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Autophagy is a highly conserved 'self-digesting' mechanism used in eukaryotes to degrade and recycle cellular components by enclosing them in a double membrane compartment and delivering them to lytic organelles (lysosomes or vacuoles). Extensive studies in plants have revealed how autophagy is intricately linked to essential aspects of metabolism and growth, in both normal and stress conditions, including cellular and organelle homeostasis, nutrient recycling, development, responses to biotic and abiotic stresses, senescence and cell death. However, knowledge regarding autophagic processes in other photosynthetic organisms remains limited. In this review, we attempt to summarize the current understanding of autophagy in algae from a metabolic, molecular and evolutionary perspective. We focus on the composition and conservation of the autophagy molecular machinery in eukaryotes and discuss the role of autophagy in metabolic regulation, cellular homeostasis and stress adaptation in algae. This article is part of the theme issue 'The evolution of plant metabolism'. [ABSTRACT FROM AUTHOR]

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis. [Display omitted] • Cellular and molecular changes in the mammary gland with age • Midkine is a key driver of aging-related changes and mammary tumorigenesis • High midkine levels are associated with higher risk of breast cancer in younger women Yan et al. reveal age-related changes in the rat mammary gland, identifying a unique aging-associated luminal progenitor population. Midkine treatment mimics the effects of aging and promotes mammary tumorigenesis. Elevated midkine levels are associated with increased breast cancer risk in younger women highlighting its role in age-related tumor initiation. [ABSTRACT FROM AUTHOR]

While links between certain chronotypes and poorer health outcomes have been well established in previous studies, few studies have examined the relationship between chronotype and cellular aging. Using data from the California Teachers Study (CTS), the present study evaluates the relationship between cellular aging and chronobiology through an analysis of leukocyte telomere length (LTL) and chronotype among 817 predominantly postmenopausal women with no history of cancer and occupations not associated with night-shift work. Unconditional logistic regression models were run to estimate odds ratios (ORs) for each chronotype category, adjusted for age, ethnicity, and smoking status. Analyses were then stratified by potential modifiers to assess whether results varied among specific subgroups within the sample. Women who reported being current evening types and evening types from teen years to now were significantly less likely to have short LTL compared to women who reported being current morning types or morning types from teen years to now (OR = 0.72; 95% CI = 0.53-0.98; OR = 0.57; 95% CI = 0.39-0.84). Our results suggest that women with no history of cancer who identify as evening chronotypes may undergo decreased cellular aging compared to women in the same population who identify as morning types. Further studies on populations of postmenopausal women are warranted. [ABSTRACT FROM AUTHOR]

With increasing age, the reproductive performance of women and female animals declines. However, the molecular mechanisms underlying ovarian aging and age-related fertility decline remain unclear. Granulosa cells (GCs) are suspected to play an important role in reproductive aging, and their proliferation, apoptosis, and steroid hormone secretion are used to determine the fate of follicles and ovarian function. First, we found that the proliferative ability of GCs from the old mouse group (10-month-old) decreased compared with that from the young mouse group (6-week-old), and cell cycle arrest occurred in old mice. To investigate changes in protein modification, we compared the levels of protein acetylation in GCs from young and old mice. We found that the K1118, K1120, K1122, and K1124 sites of DNA methyltransferase 1 (DNMT1) were increasingly acetylated with age, resulting in a decrease in DNMT1 protein expression. Therefore, we performed whole-genome methylation sequencing of GCs in the two groups and found that the CG methylation levels in the old group were lower than those in the young group. Furthermore, the inhibition of DNMT1 expression in GCs resulted in cell cycle arrest. This study revealed the dynamics and importance of protein acetylation and DNA methylation in GCs during reproductive aging. The findings provide a theoretical basis for studying the mechanism of reproductive aging in mammals. [ABSTRACT FROM AUTHOR]

Direct cell-type conversion of somatic cells into cell types of interest has garnered great attention because it circumvents rejuvenation and preserves the hallmarks of cellular aging (unlike induced pluripotent stem cells [iPSCs]) and is more suitable for modeling diseases with strong age-related and epigenetic contributions. Fibroblasts are commonly used for direct conversion; however, obtaining these cells requires highly invasive skin biopsies. Urine-derived cells (UDCs) are an alternative cell source and can be obtained via noninvasive procedures. Herein, induced motor neuron-like cells (iMNs) were generated from UDCs by transducing transcription factors involved in motor neuron (MN) differentiation. iMNs exhibited neuronal morphology, upregulation of pan-neuron and MN markers, and MN functionality, including spontaneous calcium oscillation and bungarotoxin-positive neuromuscular junction formation, when co-cultured with myotubes. Altogether, the findings of this study indicated that UDCs can be converted to functional MNs. This technology may allow us to understand disease pathogenesis and progression and discover biomarkers and drugs for MN-related diseases at the population level. [ABSTRACT FROM AUTHOR]

Background: The telomere has long been regarded as a dependable biomarker for cellular senescence. The lung function can reflect the function and status of the lungs. As individuals age beyond adulthood, there is a gradual decline in lung function. However, the existence of a associated between leukocyte telomere length (LTL) and lung function remains uncertain. Methods: A two-sample Mendelian randomization (MR) analysis was used. The Single-nucleotide polymorphisms (SNPs) of LTL from the genome-wide association (GWAS) study were used as exposure instruments variable, and the lung function indicator including Forced expiratory volume in 1-s (FEV1), FEV1 Best measure, FEV1 predicted and Forced vital capacity (FVC) from the Neale Lab and MRC-IEU were used as outcomes. The associated between the exposures and outcomes was assessed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Sensitivity analysis was conducted using Cochran's Q-test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and Steriger test. Results: Using the IVW method, a significant association was identified between genetically determined telomere length extension and enhanced lung function in FEV1, with ukb-a-336 (P = 0.127, OR = 1.028,95CI% = 1.003–1.042) and ukb-b-19657 (P = 7.26E-05, OR = 1.051,95CI% = 1.025–1.077),in FEV1 predicted, ukb-a-234 (P = 0.013, OR = 1.029,95CI% = 1.003–1.042), ukb-b-8428 (P = 0.001, OR = 1.032,95CI% = 1.012–1.052), in FEV1 best measure, ukb-a-231 (P = 7.24E-05, OR = 1.050,95CI% = 1.025–1.075), ukb-b-11141 (P = 1.40E-09, OR = 1.067,95CI% = 1.045–1.090).The sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy.Meanwhile, the Steriger test results also indicate that the directionality between exposure and outcome is correct. Therefore, the results indicated robustness. Conclusion: There is a correlation between longer LTL and better lung function in the European dataset. [ABSTRACT FROM AUTHOR]

