Polypyrimidine Tract Binding protein 1 (PTB) is an alternative splicing factor linked to neuronal induction and maturation. Previously, knockdown experiments supported a model in which PTB can function as a potent reprogramming factor, able to elicit direct glia-to-neuron conversion in vivo, in both the brain and retina. However, later lineage tracing and genetic knockouts of PTB did not support direct neuronal reprogramming. Nevertheless, consistent with the PTB depletion experiments, we show that antisense knockdown of PTB (ptbp1a) in the zebrafish retina can activate Müller glia-derived proliferation and that depletion of PTB can further enhance proliferation when combined with acute NMDA damage. The effects of PTB are consistent with a role in controlling key senescence and pro-inflammatory genes that are part of the senescence secretome that initiates retina regeneration.

Senescence is a complex cellular state that can be considered as a stress response phenotype. A decade ago, we suggested the intricate connections between unfolded protein response (UPR) signaling and the development of the senescent phenotype. Over the past ten years, significant advances have been made in understanding the multifaceted role of the UPR in regulating cellular senescence, highlighting its contribution to biological processes such as oxidative stress and autophagy. In this updated review, we expand these interconnections with the benefit of new insights, and we suggest that targeting specific components of the UPR could provide novel therapeutic strategies to mitigate the deleterious effects of senescence, with significant implications for age-related pathologies and geroscience.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). Key drivers of DR include mitochondrial dysfunction, oxidative stress, and chronic inflammation, which lead to premature senescence of cells within the retinal vasculature. Senolytics improve outcomes in both animal models and in patients with severe forms of DR. In this review, we discuss (i) the role of endothelial senescence in each stage of DR pathogenesis, (ii) methods for detecting senescence in cultured endothelial cells and retinal vessels, and (iii) potential mechanistic explanations for how cells within retinal vessels resist DM-driven senescence.

Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness among individuals with diabetes mellitus. Current clinical diagnostic criteria mainly base on visible vascular structure changes, which are insufficient to identify diabetic patients without clinical DR (NDR) but with dysfunctional retinopathy. This review focuses on retinal endothelial cells (RECs), the first cells to sense and respond to elevated blood glucose. As blood glucose rises, RECs undergo compensatory and transitional phases, and the correspondingly altered molecules are likely to become biomarkers and targets for early prediction and treatment of NDR with dysfunctional retinopathy. This article elaborated the possible pathophysiological processes focusing on RECs and summarized recently published and reliable biomarkers for early screening and emerging intervention strategies for NDR patients with dysfunctional retinopathy. Additionally, references for clinical medication selection and lifestyle recommendations for this population are provided. This review aims to deepen the understanding of REC biology and NDR pathophysiology, emphasizes the importance of early detection and intervention, and points out future directions to improve the diagnosis and treatment of NDR with dysfunctional retinopathy and to reduce the occurrence of DR.

We tested the ability of a single intravitreal injection of foselutoclax (hereafter UBX1325), a novel senolytic small molecule inhibitor of antiapoptotic protein B-cell lymphoma-extra large, to mitigate the impact of diabetic macular edema.

Patients with diabetic macular edema with prior suboptimal response to anti-vascular endothelial growth factor treatment were randomly assigned (1:1) to either a single intravitreal injection of 10 μg of UBX1325 or sham and were followed for up to 48 weeks. The primary trial objective was to evaluate the safety and side-effect profile of UBX1325 as assessed by ocular and systemic treatment-emergent adverse events (TEAEs). Our secondary objective was to probe efficacy, defined as mean changes from baseline for UBX1325 versus sham in best corrected visual acuity measured in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (range, 0-100 letters, higher scores indicate better vision) and retinal structure.

Between June 2021 and April 2022, 65 participants (32.3% women) were randomly assigned to either UBX1325 (n=32) or sham (n=33). There were four TEAEs of Grade 3 or greater in the sham group, of which three were considered serious, while there were five in the UBX1325 group of Grade 3 or greater and considered serious. There were no apparent between-group differences with respect to vital signs, electrocardiograms, or routine blood chemistries. For the secondary outcome of efficacy, the difference between UBX1325 and sham in mean change to week 48 in best corrected visual acuity was 5.6 more ETDRS letters (95% confidence interval, -1.5 to 12.7).

