenty-four young and forty-eight aged rats with chronic rotator cuff tear (RCT) were repaired and assigned into three groups: young group (young rats injected with fibrin at the enthesis), aged group (aged rats injected with fibrin at the enthesis), and aged + M2-Exos group (aged rats injected with fibrin containing M2-Exos at the enthesis). Six and twelve weeks after repair, enthesis regeneration was evaluated. Proteomic analysis was conducted to explore the mechanism through which M2-Exos mitigated cellular senescence. In senescent BMSCs treated with M2-Exos, there was a reduction in senescence biomarkers including senescence-associated β-galactosidase, p53, p21 and senescence associated secretory phenotype (P < .001). M2-Exos also enhanced chondrogenic potential of senescent BMSCs, reflected in higher Bern score (P < .001) and increased expression of Sox9 (P = .013), Col2a1 (P < .001), and Acan (P < .001). Histologically, aged rats treated with M2-Exos demonstrated significantly higher histological scores (P < .001 at both 6 and 12 weeks) and increased fibrocartilage regeneration at the enthesis. Biomechanically, these rats exhibited greater failure load, stiffness, and stress (all P < .001) at 12 weeks. Mechanistically, proteomic analysis suggested that M2-Exos might alleviate cellular senescence by potentially regulating DNA replication and repair. M2-Exos can significantly alleviate BMSC senescence and thereby enhance tendon-to-bone healing in an aged rat RCT model. This study suggests the potential utility of M2-Exos as a therapy for RCT in the older population.

The DNA double-strand break repair proteins γH2AX, RAD51, BRCA1, RPA70, KU80, and XRCC4 exhibit follicle-specific expression differences in the postnatal mouse ovaries from early to older ages.

Ovarian aging is closely related to a decrease in follicular reserve and oocyte quality. The precise molecular mechanisms underlying these reductions have yet to be fully elucidated. Herein, we examine spatiotemporal distribution of key proteins responsible for DNA double-strand break (DSB) repair in ovaries from early to older ages. Functional studies have shown that the γH2AX, RAD51, BRCA1, and RPA70 proteins play indispensable roles in HR-based repair pathway, while the KU80 and XRCC4 proteins are essential for successfully operating cNHEJ pathway. Female Balb/C mice were divided into five groups as follows: Prepuberty (3weeks old; n = 6), puberty (7weeks old; n = 7), postpuberty (18weeks old; n = 7), early aged (52weeks old; n = 7), and late aged (60weeks old; n = 7). The expression of DSB repair proteins, cellular senescence (β-GAL) and apoptosis (cCASP3) markers was evaluated in the ovaries using immunohistochemistry. β-GAL and cCASP3 levels progressively increased from prepuberty to aged groups (P < 0.05). Notably, γH2AX levels varied in preantral and antral follicles among the groups (P < 0.05). In aged groups, RAD51, BRCA1, KU80, and XRCC4 levels increased (P < 0.05), while RPA70 levels decreased (P < 0.05) compared to the other groups. The observed alterations were primarily attributed to altered expression in oocytes and granulosa cells of the follicles and other ovarian cells. As a result, the findings indicate that these DSB repair proteins may play a role in the repair processes and even other related cellular events in ovarian cells from early to older ages.

Exploring prognostic implications of miRNA signatures and telomere maintenance genes in kidney cancer

Kidney cancer, particularly clear cell renal cell carcinoma (KIRC), presents significant challenges in disease-specific survival. This study investigates the prognostic potential of microRNAs (miRNAs) in kidney cancers, including KIRC and kidney papillary cell carcinoma (KIRP), focusing on their interplay with telomere maintenance genes. Utilizing data from The Cancer Genome Atlas, miRNA expression profiles of 166 KIRC and 168 KIRP patients were analyzed. An evolutionary learning-based Kidney Survival Estimator identified robust miRNA signatures predictive of 5-year survival for both cancer types. For KIRC, a 37-miRNA signature showed a correlation coefficient (R) of 0.82 and mean absolute error (MAE) of 0.65 years. Similarly, for KIRP, a 23-miRNA signature exhibited an R of 0.82 and MAE of 0.64 years, demonstrating comparable predictive accuracy. These signatures also displayed diagnostic potential with Receiver Operating Characteristic curve values between 0.70 and 0.94. Bioinformatics analysis revealed targeting of key telomere-associated genes such as TERT, DKC1, CTC1, and RTEL1 by these miRNAs, implicating crucial pathways such as cellular senescence and proteoglycans in cancer. This study highlights the significant link between miRNAs and telomere genes in kidney cancer survival, offering insights for therapeutic targets and improved prognostic markers.