In preparation for a potential pregnancy, the endometrium of the uterus changes into a temporary structure called the decidua. Senescent decidual stromal cells (DSCs) are enriched in the decidua during decidualization, but the underlying mechanisms of this process remain unclear. Here, we performed single-cell RNA transcriptomics on ESCs and DSCs and found that cell senescence during decidualization is accompanied by increased levels of the branched-chain amino acid (BCAA) transporter SLC3A2. Depletion of leucine, one of the branched-chain amino acids, from cultured media decreased senescence, while high leucine diet resulted in increased senescence and high rates of embryo loss in mice. BCAAs induced senescence in DSCs via the p38 MAPK pathway. In contrast, TNFSF14+ decidual natural killer (dNK) cells were found to inhibit DSC senescence by interacting with its ligand TNFRSF14. As in mice fed high-leucine diets, both mice with NK cell depletion and Tnfrsf14-deficient mice with excessive uterine senescence experienced adverse pregnancy outcomes. Further, we found excessive uterine senescence, SLC3A2-mediated BCAA intake, and insufficient TNFRSF14 expression in the decidua of patients with recurrent spontaneous abortion. In summary, this study suggests that dNK cells maintain senescence homeostasis of DSCs via TNFSF14/TNFRSF14, providing a potential therapeutic strategy to prevent DSC senescence-associated spontaneous abortion. Synopsis: Senescent decidual stromal cells (DSCs) are known to accumulate in the endometrium in preparation for a potential pregnancy (decidualization), but the functional consequences and mechanisms of senescence induction and clearance are not well understood. Here, homeostasis of senescent DSCs is found to be controlled by decidual natural killer cells and branched-chain amino acids to ensure successful pregnancy. Cell senescence during decidualization is accompanied by increased expression of the branched-chain amino acid (BCAA) transporter SLC3A2. Excessive uterine senescence and SLC3A2-mediated BCAA intake are associated with recurrent spontaneous abortion in mice and humans. TNFSF14+ decidual natural killer cells inhibit DSC senescence through TNFRSF14, demonstrated previously to clear senescent cells in other tissues. Homeostasis of senescent cell numbers in the uterus is controlled by decidual natural killer cells and by branched-chain amino acids to ensure successful pregnancy. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio‐renal complications and guide treatment interventions in people with diabetes.We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon‐like peptide‐1 (GLP‐1) receptor agonists.Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney‐derived anti‐ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT‐2 inhibitors and GLP‐1 receptor agonists all influence pathways involved in vascular ageing.A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio‐renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes. [ABSTRACT FROM AUTHOR]

Acute liver injury (ALI) presents a challenging problem worldwide, prompting extensive research efforts. Cellular senescence has been found to be induced following ALI, and targeting cellular senescence has shown therapeutic potential. Therefore, understanding the expression of senescence-related genes in ALI can help to explore pathogenesis and treatment of this common disease. Carbon tetrachloride (CCl4) is commonly used to study ALI. Although polymerase chain reaction (PCR) is a convenient and economical molecular biology technique widely used in basic medicine, research on selecting suitable reference genes to obtain objective and reproducible PCR data is scarce. Moreover, evidence supporting the choice of reference genes for experimental studies of CCl4-induced ALI and hepatic senescence in mice is limited. In this study, we obtained murine livers at four time points (0, 12, 24, and 48 h) following CCl4 treatment. We used five algorithms (geNorm, BestKeeper, NormFinder, delta Ct, and RefFinder) to rank 12 candidate genes in real-time reverse-transcription quantitative PCR (RT-qPCR) experiments. Focusing on cellular senescence in this model, we adopted four senescence-associated secretory phenotype (SASP) genes (Il6, Il1b, Ccl2, and Ccl5) as target genes. Our results confirmed Gapdh and Tbp as suitable reference genes in murine CCl4-induced ALI models. Furthermore, we provide a table of published studies recommending reference genes for various liver disease models. This study provides a valuable reference for enhancing the reliability and reproducibility of ALI molecular findings. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common type of arthritis characterized by progressive cartilage degradation, with its pathogenesis closely related to chondrocyte autophagy. Chondrocytes are the only cells in articular cartilage, and the function of chondrocytes plays a vital role in maintaining articular cartilage homeostasis. Autophagy, an intracellular degradation system that regulates energy metabolism in cells, plays an incredibly important role in OA. During the early stages of OA, autophagy is enhanced in chondrocytes, acting as an adaptive mechanism to protect them from various environmental changes. However, with the progress of OA, chondrocyte autophagy gradually decreases, leading to the accumulation of damaged organelles and macromolecules within the cell, prompting chondrocyte apoptosis. Numerous studies have shown that cartilage degradation is influenced by the senescence and apoptosis of chondrocytes, which are associated with reduced autophagy. The relationship between autophagy, senescence, and apoptosis is complex. While autophagy is generally believed to inhibit cellular senescence and apoptosis to promote cell survival, recent studies have shown that some proteins are degraded by selective autophagy, leading to the secretion of the senescence-associated secretory phenotype (SASP) or increased SA-β-Gal activity in senescent cells within the damaged region of human OA cartilage. Autophagy activation may lead to different outcomes depending on the timing, duration, or type of its activation. Thus, our study explored the complex relationship between chondrocyte autophagy and OA, as well as the related regulatory molecules and signaling pathways, providing new insights for the future development of safe and effective drugs targeting chondrocyte autophagy to improve OA. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease most commonly encountered in older individuals. Several decades of research have contributed to a better understanding of its pathogenesis, though only two drugs thus far have shown treatment efficacy, i.e., by slowing the decline of lung function. The pathogenesis of IPF remains incompletely understood and involves multiple complex interactions and mechanisms working in tandem or separately to result in unchecked deposition of extracellular matrix components and collagen characteristic of the disease. These mechanisms include aberrant response to injury in the alveolar epithelium, inappropriate communication between epithelial cells and mesenchymal cells, imbalances between oxidative injury and tissue repair, recruitment of inflammatory pathways that induce fibrosis, and cell senescence leading to sustained activation and proliferation of fibroblasts and myofibroblasts. Targeted approaches to each of these mechanistic pathways have led to recent clinical studies evaluating the safety and efficacy of several agents. This review highlights selected concepts in the pathogenesis of IPF as a rationale for understanding current or future therapeutic approaches, followed by a review of several selected agents and their recent or active clinical studies. Current novel therapies include approaches to attenuating or modifying specific cellular or signaling processes in the fibrotic pathway, modifying inflammatory and metabolic derangements, and minimizing inappropriate cell senescence. [ABSTRACT FROM AUTHOR]

Microplastics and nanoplastics (MNPs) are ubiquitous environmental contaminants. Their prevalence, persistence, and increasing industrial production have led to questions about their long-term impact on human and animal health. This narrative review describes the effects of MNPs on oxidative stress, inflammation, and aging. Exposure to MNPs leads to increased production of reactive oxygen species (ROS) across multiple experimental models, including cell lines, organoids, and animal systems. ROS can cause damage to cellular macromolecules such as DNA, proteins, and lipids. Direct interaction between MNPs and immune cells or an indirect result of oxidative stress-mediated cellular damage may lead to increased production of pro-inflammatory cytokines throughout different MNP-exposure conditions. This inflammatory response is a common feature in the pathogenesis of neurodegenerative, cardiovascular, and other age-related diseases. MNPs also act as cell senescence inducers by promoting mitochondrial dysfunction, impairing autophagy, and activating DNA damage responses, exacerbating cellular aging altogether. Increased senescence of reproductive cells and transfer of MNPs/induced damages from parents to offspring in animals further corroborates the transgenerational health risks of the tiny particles. This review aims to provoke a deeper investigation into the notorious effects these pervasive particles may have on human well-being and longevity. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Oxidative stress (OS) and inflammation are the major contributors to BPD. Despite aggressive treatments, BPD prevalence remains unchanged, which underscores the urgent need to explore more potential therapies. The endoplasmic reticulum (ER) plays crucial roles in surfactant and protein synthesis, assisting mitochondrial function, and maintaining metabolic homeostasis. Under OS, disturbed metabolism and protein folding transform the ER structure to refold proteins and help degrade non-essential proteins to resume cell homeostasis. When OS becomes excessive, the endogenous chaperone will leave the three ER stress sensors to allow subsequent changes, including cell death and senescence, impairing the growth potential of organs. The contributing role of ER stress in BPD is confirmed by reproducing the BPD phenotype in rat pups by ER stress inducers. Although chemical chaperones attenuate BPD, ER stress is still associated with cellular senescence. N-acetyl-lysyltyrosylcysteine amide (KYC) is a myeloperoxidase inhibitor that attenuates ER stress and senescence as a systems pharmacology agent. In this review, we describe the role of ER stress in BPD and discuss the therapeutic potentials of chemical chaperones and KYC, highlighting their promising role in future therapeutic interventions. [ABSTRACT FROM AUTHOR]