In this sham-controlled trial there were no TEAEs that led to discontinuation of treatment with UBX1325 compared with sham. There were trends suggestive of potential efficacy; larger trials are needed to further evaluate these findings. (Funded by UNITY Biotechnology; ClinicalTrials.gov number, NCT04857996.).

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention.

Aging serves as a pivotal factor in the etiology of numerous diseases, such as Alzheimer's disease (AD), Parkinson's disease, diabetes, osteoarthritis, atherosclerosis and aging-related macular degeneration. Notably, these diseases often interact with AD through various pathways, facilitating the onset or progression of one another. Semaphorin 3 A (Sema3A), a protein that is essential for axonal guidance during neural development, has recently been identified as a novel regulator in the pathogenesis and progression of multiple aging-related diseases. This article provides a comprehensive review of the expression patterns and mechanisms of action of Sema3A in these diseases. Specifically, Sema3A influences the occurrence and development of aging-related diseases by participating in oxidative stress, inflammatory responses, apoptosis, and synaptic plasticity. Therefore, therapeutic strategies targeting Sema3A present promising avenues for delaying the progression of aging-related diseases and offer novel insights and strategies for their treatment.

The Mary Tyler Moore Vision Initiative (MTM Vision) honors Mary Tyler Moore's commitment to ending vision loss from diabetes. Founded by Moore's husband, Dr. S. Robert Levine, MTM Vision aims to accelerate breakthroughs in diabetic retinal disease (DRD). At the MTM Vision Symposium 2024 on Curing Vision Loss from Diabetes, experts highlighted the urgent need for updated DRD staging systems, clinically relevant endpoints, and novel biomarkers to detect early disease changes. MTM Vision is advancing two clinical trials in collaboration with the DRCR Retina Network, launching a public awareness campaign, and welcoming Boehringer Ingelheim as the first founding industry member of its pre-competitive Consortium. Speakers emphasized big-data strategies and artificial intelligence (AI)-driven tools to improve DRD diagnosis, risk prediction, and personalized treatment. They also showcased new efforts to bridge academic discoveries with industry expertise, illustrating promising work on vascular regeneration and cellular senescence that may yield future therapies. The MTM Vision Biorepository and Resource Center is expanding tissue collections, enabling multi-omics analyses to study DRD mechanisms. Patient voices were central to the discussion, with calls for enhanced patient-reported outcomes, caregiver support, and broader education on DRD's risks. The symposium also underscored the importance of integrating mental health, quality of life measures, and ongoing patient input to guide clinical research.

Ischemic retinal diseases are major causes of blindness worldwide and are characterized by pathological angiogenesis. Epigenetic alterations in response to metabolic shifts in endothelial cells (ECs) suffice to underlie excessive angiogenesis. Lactate accumulation and its subsequent histone lactylation in ECs contribute to vascular disorders. However, the regulatory mechanism of establishing and sustaining lactylation modification remains elusive. Here, we showed that lactate accumulation induced histone lactylations on H3K9 and H3K18 in neovascular ECs in the proliferative stage of oxygen-induced retinopathy. Joint CUT&Tag and scRNA-seq analyses identified Prmt5 as a target of H3K9la and H3K18la in isolated retinal ECs. EC-specific deletion of Prmt5 since the early stage of revascularization suppressed a positive feedback loop of lactate production and histone lactylation, thus inhibiting neovascular tuft formation. Mechanistically, the C-terminal intrinsically disorder region (IDR) of the transmembrane semaphorin 6A (SEMA6A) forms liquid-liquid phase separation condensates to recruit RHOA and P300, facilitating P300 phosphorylation and histone lactylation cycle. Deletion of endothelial Sema6A reduced H3K9la and H3K18la at the promoter of PRMT5 and diminished its expression. The induction of histone lactylation by SEMA6A-IDR and its pro-angiogenic effect were abrogated by deletion of Prmt5. Our study illustrates a sustainable histone lactylation machinery driven by phase separation-dependent lactyltransferase activation in dysregulated vascularization.

Zebrafish possess the innate ability to regenerate any lost or damaged retinal cell type with Müller glia serving as resident stem cells. Recently, we discovered that this process is aided by a population of damage-induced senescent immune cells. As part of the Senescence Associated Secretory Phenotype (SASP), senescent cells secrete numerous factors that can play a role in the modulation of inflammation and remodeling of the retinal microenvironment during regeneration. However, the identity of specific SASP factors that drive initiation and progression of retina regeneration remains unclear.