The Rubicon-WIPI axis regulates exosome biogenesis during ageing.

Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.

Characterization of the Prognosis and Tumor Microenvironment of Cellular Senescence-related Genes through scRNA-seq and Bulk RNA-seq Analysis in GC.

Cellular senescence (CS) is thought to be the primary cause of cancer development and progression. This study aimed to investigate the prognostic role and molecular subtypes of CS-associated genes in gastric cancer (GC). The CellAge database was utilized to acquire CS-related genes. Expression data and clinical information of GC patients were obtained from The Cancer Genome Atlas (TCGA) database. Patients were then grouped into distinct subtypes using the "Consesus- ClusterPlus" R package based on CS-related genes. An in-depth analysis was conducted to assess the gene expression, molecular function, prognosis, gene mutation, immune infiltration, and drug resistance of each subtype. In addition, a CS-associated risk model was developed based on Cox regression analysis. The nomogram, constructed on the basis of the risk score and clinical factors, was formulated to improve the clinical application of GC patients. Finally, several candidate drugs were screened based on the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset. According to the cluster result, patients were categorized into two molecular subtypes (C1 and C2). The two subtypes revealed distinct expression levels, overall survival (OS) and clinical presentations, mutation profiles, tumor microenvironment (TME), and drug resistance. A risk model was developed by selecting eight genes from the differential expression genes (DEGs) between two molecular subtypes. Patients with GC were categorized into two risk groups, with the high-risk group exhibiting a poor prognosis, a higher TME level, and increased expression of immune checkpoints. Function enrichment results suggested that genes were enriched in DNA repaired pathway in the low-risk group. Moreover, the Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that immunotherapy is likely to be more beneficial for patients in the low-risk group. Drug analysis results revealed that several drugs, including ML210, ML162, dasatinib, idronoxil, and temsirolimus, may contribute to the treatment of GC patients in the high-risk group. Moreover, the risk model genes presented a distinct expression in single-cell levels in the GSE150290 dataset. The two molecular subtypes, with their own individual OS rate, expression patterns, and immune infiltration, lay the foundation for further exploration into the GC molecular mechanism. The eight gene signatures could effectively predict the GC prognosis and can serve as reliable markers for GC patients.

Hydrogen sulfide mitigates mitochondrial dysfunction and cellular senescence in diabetic patients: Potential therapeutic applications.

Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca2+) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H2S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.

Antioxidant activity, physico-chemical properties, and bioactive compounds of Nigella sativa seeds and oil impacted by microwave processing technique

Strongly anti-oxidant and medicinal, Nigella sativa L (NS) is utilized in conventional medicine to address a range of illnesses, including gastrointestinal, inflammatory and rheumatic illnesses. This study was carried out to investigate the effects of microwave processing on the physico-chemical properties of Moroccan-grown Nigella sativa seeds and oils, as well as to investigate the antioxidant qualities of black cumin oils under conditions of accelerated oxidation. The study's specific goal was to ascertain the effects of varying microwave power levels (500 and 750 W) and roasting times (5, 10, and 15 min) on the black cumin oils' quality indices, fatty acid and sterol content, carotenoid and chlorophyll levels, mineral profile, tocopherol amount, and overall antioxidant activity. To this end, the seeds of black cumin were roasted at two power levels (500 and 750 W) and for three different periods (5, 10, and 15 min) in a microwave oven. The obtained results show that the duration and the processing power did not significantly influence the amount of sterols and fatty acids. In contrast, the quality indices, physico-chemical properties, carotenoid and chlorophyll contents, mineral profile, and tocopherol amount were influenced by the microwave processing. A significant decline in the antioxidant activity was recorded from 45.01 ± 0.81 % (unroasted cumin seeds) to 4.32 ± 0.91 % (750 W/5 min). Based on these findings, the black cumin oil preparations should be handled carefully and the oil must be protected once extracted. The stability and preservation of antioxidants are crucial steps against pro-oxidant and inflammatory conditions that could favour cellular senescence and accelerate aging processes.