Phenotype distortion of lung resident mesenchymal stem cells (MSC) in preterm infants is a hallmark event in the pathogenesis of bronchopulmonary dysplasia (BPD). Here, we evaluated the impact of cyclic mechanical stretch (CMS) and hyperoxia (HOX). The negative action of HOX on proliferation and cell death was more pronounced at 80% than at 40%. Although the impact of CMS alone was modest, CMS plus HOX displayed the strongest effect sizes. Exposure to CMS and/or HOX induced the downregulation of PDGFRα, and cellular senescence preceded by p21 accumulation. p21 interference interfered with cellular senescence and resulted in aggravated cell death, arguing for a prosurvival mechanism. HOX 40% and limited exposure to HOX 80% prevailed in a reversible phenotype with reuptake of proliferation, while prolonged exposure to HOX 80% resulted in definite MSC growth arrest. Our mechanistic data explain how HOX and CMS induce the effects on MSC phenotype disruption. The results are congruent with the clinical observation that preterm infants requiring supplemental oxygen plus mechanical ventilation are at particular risk for BPD. Although inhibiting p21 is not a feasible approach, limiting the duration and magnitude of the exposures is promising. NEW & NOTEWORTHY: Rarefication of lung mesenchymal stem cells (MSC) due to exposure to cyclic mechanical stretch (CMS) during mechanical ventilation with oxygen-rich gas is a hallmark of bronchopulmonary dysplasia in preterm infants, but the pathomechanistic understanding is incomplete. Our studies identify a common signaling mechanism mediated by p21 accumulation, leading to cellular senescence and cell death, most pronounced during the combined exposure with in principle reversible phenotype change depending on strength and duration of exposures. [ABSTRACT FROM AUTHOR]

Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel tumor microenvironment (TME) and boost antitumor immunity. However, this potential needs to be sophisticatedly wielded to avoid additional immunosuppressive capacity of senescent cells. Our study shows that blocking the JAK2/STAT3 pathway enhances immunogenic efficacy of Aurora kinase inhibitor alisertib (Ali)-induced senescence by reducing immunosuppressive senescence-associated secretory phenotype (SASP) while preserving immunogenic SASP. Hypothesizing that SASP reprogramming with Ali and JAK2 inhibitor ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed of Ali and Rux with a fully active pharmaceutical ingredient. Immunization with Ali-Rux-orchestrated senescent cells promotes stronger activation of antigen-presenting cells, enhancing antitumor immune surveillance. This approach remodels the TME by increasing CD8+ T cell and NK recruitment and activation while decreasing MDSCs. Combined with PD-L1 blockade, Ali-Rux elicits a durable antitumor immune response, suggesting the TME reshaping approach as a potential cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cellular senescence is described as an irreversible cell cycle arrest for proliferating cells and is associated with the secretion of senescence associated secretory phenotype factors. It has been known to accumulate with age and is regarded as a key driver of aging‐associated skin pathologies. However, the lack of markers of skin senescence and partially understood skin cellular senescence mechanisms has limited the exploration of skin aging and anti‐skin aging strategies. Recently, intracellular calcium signaling has emerged as an important regulator of cellular senescence and aging. However, little is known about the modulation of skin cellular senescence by calcium‐associated factors. Here, we found that the expression of calcium channel transient receptor potential melastatin 7 (TRPM7) is elevated during skin keratinocyte senescence and aging. Importantly, TRPM7 promotes skin keratinocyte senescence by triggering intracellular calcium transfer from the endoplasmic reticulum to the mitochondria; accumulation of mitochondrial calcium then induces a drop in mitochondrial membrane potential and reactive oxygen species production, leading to subsequent nuclear enlargement and DNA damage. Altogether, these findings indicate that TRPM7 controls skin keratinocyte senescence through regulating intracellular calcium signaling, and thus, shed light on novel strategies for anti‐skin aging therapy. [ABSTRACT FROM AUTHOR]

Drosophila nephrocytes are specialised cells that share critical functional, morphological, and molecular features with mammalian podocytes. Accordingly, nephrocytes represent a preferred invertebrate model for human glomerular disease. Here, we established a method for cell-specific isolation of the two types of Drosophila nephrocytes, garland and pericardial cells, from animals of different developmental stages and ages. Mass spectrometry-based proteomics and RNA-Seq-based transcriptomics were applied to characterise the proteome and transcriptome of the respective cells in an integrated and complementary manner. We observed characteristic changes in the proteome and transcriptome due to cellular ageing. Furthermore, functional enrichment analyses suggested that larval and adult nephrocytes, as well as garland and pericardial nephrocytes, fulfil distinct physiological functions. In addition, the pericardial nephrocytes were characterised by transcriptomic and proteomic profiles suggesting an atypical energy metabolism with very low oxidative phosphorylation rates. Moreover, the nephrocytes displayed typical signatures of extensive immune signalling and showed an active antimicrobial response to an infection. Factor-specific comparisons identified novel candidate proteins either expressed and secreted by the nephrocytes or sequestered by them. The data generated in this study represent a valuable basis for a more specific application of the Drosophila model in analysing renal cell function in health and disease. Combined transcriptomic and proteomic analyses of the two types of Drosophila nephrocytes – pericardial cells and garland cells – provide information on their individual physiological significance. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is a first-line treatment for colorectal cancer, but side effects such as severe diarrhea are common in clinical use and have been linked to its induction of normal cell senescence. Chloramphenicol (CAP) is an antibiotic commonly used to treat typhoid or anaerobic infections, but its senescence-related aspects have not been thoroughly investigated. Here, we used 5-FU to induce senescence in human umbilical vein endothelial cells (HUVECs) and investigated the relationship between CAP and cellular senescence at the cellular level. In a model of cellular senescence induced by 5-FU treatment, we discovered that CAP treatment reversed the rise in the percentage of senescence-associated galactosidase (SA-β-gal)-positive cells and decreased the expression of senescence-associated proteins (p16), senescence-associated genes (p21), and senescence-associated secretory phenotypes (SASPs: IL-6, TNF-α). In addition, CAP subsequently restored the autophagic process inhibited by 5-FU and upregulated the levels of autophagy-related proteins. Mechanistically, we found that CAP restored autophagic flux by inhibiting the mTOR pathway, which in turn alleviated FU-induced cellular senescence. Our findings suggest that CAP may help prevent cellular senescence and restore autophagy, opening up new possibilities and approaches for the clinical management of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: The role of senescence in disease contexts is complex, however there is considerable evidence that depletion of senescent cells improves outcomes in a variety of contexts particularly related to aging, cognition, and neurodegeneration. Much research has shown previously that inflammation can promote cellular senescence. Microglia are a central nervous system innate immune cell that undergo senescence with aging and during neurodegeneration. The contribution of senescent microglia to multiple sclerosis, an inflammatory neurodegenerative disease, is not clear, but microglia are strongly implicated in chronic active lesion pathology, tissue injury, and disease progression. Drugs that could specifically eliminate dysregulated microglia in multiple sclerosis are therefore of great interest to the field. Results: A single-cell analysis of brain tissue from mice subjected to experimental autoimmune encephalomyelitis (EAE), a mouse model of CNS inflammation that models aspects of multiple sclerosis (MS), identified microglia with a strong transcriptional signature of senescence including the presence of BCL2-family gene transcripts. Microglia expressing Bcl2l1 had higher expression of pro-inflammatory and senescence associated genes than their Bcl2l1 negative counterparts in EAE, suggesting they may exacerbate inflammation. Notably, in human single-nucleus sequencing from MS, BCL2L1 positive microglia were enriched in lesions with active inflammatory pathology, and likewise demonstrated increased expression of immune genes suggesting they may be proinflammatory and contribute to disease processes in chronic active lesions. Employing a small molecule BCL2-family inhibitor, Navitoclax (ABT-263), significantly reduced the presence of microglia and macrophages in the EAE spinal cord, suggesting that these cells can be targeted by senolytic treatment. ABT-263 treatment had a profound effect on EAE mice: decreasing motor symptom severity, improving visual acuity, promoting neuronal survival, and decreasing white matter inflammation. Conclusion: These results support the hypothesis that microglia and macrophages exhibit transcriptional features of cellular senescence in EAE and MS, and that microglia expressing Bcl2l1 demonstrate a proinflammatory signature that may exacerbate inflammation resulting in negative outcomes in neuroinflammatory disease. Depleting microglia and macrophages using a senolytic results in robust improvement in EAE disease severity, including across measures of neurodegeneration, inflammation, and demyelination, and may therefore represent a novel strategy to address disease progression in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD. [ABSTRACT FROM AUTHOR]