We mined the SASP Atlas and publicly available RNAseq datasets to identify common, differentially expressed SASP factors after retina injury. These datasets included two distinct acute damage regimens, as well as two chronic, genetic models of retina degeneration. We identified overlapping factors between these models and used genetic knockdown experiments, qRT/PCR and immunohistochemical staining to test a role for one of these factors (npm1a).

We discovered an overlapping set of 31 SASP-related regeneration factors across all data sets and damage paradigms. These factors are upregulated after damage with functions that span the innate immune system, autophagic processing, cell cycle regulation, and cellular stress responses. From among these, we show that depletion of Nucleophosmin 1 (npm1a) inhibits retina regeneration and decreases senescent cell detection after damage.

Our data suggest that differential expression of SASP factors promotes initiation and progression of retina regeneration after both acute and chronic retinal damage. The existence of a common, overlapping set of 31 factors provides a group of novel therapeutic targets for retina regeneration studies.

To evaluate the association of biological age acceleration with incident glaucoma risk and examine whether genetic predisposition modifies it.

We included 318,556 UK Biobank participants without baseline glaucoma. Biological age was calculated using the Klemera-Doubal method Biological Age (KDM-BA) and PhenoAge algorithms. Hazard ratios (HRs) and 95% confidence intervals (CIs) of the association between biological age acceleration and incident glaucoma, and their interaction with genetic risk were analyzed by Cox regression models. Mendelian randomization analyses investigated causal associations.

After a median follow-up of 13.5 years, 6553 participants developed glaucoma. Biological age acceleration was associated with an increased glaucoma risk. Each 5-year increment in biological age acceleration was linked to higher glaucoma risk (KDM-BA acceleration: HR, 1.12, 95% CI, 1.07-1.16; PhenoAge acceleration, HR, 1.09, 95% CI, 1.06-1.13). Biologically older participants had a higher glaucoma risk than younger participants (KDM-BA acceleration, HR, 1.10, 95% CI, 1.05-1.16; PhenoAge acceleration, HR, 1.07, 95% CI, 1.02-1.13). Genetic risk modified these relationships (all P for interactions < 0.05). Biologically older participants with high genetic risk had the highest glaucoma risk (KDM-BA acceleration, HR, 2.33, 95% CI, 2.15-2.52; PhenoAge acceleration, HR, 2.21, 95% CI, 2.05-2.38). No causal relationships were found in the Mendelian randomization analysis.

Biological age acceleration was associated with an increased glaucoma risk, and this relationship was modified by genetic risk. However, no causal relationship was established, and further research is needed to investigate the nature of the association.

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

Recent research has raised concerns about the association between metformin treatment in patients with diabetes mellitus (DM) and an increased risk of diabetic retinopathy. We sought to investigate this relationship, specifically examining if metformin use affects diabetic retinopathy risk in a dose-dependent manner.

This study was a secondary data analysis based on a nationwide population database in Taiwan. Patients with new-onset DM, an age of 20 years or older, and a diagnosis of type 2 DM received at any time during 2002-2013 were included in the study. Patients diagnosed with new-onset type 2 DM between 2002 and 2013 were enrolled as the study population. We divided them into two groups: those treated with metformin and those treated with sulfonylureas. A Cox proportional hazards model was employed to estimate the risk of diabetic retinopathy after 5 years of follow-up, including cumulative defined daily dose and intensity of metformin treatment.

A total of 241,231 patients received treatment with metformin, while 152,617 patients were treated with sulfonylureas. Compared with patients treated with sulfonylureas, patients who received metformin treatment, at a cumulative defined daily dose < 30, had a lower risk of diabetic retinopathy (adjusted hazard ratio = 0.77; 95% confidence interval 0.60-0.98). However, those with varying defined daily doses, especially at a higher metformin treatment level (> 25 defined daily dose), had a 2.43 times higher risk of diabetic retinopathy (95% confidence interval 1.37-4.30) compared with patients treated with sulfonylureas.

Patients with DM treated with a lower cumulative dosage of metformin showed beneficial effects that were associated with a lower risk of diabetic retinopathy. In contrast, a higher intensity of metformin use had a greater risk of diabetic retinopathy.