53123 Role of Cellular Senescence in Human Diabetic Foot Ulcers

53123 Role of Cellular Senescence in Human Diabetic Foot Ulcers

Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities

Deficiency of adenosine deaminase 2 (DADA2) is a complex monogenic disease caused by recessive mutations in the ADA2 gene. DADA2 exhibits a broad clinical spectrum encompassing vasculitis, immunodeficiency, and hematological abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored. This study comprehensively examined the BM and peripheral blood of pediatric and adult patients with DADA2 presenting rheumatologic/immunologic symptoms or severe hematological manifestations. Immunophenotyping of hematopoietic stem cells (HSCs), progenitor cells, and mature cell populations was performed for 18 patients with DADA2. We also conducted a characterization of the mesenchymal stromal cells (MSCs). Our study revealed a significant decrease in primitive HSCs and progenitor cells, alongside their reduced clonogenic capacity and multilineage differentiation potential. These BM defects were evident in patients with both severe and non-severe hematological manifestations, including pediatric patients, demonstrating that BM disruption can emerge silently and early on, even in patients who do not show obvious hematological symptoms. Beyond stem cells, there was a reduction in mature cell populations in the BM and peripheral blood, affecting myeloid, erythroid, and lymphoid populations. Furthermore, BM MSCs in DADA2 patients exhibited reduced clonogenic and proliferation capabilities and were more prone to undergo cellular senescence marked by elevated DNA damage. Our exploration into the BM landscape of DADA2 patients sheds light on the critical hematological dimension of the disease and emphasizes the importance of vigilant monitoring, even in the case of subclinical presentation.

Aging-Associated Molecular Changes in Human Alveolar Type I Cells.

Human alveolar type I (AT1) cells are specialized epithelial cells that line the alveoli in the lungs where gas exchange occurs. The primary function of AT1 cells is not only to facilitate efficient gas exchange between the air and the blood in the lungs, but also to contribute to the structural integrity of the alveoli to maintain lung function and homeostasis. Aging has notable effects on the structure, function, and regenerative capacity of human AT1 cells. However, our understanding of the molecular mechanisms driving these age-related changes in AT1 cells remains limited. Leveraging a recent single-cell transcriptomics dataset we generated on healthy human lungs, we identified a series of significant molecular alterations in AT1 cells from aged lungs. Notably, the aged AT1 cells exhibited increased cellular senescence and chemokine gene expression, alongside diminished epithelial features such as decreases in cell junctions, endocytosis, and pulmonary matrisome gene expression. Gene set analyses also indicated that aged AT1 cells were resistant to apoptosis, a crucial mechanism for turnover and renewal of AT1 cells, thereby ensuring alveolar integrity and function. Further research on these alterations is imperative to fully elucidate the impact on AT1 cells and is indispensable for developing effective therapies to preserve lung function and promote healthy aging.

Abstract 76: CASC15 lncRNA as a Mediator of Vascular Senescence in the Renin-Angiotensin System

The renin-angiotensin system (RAS) regulates vascular function and maintains blood pressure homeostasis. Angiotensin-II (Ang-II) and angiotensin-1-7 (Ang-1-7) have opposing effects on vascular health. Ang-II promotes vascular senescence and pathophysiological remodeling by inducing oxidative stress, inflammation, vascular hypertrophy, and endothelial dysfunction. In contrast, Ang-1-7, known for its vasodilatory, anti-inflammatory, and antioxidative properties, counteracts these detrimental effects, enhancing endothelial function, reducing oxidative stress, and inhibiting inflammation. Our laboratory has identified the long non-coding RNA CASC15 as a critical regulatory element within the RAS. CASC15 expression is significantly repressed by Ang-II in aortic vascular smooth muscle cells (SMCs), showing a 59.25% decrease compared to the vehicle control (n=10, p=0.000333). Loss of CASC15 induces cellular senescence, increasing senescent cells from a mean of 14.09% (control inhibitor, n=9, SEM=4.824) to 57.79% (CASC15 inhibitor, n=9, SEM=6.420, p&lt;0.0001), and leads to vascular hypertrophy, with cell area increasing from a mean of 46.89% (control inhibitor, n=8, SEM=9.229) to 221.2% (CASC15 inhibitor, n=9, SEM=67.53, p=0.0300). We hypothesize that CASC15 repression by Ang-II (1 µM) contributes to vascular senescence and increased DNA damage, while Ang-1-7 (1 µM) preserves CASC15 expression and mitigates these effects. Pro-senescent stressors like hydrogen peroxide and doxorubicin also repress CASC15 expression in SMCs. Using RT-qPCR, we observed decreases in CASC15 expression by 29.56% (hydrogen peroxide vs. vehicle, n=4, p=0.0790) and 44.09% (doxorubicin vs. vehicle, n=3, p=0.0733). Ang-1-7 alone did not significantly change CASC15 expression, but combined with Ang-II, it showed potential recovery from 40% repression to 94% recovery. Further research is needed. Immunofluorescence against gamma-H2AX revealed increased DNA damage in SMCs lacking CASC15, with positive foci increasing from 26.27% (control inhibitor, n=4, SEM=1.459) to 63.71% (CASC15 inhibitor, n=4, SEM=1.806, p=0.0009). In conclusion, CASC15 is a crucial regulator within the RAS. Its repression by Ang-II promotes vascular senescence, hypertrophy, and DNA damage, effects countered by Ang-1-7. Targeting CASC15 could offer new strategies for mitigating vascular aging and improving vascular health, particularly in chronic kidney disease.