A supplemented collagen peptide composition (SCPC) containing microbe-fermented collagen peptide, collagen tripeptide, elastin peptide, and sodium hyaluronate was investigated to determine its effects on skin aging, skin elasticity, and tissue regeneration in zebrafish. β-Galactosidase activity was inhibited, while telomerase activity was elevated, by exposure to 0.977 μL/mL of SCPC in an H 2 O 2 -induced aging zebrafish model, indicating that SCPC can delay cell senescence. Expression of the collagen I gene col1a1a was up-regulated by exposure to 62.5 μL/mL of SCPC, indicating that SCPC can improve skin elasticity. Regrowth of the injured caudal fin was enhanced by exposure to only 0.122 μL/mL of SCPC. These improvements to skin aging, elasticity, and tissue regeneration in zebrafish suggest that this SCPC has potential as a functional food with beneficial effects on skin health and aging resistance in humans. [Display omitted] • Zebrafish were used for building animal models. • Effects of the supplemented collagen peptide composition on the skin. • Inhibiting β-galactosidase activity and elevated telomerase activity. • Up-regulated the expression of collagen I gene col1a1a. • Enhanced the regrowth of injured caudal fin. [ABSTRACT FROM AUTHOR]

Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer's disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed. [ABSTRACT FROM AUTHOR]

Aim: Obstructive sleep apnea (OSA) is a growing health problem affecting nearly 1 billion people worldwide. The landmark feature of OSA is chronic intermittent hypoxia (CIH), accounting for multiple organ damage, including heart disease. CIH profoundly alters both visceral white adipose tissue (WAT) and heart structure and function, but little is known regarding inter‐organ interaction in the context of CIH. We recently showed that visceral WAT senescence drives myocardial alterations in aged mice without CIH. Here, we aimed at investigating whether CIH induces a premature visceral WAT senescent phenotype, triggering subsequent cardiac remodeling. Methods: In a first experiment, 10‐week‐old C57bl6J male mice (n = 10/group) were exposed to 14 days of CIH (8 h daily, 5%–21% cyclic inspired oxygen fraction, 60 s per cycle). In a second series, mice were submitted to either epididymal WAT surgical lipectomy or sham surgery before CIH exposure. Finally, we used p53 deficient mice or Wild‐type (WT) littermates, also exposed to the same CIH protocol. Epididymal WAT was assessed for fibrosis, DNA damages, oxidative stress, markers of senescence (p16, p21, and p53), and inflammation by RT‐qPCR and histology, and myocardium was assessed for fibrosis and cardiomyocyte hypertrophy. Results: CIH‐induced epididymal WAT remodeling characterized by increased fibrosis, oxidative stress, DNA damage response, inflammation, and increased expression of senescent markers. CIH‐induced epididymal WAT remodeling was associated with subtle and early myocardial interstitial fibrosis. Both epididymal WAT surgical lipectomy and p53 deletion prevented CIH‐induced myocardial fibrosis. Conclusion: Short‐term exposure to CIH induces epididymal WAT senescent remodeling and cardiac interstitial fibrosis, the latter being prevented by lipectomy. This finding strongly suggests visceral WAT senescence as a new target to mitigate OSA‐related cardiac disorders. [ABSTRACT FROM AUTHOR]

Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation is decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and clinical characteristics of HCC, as well as responses to anti-programmed cell death protein 1 (PD-1) treatment. Subcutaneous xenograft, orthotopic xenograft, Trp53 Δhep/Δhep ; MYC - and Ctnnb oe ; MET oe -driven mouse models were adopted to validate the effects of GCDH on HCC suppression. GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the SASP (senescence-associated secretory cell phenotype) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-PD-1 therapy. GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment via the SASP. The GCDHlow population is responsive to anti-PD-1 therapy because of the increased presence of PD-1+CD8+ T cells. Glutaryl-CoA dehydrogenase (GCDH) is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Herein, we show that GCDH inhibits hepatocellular carcinoma (HCC) progression via crotonylation-induced suppression of the pentose phosphate pathway and glycolysis, resulting in HCC cell senescence. We also found that more PD-1+CD8+ T cells are present in the GCDHlow population, who are thus more responsive to anti-PD-1 therapy. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH. [Display omitted] • Proteomics data and clinical validation link GCDH to HCC suppression. • GCDH depletion promotes HCC initiation, development and metastasis. • GCDH suppresses PPP and glycolysis via crotonylation of PGD, TKT and ALDOC, which further induces cell senescence. • GCDH-driven HCC senescence shapes an anti-tumor microenvironment. [ABSTRACT FROM AUTHOR]

Background and Purpose: Colorectal cancer (CRC) ranks second in mortality worldwide and requires effective and affordable remedies. Cyclovirobuxine D (CVB‐D) is the main effective component of Huangyangning tablet, an approved traditional patent medicine, which is mainly used for cardiovascular treatment. As a multibioactive natural compound, CVB‐D possesses underlying anticancer activities. Experimental Approach: Cell viability and clone‐forming ability were determined in human CRC lines. Western blot, immunofluorescence assay, transmission electron microscopy and senescence‐associated β‐galactosidase (SA‐β‐Gal) staining were utilized to investigate cell autophagy and senescence. The molecular mechanisms were explored by virtual prediction and experimental validation. Patient‐derived xenograft (PDX), dextran sulfate sodium salt (DSS), and azomethane (AOM)/DSS mouse models were employed for in vivo studies. Key Results: CVB‐D inhibited the growth and development of advanced CRC cells / mice by inducing autophagic and senescent activities through the chaperonin containing TCP1 subunit 3 (CCT3)/yes‐associated protein (YAP) axis. CVB‐D acted as a promising inhibitor of CCT3 by interacting with its ATP site. In PDX tumours, CVB‐D showed potential therapeutic effects by targeting CCT3. Treatment with CVB‐D alleviated the mouse model of colitis induced by DSS and attenuated AOM/DSS‐induced formation of adenomatous polyps by its action on CCT3. Conclusions and Implications: Our study has provided a scientific basis for the suggestion that CVB‐D may be recognized as a prospective drug candidate for the therapy of CRC in patients. [ABSTRACT FROM AUTHOR]