Allograft rejection remains a major cause of failure in high-risk corneal transplants, but the underlying mechanisms are not fully understood. This study aimed to investigate the contribution of transplantation stress-induced cellular senescence to corneal allograft rejection and to elucidate the associated molecular mechanisms.

Age-matched murine corneal transplantation models were established. Cellular senescence was evaluated using senescence-associated β-galactosidase (SA-β-Gal) staining, western blot, and immunofluorescence staining. The role of cellular senescence in corneal allograft rejection was analyzed using p16 knockout mice and adoptive transfer experiments. Senolytic treatment with ABT-263 was administered intraperitoneally to evaluate its effects on corneal allograft rejection. RNA sequencing and pharmacological approaches were employed to identify the underlying mechanisms.

Surgical injury induced a senescence-like phenotype in both donor corneas and recipient corneal beds, characterized by an increased accumulation of SA-β-Gal-positive cells in the corneal endothelium and stroma and elevated expression of senescence markers p16 and p21. Using genetic and adoptive transfer models, transplantation stress-induced senescence was shown to exacerbate corneal allograft rejection. Importantly, clearance of senescent cells by ABT-263 significantly suppressed ocular alloresponses and immune rejection. Mechanistically, RNA sequencing and loss-of-function experiments demonstrated that the anti-rejection effects of senolytic treatment were closely dependent on angiotensin-converting enzyme 2 (ACE2).

These findings highlight transplantation stress-induced senescence as a pivotal pathogenic factor in corneal allograft rejection. Senolytic therapy emerges as a potential novel strategy to mitigate transplant rejection and improve corneal allograft survival.

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth factor signaling (IIS), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase. The dysregulation of these pathways contributes to insulin resistance, impaired autophagy, exacerbated oxidative stress, and mitochondrial dysfunction, further enhancing cellular senescence and systemic metabolic derangements. On the other hand, dysfunctional endothelial cells and adipocytes contribute to systemic inflammation, reduced nitric oxide production, and altered lipid metabolism. Numerous factors, including extracellular vesicles, mediate pathological communication between the vascular system and adipose tissue, amplifying metabolic imbalances. Meanwhile, caloric restriction (CR) emerges as a potent intervention to counteract overnutrition effects, improve mitochondrial function, reduce oxidative stress, and restore metabolic balance. CR modulates pathways such as IIS, mTOR, and sirtuins, enhancing glucose and lipid metabolism, reducing inflammation, and promoting autophagy. CR can extend the health span and mitigate age-related diseases by delaying cellular senescence and improving healthy endothelial-adipocyte interactions. This review highlights the crosstalk between endothelial cells and adipocytes, emphasizing CR potential in counteracting overnutrition-induced senescence and restoring vascular homeostasis.

Ever since the US Food and Drug Administration (FDA) approved the first vascular endothelial growth factor (VEGF) antagonist 2 decades ago, inhibitors of VEGF have revolutionized the treatment of a variety of ocular disorders involving pathologic neovascularization and retinal exudation. In this perspective, we evaluate the current status of anti-VEGF therapies and the real-world challenges encountered with maintaining therapeutic outcomes. Finally, we describe novel VEGF-based and combinatorial approaches that are in clinical development.

In recent years, the adaptive immune system has gained a significant amount of attention due to its potential role in age-related macular degeneration (AMD). Orthologous approaches including cellular and animal models as well as pilot clinical trials have paved the way to understand the occurrence, alterations, and interactions of T cell populations in the retina. Interestingly, the notions of the involvement of the adaptive immune system in AMD have also gained support through recent findings in various neurodegenerative and chronic low-grade diseases, including multiple sclerosis, Parkinson's disease, or arteriosclerosis. In this group of pathologies, cells of the adaptive immune system bypass immune barriers and fuel inflammatory processes at immune-privileged sites. These findings have pointed at immunosenescence as a critical pro-inflammatory process involving T cell biology. Using a murine model relevant to the pathophysiology of geographic atrophy, we have demonstrated that specific populations of memory T cells are recruited to the retina prior to neurodegeneration. The investigation of these retinas at later degenerative stages revealed the presence of activated cytotoxic T cells at the injury site. These compelling results support the participation of the adaptive immune system in retina degeneration and highlight the potential of T cell populations as an early therapeutic target to slow the progression of AMD.