Curcumin Inhibits TORC1 and Prolongs the Lifespan of Cells with Mitochondrial Dysfunction.

Aging is an inevitable biological process that contributes to the onset of age-related diseases, often as a result of mitochondrial dysfunction. Understanding the mechanisms behind aging is crucial for developing therapeutic interventions. This study investigates the effects of curcumin on postmitotic cellular lifespan (PoMiCL) during chronological aging in yeast, a widely used model for human postmitotic cellular aging. Our findings reveal that curcumin significantly prolongs the PoMiCL of wildtype yeast cells, with the most pronounced effects observed at lower concentrations, indicating a hormetic response. Importantly, curcumin also extends the lifespan of postmitotic cells with mitochondrial deficiencies, although the hormetic effect is absent in these defective cells. Mechanistically, curcumin inhibits TORC1 activity, enhances ATP levels, and induces oxidative stress. These results suggest that curcumin has the potential to modulate aging and offer therapeutic insights into age-related diseases, highlighting the importance of context in its effects.

406.1: YTHDF3 regulates IGF1R to aggravate pancreatic islets cellular aging and dysfunction.

406.1: YTHDF3 regulates IGF1R to aggravate pancreatic islets cellular aging and dysfunction.

Piceatannol reduces radiation-induced DNA double-strand breaks by suppressing superoxide production and enhancing ATM-dependent repair efficiency

In contemporary society, humans are susceptible to various radiation-borne hazards, including exposure to therapeutic modalities using low-linear energy transfer (low-LET) radiations (X-rays and γ-rays), natural high-LET radiation sourced from cosmic rays, as well as nuclear accidents such as the Fukushima Daiichi Nuclear Power Plant incident. Therefore, this threat incites an imminent necessity to develop novel radioprotective agents against a wide range of LET radiation and elucidate the underlying molecular mechanisms. This study aimed at assessing the radioprotectivity of Piceatannol (PIC), a potent antioxidant polyphenol present in abundance in passion fruit, by investigating its effects on radiation-induced reactive oxygen species (ROS) production and the consequent DNA double-strand break (DSB) capacity and cellular senescence. Specifically, total ROS was evaluated by DCFDA staining, mitochondrial superoxide by MitoSOX staining, DSB by γ-H2AX immunostaining, and cellular senescence by Senescence-associated-β-galactosidase staining.The results demonstrated that PIC administration prior to exposure to both X-ray and high-LET radiation impeded radiation-induced DSB by suppressing ROS production. Interestingly, post-irradiation PIC treatment did not alter ROS levels but enhanced the efficiency of Ataxia Telangiectasia Mutated (ATM)-mediated DSB repair. Additionally, post-irradiation PIC treatment diminished senescence-associated beta-galactosidase levels, indicating that it hinders cellular senescence.Conclusively, PIC exerts radioprotective effects against a wide range of LET radiation. The study findings validate the potential application of PIC not only as a radical scavenger but also as a novel DSB repair-activating radioprotective agent.