• High-fat diet increases neuroinflammation and accelerates ageing. • Microglia dysfunction can exacerbate neuroinflammation. • Gut microbiota modulates microglia activation and functionality. • Administration of prebiotics alleviated harmful effects of long-term high-fat diet. Ageing is characterised by a progressive increase in systemic inflammation and especially neuroinflammation. Neuroinflammation is associated with altered brain states that affect behaviour, such as an increased level of anxiety with a concomitant decline in cognitive abilities. Although multiple factors play a role in the development of neuroinflammation, microglia have emerged as a crucial target. Microglia are the only macrophage population in the CNS parenchyma that plays a crucial role in maintaining homeostasis and in the immune response, which depends on the activation and subsequent deactivation of microglia. Therefore, microglial dysfunction has a major impact on neuroinflammation. The gut microbiota has been shown to significantly influence microglia from birth to adulthood in terms of development, proliferation, and function. Diet is a key modulating factor that influences the composition of the gut microbiota, along with prebiotics that support the growth of beneficial gut bacteria. Although the role of diet in neuroinflammation and behaviour has been well established, its relationship with microglia functionality is less explored. This article establishes a link between diet, animal behaviour and the functionality of microglia. The results of this research stem from experiments on mouse behaviour, i.e., memory, anxiety, and studies on microglia functionality, i.e., cytochemistry (phagocytosis, cellular senescence, and ROS assays), gene expression and protein quantification. In addition, shotgun sequencing was performed to identify specific bacterial families that may play a crucial role in the brain function. The results showed negative effects of long-term consumption of a high fat diet on ageing mice, epitomised by increased body weight, glucose intolerance, anxiety, cognitive impairment and microglia dysfunction compared to ageing mice on a control diet. These effects were a consequence of the changes in gut microbiota modulated by the diet. However, by adding the prebiotics fructo- and galacto-oligosaccharides, we were able to mitigate the deleterious effects of a long-term high-fat diet. [ABSTRACT FROM AUTHOR]

Fertilization capacity and embryo survival rate are decreased in postovulatory aging oocytes, which results in a reduced reproductive rate in female animals. However, the key regulatory genes and related regulatory mechanisms involved in the process of postovulatory aging in oocytes remain unclear. In this study, RNA-Seq revealed that 3237 genes were differentially expressed in porcine oocytes between the MII and aging stages (MII + 24 h). The expression level of FOXM1 was increased at the aging stage, and FOXM1 was also observed to be enriched in many key biological processes, such as cell senescence, response to oxidative stress, and transcription, during porcine oocyte aging. Previous studies have shown that FOXM1 is involved in the regulation of various biological processes, such as oxidative stress, DNA damage repair, mitochondrial function, and cellular senescence, which suggests that FOXM1 may play a crucial role in the process of postovulatory aging. Therefore, in this study, we investigated the effects and mechanisms of FOXM1 on oxidative stress, mitochondrial function, DNA damage, and apoptosis during oocyte aging. Our study revealed that aging oocytes exhibited significantly increased ROS levels and significantly decreased GSH, SOD, T-AOC, and CAT levels than did oocytes at the MII stage and that FOXM1 inhibition exacerbated the changes in these levels in aging oocytes. In addition, FOXM1 inhibition increased the levels of DNA damage, apoptosis, and cell senescence in aging oocytes. A p21 inhibitor alleviated the effects of FOXM1 inhibition on oxidative stress, mitochondrial function, and DNA damage and thus alleviated the degree of senescence in aging oocytes. These results indicate that FOXM1 plays a crucial role in porcine oocyte aging. This study contributes to the understanding of the function and mechanism of FOXM1 during porcine oocyte aging and provides a theoretical basis for preventing oocyte aging and optimizing conditions for the in vitro culture of oocytes. • FOXM1 inhibition exacerbated oxidative stress in aging oocytes. • FOXM1 inhibition exacerbated mitochondrial dysfunction in aging oocytes. • FOXM1 inhibition exacerbated DNA damage and apoptosis in aging oocytes. • FOXM1 regulated oxidative stress, mitochondrial function, and DNA damage by p21. [ABSTRACT FROM AUTHOR]

Stem cell loss in aging and disease is associated with nuclear deformation. Yet, how nuclear shape influences stem cell homeostasis is poorly understood. We investigated this connection using Drosophila germline stem cells, as survival of these stem cells is compromised by dysfunction of the nuclear lamina, the extensive protein network that lines the inner nuclear membrane and gives shape to the nucleus. To induce nuclear distortion in germline stem cells, we used the GAL4-UAS system to increase expression of the permanently farnesylated nuclear lamina protein, Kugelkern, a rate limiting factor for nuclear growth. We show that elevated Kugelkern levels cause severe nuclear distortion in germline stem cells, including extensive thickening and lobulation of the nuclear envelope and nuclear lamina, as well as alteration of internal nuclear compartments. Despite these changes, germline stem cell number, proliferation, and female fertility are preserved, even as females age. Collectively, these data demonstrate that disruption of nuclear architecture does not cause a failure of germline stem cell survival or homeostasis, revealing that nuclear deformation does not invariably promote stem cell loss. [Display omitted] • Nuclear lamina (NL) assembly is unaffected by nuclear envelope expansion. • Nuclear envelope (NE) expansion alters structure of internal nuclear compartments. • Excess NE and NL do not interfere with centrosome remodeling in GSC mitosis. • NL distortion is not sufficient to promote a failure of GSC survival or homeostasis. • Functional consequences of nuclear distortion are contextual. [ABSTRACT FROM AUTHOR]

Nrf2 is a master transcriptional regulator of a number of genes involved in the adaptive response to oxidative stress. Among the genes upregulated by Nrf2, heme oxygenase-1 (HO-1) has received significant attention, given that the products of HO-1-induced heme catabolism have well established antioxidant and anti-inflammatory properties. This is evidenced in numerous models of inflammatory and autoimmune disease whereby induction of HO-1 expression or administration of tolerable amounts of HO-1 reaction products can ameliorate disease symptoms. Unsurprisingly, Nrf2 and HO-1 are now considered viable drug targets for a number of conditions. In recent years, the term 'inflammaging' has been used to describe the low-grade chronic inflammation observed in aging/aged cells. Increased oxidative stress is also a key factor associated with aging and there is convincing evidence that Nrf2, not only declines with age, but that Nrf2 and HO-1 can reduce cellular senescence and the senescenceassociated secretory phenotype (SASP) which is now considered an underlying driver of age-related inflammatory disease. In this review, we describe the role of oxidative stress in 'inflammaging' and highlight the potential anti-aging properties of the Nrf2-HO-1 system. We also highlight established and newly emerging Nrf2 activators and their therapeutic application in age-related disease. [ABSTRACT FROM AUTHOR]

Recently, cellular senescence-induced unstable carotid plaques have gained increasing attention. In this study, we utilized bioinformatics and machine learning methods to investigate the correlation between cellular senescence and the pathological mechanisms of unstable carotid plaques. Our aim was to elucidate the causes of unstable carotid plaque progression and identify new therapeutic strategies. First, differential expression analysis was performed on the test set GSE43292 to identify differentially expressed genes (DEGs) between the unstable plaque group and the control group. These DEGs were intersected with cellular senescence-associated genes to obtain 40 cellular senescence-associated DEGs. Subsequently, key genes were then identified through weighted gene co-expression network analysis, random forest, Recursive Feature Elimination for Support Vector Machines algorithm and cytoHubba plugin. The intersection yielded 3 CSA-signature genes, which were validated in the external validation set GSE163154. Additionally, we assessed the relationship between these CSA-signature genes and the immune landscape of the unstable plaque group. This study suggests that cellular senescence may play an important role in the progression mechanism of unstable plaques and is closely related to the influence of the immune microenvironment. Our research lays the foundation for studying the progression mechanism of unstable carotid plaques and provides some reference for targeted therapy. [ABSTRACT FROM AUTHOR]