Cellular senescence is a state of permanent proliferative arrest that occurs in response to DNA damage-inducing endogenous and exogenous stresses, and is often accompanied by dynamic molecular changes such as a senescence-associated secretory phenotype (SASP). Accumulating evidence indicates that age-associated increases in the upstream and downstream signals of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are closely related to the induction of cellular senescence and its phenotype. Furthermore, elevated levels of pro-inflammatory SASP factors with aging can be both a cause and consequence of several cell death modes, suggesting the reciprocal effects of cellular senescence and cells undergoing regulated cell death. Here, we review the critical molecular pathways of the regulated cell death forms and describe the crosstalk between aging-related signals and cancer. In addition, we discuss how targeting regulated cell death could be harnessed in therapeutic interventions for cancer. ABBREVIATIONS: Abbreviations that are not standard in this field are defined at their first occurrence in the article and are used consistently throughout the article.

To explore the relationship between gut microbiome, gut mycobiome, and intraocular (aqueous humor) microbiome dysbiosis in people with type 2 diabetes (T2DM) and diabetic retinopathy (DR).

Multiple case-control studies.

We evaluated three groups of people: healthy controls (HC), people with T2DM without retinopathy, and those with DR. The study samples included fecal matter (30-50 g) and aqueous humor (0.05-0.1 mL). After amplicon sequencing, we analyzed microbiome profiles (V3-V4 region of bacterial 16S rRNA gene) and mycobiome (ITS2 region of fungal rRNA gene). The main outcome measures were relative abundance, α and β diversity, and dysbiotic bacteria and fungi, analyzed based on the inferred functions of the taxa.

We recruited 82 people for gut microbiome (30 HC, 24 DM, and 28 DR); 75 people for gut mycobiome (30 HC, 21 DM, and 24 DR); and 12 people for aqueous humor microbiome (4 each HC, DM, and DR) studies. Generally, there was an increased abundance of pro-inflammatory and pathogenic microorganisms and a decreased abundance of anti-inflammatory and probiotic microorganisms. The differences were higher between HC and DM/DR than between DM and DR. In aqueous humor, there was a wider separation in microbiome profiles of people with DR than their gut microbiome.

The gut and aqueous humor microbiota of people with diabetes and DR may differ from those without diabetes. Given these unique observations in individuals living in one region of India, further research involving people from different regions is required to identify indices for possible regional or global use.

Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system, this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Here, we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that dexamethasone, a broad-spectrum corticosteroid, suppresses initial formation of pathological preretinal neovascularization in early stages of disease, yet blunts reparative inflammation by impairing distinct myeloid cell populations, and hence reduces beneficial vascular remodeling in later stages of disease. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing lysozyme 2 are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered, particularly in stages associated with persistent neovascularization.

Diabetic retinopathy (DR) is a diabetic complication that results in visual impairment and relevant retinal diseases. Current therapeutic strategies on DR primarily focus on antiangiogenic therapies, which particularly target vascular endothelial growth factor and its related signaling transduction. However, these therapies still have limitations due to the intricate pathogenesis of DR. Emerging studies have shown that premature senescence of endothelial cells (ECs) in a hyperglycemic environment is involved in the disease process of DR and plays multiple roles at different stages. Moreover, these surprising discoveries have driven the development of senotherapeutics and strategies targeting senescent endothelial cells (SECs), which present challenging but promising prospects in DR treatment. In this review, we focus on the inducers and mechanisms of EC senescence in the pathogenesis of DR and summarize the current research advances in the development of senotherapeutics and strategies that target SECs for DR treatment. Herein, we highlight the role played by key factors at different stages of EC senescence, which will be critical for facilitating the development of future innovative treatment strategies that target the different stages of senescence in DR.

Neovascular age-related macular degeneration (nAMD), a leading cause of blindness in older adults, presents a challenging pathophysiology involving choroidal neovascularization (CNV) and retinal degeneration. Current treatments relying on intravitreal (IVT) administration of anti-angiogenic agents are costly and of moderate effectiveness. Metformin, the common anti-diabetic drug, has been associated with decreased odds of developing AMD. Studies have shown that metformin can mitigate cellular aging, neoangiogenesis, and inflammation across multiple diseases. This preclinical study assessed metformin's impact on vessel growth using choroidal explants before exploring IVT metformin's effects on laser-induced CNV and light-induced retinal degeneration in C57BL/6J and BALB/cJ mice, respectively. Metformin reduced new vessel growth in choroidal explants in a dose-dependent relationship. Following laser induction, IVT metformin suppressed CNV and decreased peripheral infiltration of IBA1+ macrophages/microglia. Furthermore, IVT metformin protected against retinal thinning in response to light-induced degeneration. IVT metformin downregulated genes in the choroid and retinal pigment epithelium which are associated with angiogenesis and inflammation, two key processes that drive nAMD progression. These findings underscore metformin's capacity as an anti-angiogenic and neuroprotective agent, demonstrating this drug's potential as an accessible option to help manage nAMD.