Transcriptomic analysis reveals interactive effects of polyvinyl chloride microplastics and cadmium on Mytilus galloprovincialis: Insights into non-coding RNA responses and environmental implications

Despite increasing concerns regarding the interactions of microplastic and heavy metal pollution, there is limited knowledge on the molecular responses of marine organisms to these stressors. In this study, we used whole-transcriptome sequencing to investigate the molecular responses of the ecologically and economically important bivalve Mytilus galloprovincialis to individual and combined exposures of environmentally relevant concentrations of PVC microplastics and cadmium (Cd). Our results revealed distinct transcriptional changes in M. galloprovincialis, with significant overlap in the differentially expressed genes between the individual and combined exposure groups. Genes involved in cellular senescence, oxidative stress, and galactose metabolism were differentially expressed. Additionally, key signaling pathways related to apoptosis and drug metabolism were significantly modulated. Notably, the interaction of PVC microplastics and Cd resulted in differential expression of genes involved in drug metabolism and longevity regulating compared to single exposures. This suggests that the interaction between these two stressors may have amplified effects on mussel health. Overall, this comprehensive transcriptomic analysis provides valuable insights into the adaptive and detrimental responses of M. galloprovincialis to PVC microplastics and Cd in the environment.

Integrating Machine Learning with Multi-Omics Technologies in Geroscience: Towards Personalized Medicine.

Aging is a fundamental biological process characterized by a progressive decline in physiological functions and an increased susceptibility to diseases. Understanding aging at the molecular level is crucial for developing interventions that could delay or reverse its effects. This review explores the integration of machine learning (ML) with multi-omics technologies-including genomics, transcriptomics, epigenomics, proteomics, and metabolomics-in studying the molecular hallmarks of aging to develop personalized medicine interventions. These hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Using ML to analyze big and complex datasets helps uncover detailed molecular interactions and pathways that play a role in aging. The advances of ML can facilitate the discovery of biomarkers and therapeutic targets, offering insights into personalized anti-aging strategies. With these developments, the future points toward a better understanding of the aging process, aiming ultimately to promote healthy aging and extend life expectancy.

Mendelian randomization reveals potential causal relationships between cellular senescence-related genes and multiple cancer risks

Cellular senescence is widely acknowledged as having strong associations with cancer. However, the intricate relationships between cellular senescence-related (CSR) genes and cancer risk remain poorly explored, with insights on causality remaining elusive. In this study, Mendelian Randomization (MR) analyses were used to draw causal inferences from 866 CSR genes as exposures and summary statistics for 18 common cancers as outcomes. We focused on genetic variants affecting gene expression, DNA methylation, and protein expression quantitative trait loci (cis-eQTL, cis-mQTL, and cis-pQTL, respectively), which were strongly linked to CSR genes alterations. Variants were selected as instrumental variables (IVs) and analyzed for causality with cancer using both summary-data-based MR (SMR) and two-sample MR (TSMR) approaches. Bayesian colocalization was used to unravel potential regulatory mechanisms underpinning risk variants in cancer, and further validate the robustness of MR results. We identified five CSR genes (CNOT6, DNMT3B, MAP2K1, TBPL1, and SREBF1), 18 DNA methylation genes, and LAYN protein expression which were all causally associated with different cancer types. Beyond causality, a comprehensive analysis of gene function, pathways, and druggability values was also conducted. These findings provide a robust foundation for unravelling CSR genes molecular mechanisms and promoting clinical drug development for cancer.

The interplay between aging and inflammation and its role in chronic disease development

This paper explores the complex relationship between aging and inflammation and its impact on the development of chronic diseases. Aging is an important contributor to elevated levels of inflammation, with mechanisms including changes in immune regulatory function, chronic low-grade inflammation, cellular aging and tissue damage, changes in gene expression, and increased oxidative stress. These inflammatory processes not only accelerate aging itself, but also promote the development of chronic diseases such as cardiovascular disease (CVD) and Alzheimers disease (AD). The article goes on to address other modern anti-inflammatory treatment approaches, such as biologics, JAK inhibitors, and nonsteroidal anti-inflammatory medications. These treatments help manage and mitigate aging-related pathologies by targeting key molecules and pathways of inflammation. A better comprehension of the relationship between inflammation and aging may serve as the foundation for the creation of novel therapeutic approaches that, in addition to reducing inflammatory reactions, may also prevent or slow the advancement of illnesses associated with age. This article aims to improve medical and scientific understanding of the relationship between inflammation and aging and to encourage the development and use of more potent therapies to lessen the burden of chronic illnesses and enhance the quality of life for the aged.