Immunosenescence impacts both the innate and adaptive immune systems, predominantly affecting certain immune cell types. A notable manifestation of immunosenescence is the diminished efficacy of adaptive immunity. The excessive senescence of immune cells, particularly T cells, leads to marked immune deficiency, consequently escalating the risk of infections, tumors, and age-associated disorders. Lymphocytes, especially T cells, are subject to both replicative and premature senescence. Telomerase reverse transcriptase (TERT) and telomerase have multifaceted roles in regulating cellular behavior, possessing the ability to counteract both replicative and premature senescence in lymphocytes. This review encapsulates recent advancements in understanding immunosenescence, with a focus on T cell senescence, and the regulatory mechanisms involving TERT/telomerase. Additionally, it comprehensively discusses strategies aimed at inhibiting immunosenescence by augmenting TERT/ telomerase activity. [ABSTRACT FROM AUTHOR]

Background: Aberrant fatty acid metabolism (FAM) plays a critical role in the tumorigenesis of human malignancies. However, studies on its impact in lung adenocarcinoma (LUAD) are limited. Methods: We developed a prognostic signature comprising 10 FAM-related genes (GPR115, SOAT2, CDH17, MOGAT2, COL11A1, TCN1, LGR5, SLC34A2, RHOV, and DKK1) using data from LUAD patients in The Cancer Genome Atlas (TCGA). This signature was validated using six independent LUAD datasets from the Gene Expression Omnibus (GEO). Patients were classified into high- and low-risk groups, and overall survival (OS) was compared by Kaplan-Meier analysis. The signature’s independence as a prognostic indicator was assessed after adjusting for clinicopathological features. Receiver operating characteristic (ROC) analysis validated the signature. Tumor immune microenvironment (TIME) was analyzed using ESTIMATE and multiple deconvolution algorithms. Functional assays, including CCK8, cell cycle, apoptosis, transwell, and wound healing assays, were performed on MOGAT2-silenced H1299 cells using CRISPR/Cas9 technology. Results: Low-risk group patients exhibited decreased OS. The signature was an independent prognostic indicator and demonstrated strong risk-stratification utility for disease relapse/progression. ROC analysis confirmed the signature’s validity across validation sets. TIME analysis revealed higher infiltration of CD8+ T cells, natural killers, and B cells, and lower tumor purity, stemness index, and tumor mutation burden (TMB) in low-risk patients. These patients also showed elevated T cell receptor richness and diversity, along with reduced immune cell senescence. High-risk patients exhibited enrichment in pathways related to resistance to immune checkpoint blockades, such as DNA repair, hypoxia, epithelial-mesenchymal transition, and the G2M checkpoint. LUAD patients receiving anti-PD-1 treatment had lower risk scores among responders compared to non-responders. MOGAT2 was expressed at higher levels in low-risk LUAD patients. Functional assays revealed that MOGAT2 knockdown in H1299 cells promoted proliferation and migration, induced G2 cell cycle arrest, and decreased apoptosis. Conclusions: This FAM-related gene signature provides a valuable tool for prognostic stratification and monitoring of TIME and immunotherapy responses in LUAD. MOGAT2 is identified as a potential anti-tumor regulator, offering new insights into its role in LUAD pathogenesis. [ABSTRACT FROM AUTHOR]

Cutaneous wound healing is a complex multi-step process that is highly controlled, ensuring efficient repair to damaged tissue and restoring tissue architecture. Multiple cell types play a critical role in wound healing, and perturbations in this can lead to non-healing wounds or scarring and fibrosis. Thus, the process is tightly regulated and controlled. Cellular senescence is defined as irreversible cell cycle arrest and is associated with various phenotypic changes and metabolic alterations and coupled to a secretory program. Its role in wound healing, at least in the acute setting, appears to help promote appropriate mechanisms leading to the complete restoration of tissue architecture. Opposing this is the role of senescence in chronic wounds where it can lead to either chronic non-healing wounds or fibrosis. Given the two opposing outcomes of wound healing in either acute or chronic settings, this has led to disparate views on the role of senescence in wound healing. This review aims to consolidate knowledge on the role of senescence and aging in wound healing, examining the nuances of the roles in the acute or chronic settings, and attempts to evaluate the modulation of this to promote efficient wound healing. [ABSTRACT FROM AUTHOR]

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer's disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes. [ABSTRACT FROM AUTHOR]

AbstractBy establishing an in vitro model of D-Gal-induced brain neuronal cell (HT-22) senescence, it was found that TAX treatment significantly increased the activities of SOD and GSH, while decreasing MDA levels in aging HT-22 cells, indicating that TAX effectively restored the total antioxidant capacity and antioxidant enzyme activity of aging HT-22 cells induced by D-Gal, and attenuated cellular oxidative stress injury. In addition, taxifolin could also protect HT-22 cells from aging by up-regulating SIRT1 while reducing the expression of Ac-p53, indicating that TAX may be an active substance that can effectively delay cell aging. [ABSTRACT FROM AUTHOR]

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age‐related diseases. This study examines age‐associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age‐dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi‐omics approaches identified chronological age‐related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi‐omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation—a hallmark of RBC aging—and lower post‐transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a common joint disease that leads to chronic pain and functional limitations. Recent research has revealed soluble fibroblast activation protein (FAP) secreted from OA synovium could degrade type II collagen (Col2) in cartilage to promote the progression of OA. This study aimed to reveal the role of FAP from chondrocytes in OA and develop a novel lipid nanoparticle (LNP)-FAP siRNA delivery system for OA treatment. Methods: The expression of FAP in the cartilage of knee OA patients was investigated using [68 Ga]Ga-FAPI-04 PET in vivo and immunofluorescence, western blotting, and RT-qPCR in vitro. Cell senescence was determined by senescence-associated β-galactosidase (SA-β-Gal) assay after FAP overexpressing or knockdown in chondrocytes. An OA model with chondrocyte-specific FAP knockout mice was applied to investigate the role of FAP in chondrocyte senescence and OA development. The therapeutic effects of lipid nanoparticle (LNP) @FAP siRNA on cartilage degeneration were evaluated in the rat OA model. Results: Our study found that higher [68 Ga]Ga-FAPI-04 uptake was detected in knee OA patients by PET/CT scan. FAP mRNA and protein levels were highly expressed in OA-damaged cartilage. Moreover, we found that overexpression of FAP promotes chondrocyte senescence, and the genetic knockout of FAP in chondrocytes alleviates OA. Knockdown FAP by siRNA could alleviate chondrocyte senescence and suppress the NF-κB pathway to reduce the senescence-associated secretory phenotype (SASP). In the rat model of OA, intraarticular injection of LNP@FAP siRNA can reduce senescent cells and ameliorate cartilage destruction. Conclusion: FAP-positive chondrocytes play a significant role in the pathogenesis of OA. Targeting these cells selectively has the potential to mitigate the progression of the disease. Our study provides valuable insights into the intraarticular injection of LNP@FAP siRNA as a promising strategy for the treatment of OA. [ABSTRACT FROM AUTHOR]

Adiponectin receptor signaling represents a promising therapeutic target for age‐related conditions such as osteoporosis and diabetes. However, the literature presents conflicting evidence regarding the role of adiponectin signaling in bone homeostasis and fracture repair across different health states, ages, and disease conditions. These inconsistencies may arise from the complex endocrine and paracrine feedback mechanisms regulating adiponectin, as well as the variability in adiponectin isoforms and receptor expressions. In this study, we observed differential expression of adiponectin receptors in the bone marrow (BM) of aged mice, characterized by elevated levels of adiponectin receptor 2 and reduced levels of receptor 1, as corroborated by both single‐cell sequencing and in vivo staining. Additionally, circulating levels of adiponectin and its local expression were significantly higher in aged mice compared to younger counterparts. Treatment with adiponectin receptor agonist, AdipoRon, enhanced bone regeneration and repair in young mice by promoting osteogenesis and reducing osteoclastogenesis. Conversely, in aged mice, AdipoRon treatment led to cellular senescence, delayed bone repair, and inhibited osteogenic activity. Notably, the adiponectin receptor 1‐Wnt and adiponectin receptor 2‐MAPK and mTOR signaling pathways were differentially activated in AdipoRon‐treated BM mesenchymal stem cells from young and aged mice. Additionally, the NF‐κB, and AKT pathways were consistently downregulated in BM macrophages of both age groups following AdipoRon administration. In conclusion, aging significantly modulates the impact of adiponectin receptor signaling on BM mesenchymal stem cells. This modulation is potentially attributable to changes in receptor transcription and distribution, as well as differential activation of downstream signaling pathways. [ABSTRACT FROM AUTHOR]