Background/Objectives: The objective of this study was to determine the treatment effect of foselutoclax in neovascular age-related macular degeneration (AMD) by multifocal electroretinography (mfERG) and evaluate mfERG as a potential clinical endpoint in AMD studies. Methods: A total of five subjects were included in the study who had active choroidal neovascularization and a history of at least two anti-vascular endothelial growth factor (VEGF) injections in the last 6 months. Subjects received a 50 µL intravitreal injection of foselutoclax at the baseline visit and Weeks 4, 24, and 28 of the study period. Results: After foselutoclax treatment, the largest improvement in the mfERG N1-P1 response density occurred at Week 8 as three of five subjects achieved a ≥20% gain. In addition, three of five subjects demonstrated a BCVA improvement of ≥5 ETDRS letters over baseline at Weeks 4, 8, and 24. The mean change in BCVA demonstrated statistical significance in Weeks 4 and 8, showing increases of 5 (p = 0.02) and 6.2 (p = 0.02) letters, respectively. Conclusions: Foselutoclax treatment was shown to have the potential to recover outer retinal function as determined by mfERG and BCVA at approximately Week 8 of treatment.

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

Diabetic retinopathy (DR) is a major cause of vision loss and blindness in adults. Cellular senescence was involved in the pathogenesis of early-stage DR and is positively correlated with progression. Thus, our study aimed at exploring the effect and potential mechanism of Mesenchymal stem cells-derived exosomes (MSCs-EXOs) on Retinal Pigment Epithelial (RPE) cells senescence at an early stage of DR in vivo and in vitro. ARPE-19 cells were incubated in high glucose (HG) medium mixed with MSCs-EXOs to observe the changes in cell viability. Senescence-associated β-galactosidase (SA-β-gal) staining, Western blot and qRT-PCR were used to assess the expression of senescence-related genes and antioxidant mediators. Quantitative Real-Time polymerase chain reaction (qRT-PCR), Optical coherence tomography (OCT) Hematoxylin and eosin (HE) staining and Electroretinogram (ERG) were respectively used to verify cellular senescence, the structure and function of the retina. Our findings demonstrated that MSCs-EXOs inhibited HG-induced senescence in ARPE-19 cells. Furthermore, MSCs-EXOs reduced HG-induced cell apoptosis and oxidative stress levels while promoting cell proliferation. Mechanistically, HG suppressed PI3K/AKT phosphorylation as well as nuclear factor erythroid 2-related factor 2 (Nrf2) expression along with its downstream target gene expression in ARPE-19 cells. However, MSCs-EXOs reversed these changes by alleviating cellular senescence while enhancing antioxidant activity. In line with our results in vitro, MSCs-EXOs significantly ameliorated hyperglycemia-induced senescence in DR mice by downregulating mRNA expression of P53, P21, P16, and SASP. Additionally, MSCs-EXOs improved the functional and structural integrity of the retina in DR mice. Our study revealed the protective effect of MSCs-EXOs on cellular senescence, offering new insights for the treatment of DR.

Cellular senescence contributes to ageing and age-related diseases, and multiple therapeutic strategies are being developed to counteract it. Senolytic drugs are being tested in clinical trials to eliminate senescent cells selectively, but their effects and mechanisms are still unclear. Several studies reveal that the upregulation of senescence-associated secretory phenotype (SASP) factors in senescent cells is accompanied by increased autophagic activity to counteract the endoplasmic reticulum (ER) stress. Our study shows that Doxo-induced senescent fibroblasts yield several SASP factors and exhibit increased autophagy. Interestingly, Quercetin, a bioactive flavonoid, reduces autophagy, increases ER stress, and partially triggers senescent fibroblast death. Given the role of senescent cells in cancer progression, we tested the effect of conditioned media from untreated and quercetin-treated senescent fibroblasts on osteosarcoma cells to determine whether senolytic treatment affected tumour cell behaviour. We report that the partial senescent fibroblast clearance, achieved by quercetin, reduced osteosarcoma cell invasiveness, curbing the pro-tumour effects of senescent cells. The reduction of cell autophagic activity and increased ER stress, an undescribed effect of quercetin, emerges as a new vulnerability of Doxo-induced senescent fibroblasts and may provide a potential therapeutic target for cancer treatment, suggesting novel drug combinations as a promising strategy against the tumour.

Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis, and normal tissue toxicity, TIS also has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), focusing on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Through the SASP, SnCs can mediate both resistance and response to cancer therapies. To fulfill the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as an antigen source to potentiate anti-tumor immune response. This new perspective suggests treatment approaches based on TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, which may enhance the overall benefits of cancer treatment.

The purpose of this study was to establish and validate a deep learning model to screen vascular aging using retinal fundus images. Although vascular aging is considered a novel cardiovascular risk factor, the assessment methods are currently limited and often only available in developed regions.

We used 8865 retinal fundus images and clinical parameters of 4376 patients from two independent datasets for training a deep learning algorithm. The gold standard for vascular aging was defined as a pulse wave velocity ≥1400 cm/s. The probability of the presence of vascular aging was defined as deep learning retinal vascular aging score, the Reti-aging score. We compared the performance of the deep learning model and clinical parameters by calculating the area under the receiver operating characteristics curve (AUC). We recruited clinical specialists, including ophthalmologists and geriatricians, to assess vascular aging in patients using retinal fundus images, aiming to compare the diagnostic performance between deep learning models and clinical specialists. Finally, the potential of Reti-aging score for identifying new-onset hypertension (NH) and new-onset carotid artery plaque (NCP) in the subsequent three years was examined.

The Reti-aging score model achieved an AUC of 0.826 (95% confidence interval [CI] = 0.793-0.855) and 0.779 (95% CI = 0.765-0.794) in the internal and external dataset. It showed better performance in predicting vascular aging compared with the prediction with clinical parameters. The average accuracy of ophthalmologists (66.3%) was lower than that of the Reti-aging score model, whereas geriatricians were unable to make predictions based on retinal fundus images. The Reti-aging score was associated with the risk of NH and NCP (P < 0.05).

The Reti-aging score model might serve as a novel method to predict vascular aging through analysis of retinal fundus images. Reti-aging score provides a novel indicator to predict new-onset cardiovascular diseases.

Given the robust performance of our model, it provides a new and reliable method for screening vascular aging, especially in undeveloped areas.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Malignant Melanoma that resists immunotherapy remains the deadliest form of skin cancer owing to poor clinically lasting responses. Alternative like genotoxic or targeted chemotherapy trigger various cancer cell fates after treatment including cell death and senescence. Senescent cells can be eliminated using senolytic drugs and we hypothesize that the targeted elimination of therapy-induced senescent melanoma cells could complement both conventional and immunotherapies. We utilized a panel of cells representing diverse mutational background relevant to melanoma and found that they developed distinct senescent phenotypes in response to treatment. A genotoxic combination therapy of carboplatin-paclitaxel or irradiation triggered a mixed response of cell death and senescence, irrespective of BRAF mutation profiles. DNA damage-induced senescent melanoma cells exhibited morphological changes, residual DNA damage, and increased senescence-associated secretory phenotype (SASP). In contrast, dual targeted inhibition of Braf and Mek triggered a different mixed cell fate response including senescent-like and persister cells. While persister cells could reproliferate, senescent-like cells were stably arrested, but without detectable DNA damage and senescence-associated secretory phenotype. To assess the sensitivity to senolytics we employed a novel real-time imaging-based death assay and observed that Bcl2/Bcl-XL inhibitors and piperlongumine were effective in promoting death of carboplatin-paclitaxel and irradiation-induced senescent melanoma cells, while the mixed persister cells and senescent-like cells resulting from Braf-Mek inhibition remained unresponsive. Interestingly, a direct synergy between Bcl2/Bcl-XL inhibitors and Braf-Mek inhibitors was observed when used out of the context of senescence. Overall, we highlight diverse hallmarks of melanoma senescent states and provide evidence of context-dependent senotherapeutics that could reduce treatment resistance while also discussing the limitations of this strategy in human melanoma cells.