Serine protease inhibitor clade A member 3n (Serpina3n) or its human orthologue SERPINA3 is a secretory immune‐related molecule produced primarily in the liver and brain under homeostatic conditions and up‐regulated in response to system inflammation. Yet, it remains elusive regarding its cellular identity and physiological significance in the development of the postnatal brain. Here, we reported that oligodendroglial lineage cells are the major cell population expressing Serpina3n protein in the postnatal murine CNS. Using loss‐of‐function genetic tools, we found that Serpina3n conditional knockout (cKO) from Olig2‐expressing cells does not significantly affect cognitive and motor functions in mice. Serpina3n depletion does not appear to interfere with oligodendrocyte differentiation and developmental myelination nor affects the population of other glial cells and neurons in vivo. Interestingly, Serpina3n is significantly up‐regulated in response to oxidative stress and its deficiency alleviates oxidative injury and diminishes cell senescence of oligodendrocytes in vitro. Together, our data suggest that the immune‐related molecule Serpina3n plays a minor role in neural cell development under homeostasis, yet it primes oligodendrocytes for CNS insults and regulates oligodendrocyte health under injured conditions. Our findings raise the interest in pursuing its functional significance in the CNS under disease/injury conditions. [ABSTRACT FROM AUTHOR]

Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells. How stresses result in cellular senescence is not fully understood. Here, the authors show that cell stress induces the assembly of a polyglutamylated microtubule array connecting nucleus and cilium, which aids in transporting a senescence-inducing protein. [ABSTRACT FROM AUTHOR]

As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals. [ABSTRACT FROM AUTHOR]

Background: Age-related reproductive aging is a natural and irreversible physiological process, and delaying childbearing is increasingly common all over the world. Transplantation of mesenchymal stem cells (MSCs) is considered a new and effective therapy to restore ovarian function, but the relevant mechanisms remain unclear. Recently, it has been found that there is a local Renin–angiotensin system (RAS) in human ovary and it plays a key role. Methods: After collecting follicular fluid from women who received oocyte retrieval for pure male factor infertility, the level of RAS components in it were detected, and the correlation analysis by linear regression. Then, the in vivo experiments on female C57BL/6 mice were designed to measure ovarian function, and the transcription and translation levels of RAS pathway were detected by molecular biology methods. Moreover, the role of RAS in regulating inflammation and oxidative stress in the co-culture system were explored in in vitro experiments on KGN cells. Results: First, a total of 139 samples of analyzable follicular fluid were obtained. The local RAS of ovary, which is independent of systemic RAS (P > 0.05), is affected by age (Pearson r < 0, P < 0.05) and related to ovarian function, inflammation, oxidative stress indexes and assisted reproduction laboratory outcomes (P < 0.05). Next, the ovary/body weight of aging mice decreased significantly and serum sex hormones levels changed significantly (P < 0.01). The number of functional follicles decreased, while the atresia follicles increased (P < 0.05). After MSCs transplantation, all the above measures have been partially recovered (P < 0.05). Although several RAS components in aging ovary changed, MSCs only improved the expression level of AT1R (P < 0.05). Furthermore, the secretion ability and mitochondrial membrane potential of aging KGN cells decreased, while the intracellular ROS level and the aging cells ratio increased (P < 0.01). All the above measures have been partially recovered when co-cultured with MSCs (P < 0.05). After Ang(1–7) were added into the co-culture system, the above have been more significantly restored compared with Ang II (P < 0.05). Nevertheless, there was no statistical difference in estradiol level no matter which one was added (P > 0.05). Conclusions: Together, our findings indicate that a novel possible mechanism to explain how stem cells restore age-related ovarian functional decline. [ABSTRACT FROM AUTHOR]

Despite a substantial impact on various economic and cell technology factors, the influence of electrolyte quantities is rarely addressed in research. This study examines the impact of varying electrolyte quantities on cell performance and aging processes using three different electrolytes: LP57 (1 M LiPF6 in ethylene carbonate:ethyl methyl carbonate (EC:EMC 3:7 w/w), LP572 (LP57+2 wt.% vinylene carbonate (VC)) and LP57 + absVC (18.351 mg VC). Comprehensive analytical post mortem investigations revealed that continuous excessive electrolyte decomposition determines the performance of cells using LP57, leading to enhanced irreversible lithium‐ion loss and interphase thickening with increasing electrolyte volume. Impedance rise due to the growth of the interphase was also identified as the cause of degrading cell performance with rising amounts of LP572, attributed to an increasingly pronounced consumption of VC rather than electrolyte aging effects. By varying the electrolyte quantity while maintaining a constant amount VC within the cell system, the differences in cell performance were minimized, and observed deteriorating effects were suppressed. This study demonstrates the sensitive interdependence of electrolyte volume and additive concentration, practically affecting aging behavior. Comprehensively understanding the characteristics of each individual electrolyte component and tailoring the electrolytes to cell‐specific cell properties proves to be crucial to optimize cell performance. [ABSTRACT FROM AUTHOR]

Despite significant progress in therapy, there remains a lack of substantial evidence regarding the molecular factors that lead to renal fibrosis. Neuraminidase 4 (NEU4), an enzyme that removes sialic acids from glycoconjugates, has an unclear role in chronic progressive fibrosis. Here, this study finds that NEU4 expression is markedly upregulated in mouse fibrotic kidneys induced by folic acid or unilateral ureter obstruction, and this elevation is observed in patients with renal fibrosis. NEU4 knockdown specifically in the kidney attenuates the epithelial‐to‐mesenchymal transition, reduces the production of pro‐fibrotic cytokines, and decreases cellular senescence in male mice. Conversely, NEU4 overexpression exacerbates the progression of renal fibrosis. Mechanistically, NEU4254‐388aa interacts with Yes‐associated protein (YAP) at WW2 domain (231‐263aa), promoting its nucleus translocation and activation of target genes, thereby contributing to renal fibrosis. 3,5,6,7,8,3ʹ,4ʹ‐Heptamethoxyflavone, a natural compound, is identified as a novel NEU4 inhibitor, effectively protecting mice from renal fibrosis in a NEU4‐dependent manner. Collectively, the findings suggest that NEU4 may represent a promising therapeutic target for kidney fibrosis. [ABSTRACT FROM AUTHOR]

Cellular senescence leads to the functional decline of regenerative cells such as mesenchymal stromal/stem cells (MSCs), which gives rise to chronic conditions and contributes to poor cell therapy outcomes. Aging tissues are associated with extracellular matrix (ECM) dysregulation, including loss of elastin. However, the role of the ECM in modulating senescence is underexplored. In this work, it is shown that tropoelastin, the soluble elastin precursor, is not only a marker of young MSCs but also actively preserves cell fitness and delays senescence during replicative aging. MSCs briefly exposed to tropoelastin exhibit upregulation of proliferative genes and concurrent downregulation of senescence genes. The seno‐protective benefits of tropoelastin persist during continuous, long‐term MSC culture, and significantly extend the MSC replicative lifespan. Tropoelastin‐expanded MSCs further maintain youth‐associated phenotype and function compared to age‐matched controls, including preserved clonogenic potential, minimal senescence‐associated beta‐galactosidase activity, maintained cell sizes, reduced expression of senescence markers, suppressed secretion of senescence‐associated factors, and increased production of youth‐associated proteins. This work points to the utility of exogenously‐supplemented tropoelastin for manufacturing MSCs that robustly maintain regenerative potential with age. It further reveals the active role of classical structural ECM proteins in driving cellular age‐associated fitness, potentially leading to future interventions for aging‐related pathologies. [ABSTRACT FROM AUTHOR]

The small G protein Arf1 has been identified as playing a selective role in supporting cancer stem cells (CSCs), making it an attractive target for cancer therapy. However, the current Arf1 inhibitors have limited translational potential due to their high toxicity and low specificity. In this study, two new potent small‐molecule inhibitors of Arf1, identified as DU101 and DU102, for cancer therapy are introduced. Preclinical tumor models demonstrate that these inhibitors triggered a cascade of aging in CSCs and enhance anti‐tumor immunity in mouse cancer and PDX models. Through single‐cell sequencing, the remodeling of the tumor immune microenvironment induced by these new Arf1 inhibitors is analyzed and an increase in tumor‐associated CD8+ CD4+ double‐positive T (DPT) cells is identified. These DPT cells exhibit superior features of active CD8 single‐positive T cells and a higher percentage of TCF1+PD‐1+, characteristic of stem‐like T cells. The frequency of tumor‐infiltrating stem‐like DPT cells correlates with better disease‐free survival (DFS) in cancer patients, indicating that these inhibitors may offer a novel cancer immunotherapy strategy by converting the cold tumor immune microenvironment into a hot one, thus expanding the potential for immunotherapy in cancer patients. [ABSTRACT FROM AUTHOR]

Senescence, caused by cell‐cycle arrest, is a hallmark of aging. Senescence has also been described in embryogenesis, wound healing, and acute injuries. Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and mortality. Most of the pathophysiology of human sepsis is recapitulated in the mouse model of polymicrobial sepsis, developed by cecal ligation and puncture (CLP). In this report, we demonstrate a rapid onset of cellular senescence in the liver of mice subjected to CLP‐induced sepsis, characterized by the upregulation of p21, p53, and other senescence markers, including SA‐βgal. Using RNAscope, confocal microscopy, and flow cytometry, we further confirm the emergence of p21‐expressing senescence phenotype in the liver 24 h after sepsis induction. Senescence was observed in several cell types in the liver, including hepatocytes, endothelial cells, and macrophages. We determined the landscape of senescence phenotype in murine sepsis by single‐cell sequencing, which further ascertained that this cell fate is not confined to any particular cell type but displays a heterogeneous distribution. Furthermore, we observed a significant reduction in mortality following sepsis when mice were treated with senolytics, a combination of dasatinib and quercetin, before the CLP surgery. Our experiments unequivocally demonstrated a rapid development of cellular senescence with sepsis and, for the first time, described the senescence landscape in the sepsis liver and the possible role of senescent cells in the worsening outcome following sepsis. [ABSTRACT FROM AUTHOR]

Addressing adipose niche senescence is crucial for preventing obesity‐related aging. Telomerase reverse transcriptase (TERT) is a promising target for gene therapy, but traditional methods lack precision and safety. A novel mitochondrion‐located TERT (mito‐TERT) activating approach is presented by injectable gene/short‐fiber complexes (gene/fiber‐plexes) to safely reverse adipose niche senescence from mitochondrial enhancement. The gene/fiber‐plexes are prepared from polydopamine‐coated short‐fibers to adsorb cationic dendrimers (PAMAM G3, PG3) carrying TERT plasmids and Coenzyme Q10 (CoQ10), termed PG3‐TERT@CoQ10. Upon intraperitoneal injection, the gene/fiber‐plexes adhere to the peritoneum and release PG3‐TERT@CoQ10, precisely targeting the adipose niche. Transient active oxygen scavenging by CoQ10 activates TERT transfection and endogenous mitochondrion translocation sequentially, enhancing mitochondrial function. In vitro and in vivo studies shows that gene/fiber‐plexes effectively targeted visceral adipose tissue, increased mito‐TERT levels and restored mitochondrial function. In an obese mouse model, they restored adipose tissue homeostasis and metabolic stability. RNA sequencing indicated reduced senescence‐related genes and restored cell cycle. This mito‐TERT activation strategy shows great promise for treating premature aging and metabolic diseases linked to adipose tissue senescence. [ABSTRACT FROM AUTHOR]

Obesity is one of the primary risk factors for osteoarthritis (OA), acting through cross talk among altered biomechanics, metabolism, adipokines, and dietary free fatty acid (FA) composition. Obesity and aging have been linked to cellular senescence in various tissues, resulting in increased local and systemic inflammation and immune dysfunction. We hypothesized that obesity and joint injury lead to cellular senescence that is typically associated with increased OA severity or with aging and that the ratio of omega-6 (ω-6) to omega-3 (ω-3) FAs regulates these pathologic effects. Mice were placed on an ω-6-rich high-fat diet or a lean control diet and underwent destabilization of the medial meniscus to induce OA. Obesity and joint injury significantly increased cellular senescence in subcutaneous and visceral fat as well as joint tissues such as synovium and cartilage. Using adeno-associated virus (AAV) gene therapy for fat-1, a fatty acid desaturase that converts ω-6 to ω-3 FAs, decreasing the serum ω-6:ω-3 FA ratio had a strong senomorphic and therapeutic effect, mitigating metabolic dysfunction, cellular senescence, and joint degeneration. In vitro coculture of bone marrow-derived macrophages and chondrocytes from control and AAV8-fat1-treated mice were used to examine the roles of various FA mediators in regulating chondrocyte senescence. Our results suggest that obesity and joint injury result in a premature “aging” of the joint as measured by senescence markers, and these changes can be ameliorated by altering FA composition using fat-1 gene therapy. These findings support the potential for fat-1 gene therapy to treat obesity- and/or injury-induced OA clinically [ABSTRACT FROM AUTHOR]

Background: Senescent immune cells exhibit altered gene expression and resistance to apoptosis. The prevalence of these cells increases with age and emerging data implicate senescence-associated maladaptive signaling as a potential contributor to sepsis and septic shock. The senolytic drug fisetin promotes clearance of senescent cells and is hypothesized to mitigate septic responses to infection. Methods: We are conducting a multi-center, randomized, double-blinded, adaptive allocation phase 2 clinical trial to assess the efficacy of the senolytic drug fisetin in preventing clinical deterioration of elderly patients diagnosed with sepsis. We intend to enroll and randomize 220 elderly patients (age > 65) with the clinical diagnosis of sepsis to receive either fisetin as a single oral dose of 20 mg/kg, fisetin in two oral doses of 20 mg/kg each spaced 1 day apart, or placebo. The primary outcome will be changed in the composite of cardiovascular, respiratory, and renal sequential organ failure assessment scores at 7 days from enrollment. Secondary outcomes include quantification of senescent CD3 + cells at 7 days, and 28-day assessments of organ failure-free days, days in an intensive care unit, and all-cause mortality. Discussion: This multi-center, randomized, double-blinded trial will assess the efficacy of fisetin in preventing clinical deterioration in elderly patients with sepsis and measure the effects of this drug on the prevalence of senescent immune cells. We intend that the results of this phase 2 trial will inform the design of a larger phase 3 study. Trial registration: This trial is registered to ClinicalTrials.gov under identifier NCT05758246, first posted on March 7, 2023. [ABSTRACT FROM AUTHOR]