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

Age-related macular degeneration (AMD) is a degenerative ocular disease primarily affecting central vision in the elderly. Its pathogenesis is complex, involving cellular senescence and immune homeostasis dysregulation. This review investigates the interaction between these two critical biological processes in AMD pathogenesis and their impact on disease progression. Initially, cellular senescence is analyzed, with particular emphasis on retinal damage induced by senescent retinal pigment epithelial cells. Subsequently, the occurrence of immune homeostasis dysregulation within the retina and its mechanistic role in AMD areis explored. Furthermore, the paper also discusses in detail the interplay between cellular senescence and immune responses, forming a vicious cycle that exacerbates retinal damage and may influence treatment outcomes. In summary, a deeper understanding of the interrelation between cellular senescence and immune dysregulation is vital for the developing innovative therapeutic strategies for AMD.

Radiation proctitis (RP) is a significant complication of pelvic radiation. Effective treatments for chronic RP are currently lacking. We report a case where chronic RP was successfully managed by metformin and butyrate (M-B) enema and suppository therapy.

A 70-year-old Asian male was diagnosed with prostate cancer of bilateral lobes, underwent definitive radiotherapy to the prostate of 76 Gy in 38 fractions and six months of androgen deprivation therapy. Despite a stable PSA nadir of 0.2 ng/mL for 10 months post-radiotherapy, he developed intermittent rectal bleeding, and was diagnosed as chronic RP. Symptoms persisted despite two months of oral mesalamine, mesalamine enema and hydrocortisone enema treatment. Transition to daily 2% metformin and butyrate (M-B) enema for one week led to significant improvement, followed by maintenance therapy with daily 2.0% M-B suppository for three weeks, resulting in continued reduction of rectal bleeding. Endoscopic examination and biopsy demonstrated a good therapeutic effect.

M-B enema and suppository may be an effective treatment for chronic RP.

Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor-promoting effect of senescence is mainly elicited by a senescence-associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A "one-two-punch" therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.

In this study, we carried out a clinical sample study, and in vivo and in vitro studies to evaluate the effect of SIRT6 and SIRT6-mediated vascular smooth muscle senescence on the development of abdominal aortic aneurysm (AAA).

AAA specimen showed an increased P16, P21 level and a decreased SIRT6 level compared with control aorta. Time curve study of Ang II infusion AAA model showed similar P16, P21 and SIRT6 changes at the early phase of AAA induction. The in vivo overexpression of SIRT6 significantly prevented AAA formation in Ang II infusion model. The expression of P16 and P21 was significantly reduced after SIRT6 overexpression. SIRT6 overexpression also attenuated chronic inflammation and neo-angiogenesis in Ang II infusion model. The overexpression of SIRT6 could attenuate premature senescence, inflammatory response and neo-angiogenesis in human aortic smooth muscle cells (HASMC) under Ang II stimulation.

SIRT6 overexpression could limit AAA formation via attenuation of vascular smooth muscle senescence, chronic inflammation and neovascularity.

Diabetes mellitus (DM) is a chronic metabolic disorder affecting millions of people worldwide, characterized by dysregulated glucose homeostasis and hyperglycemia. Diabetic retinopathy (DR) is one of the serious multisystemic complications. Aging is an important risk factor for DR. Endothelial sirtuin 1 (SIRT1) plays an important role in regulating the pathophysiology of glucose metabolism, cellular senescence, and aging. Liraglutide, an analog of Glucagon-like peptide 1 (GLP-1), has been widely used in the treatment of DM. However, the effects of Liraglutide on DR are less reported. Here, we investigated whether treatment with Liraglutide has beneficial effects on high glucose (HG)-induced injury in human retinal microvascular endothelial cells (HRECs). First, we found that exposure to HG reduced the expression of glucagon-like peptide 1 receptor 1 (GLP-1R). Additionally, Liraglutide ameliorated HG-induced increase in the expression of vascular endothelial growth factor-A (VEGF-A) and interleukin 6 (IL-6). Importantly, Liraglutide ameliorated cellular senescence and increased telomerase activity in HG-challenged HRECs. Liraglutide also reduced the levels of p53 and p21. Mechanistically, Liraglutide restored the expression of SIRT1 against HG. In contrast, the knockdown of SIRT1 abolished the protective effects of Liraglutide in cellular senescence of HRECs. Our findings suggest that Liraglutide might possess a benefit on DR mediated by SIRT1.