Recent advancements in our understanding of cell death mechanisms have progressed beyond traditional apoptosis to encompass various forms of regulated cell death, notably cuproptosis. This copper-dependent cell death occurs when copper interacts with lipoylated enzymes in the tricarboxylic acid cycle, leading to protein aggregation and subsequent cell death. Alongside this, immunosenescence the gradual decline in immune function due to aging has emerged as a significant factor in cancer progression and response to treatment. Innovative strategies that integrate cuproptosis and immunosenescence are showing considerable promise in cancer therapy. By leveraging the altered copper metabolism in cancer cells, cuproptosis can selectively induce cell death, effectively targeting and eliminating tumors. Simultaneously, addressing immunosenescence can rejuvenate the aging immune system, enhancing its capacity to identify and destroy cancer cells. This dual approach creates a synergistic effect, optimizing therapeutic efficacy by directly attacking tumor cells while revitalizing the immune response. Such integration bolsters the defense against cancer progression and recurrence and holds great potential for advancing cancer treatment modalities and improving patient outcomes. This paper delves into the interactions between cuproptosis and immunosenescence, emphasizing their implications for developing innovative cancer therapies.

The intestine, frequently subjected to pelvic or abdominal radiotherapy, is particularly vulnerable to delayed effects of acute radiation exposure (DEARE) owing to its high radiation sensitivity. Radiation-induced intestinal senescence, a result of DEARE, profoundly affects the well-being and quality of life of radiotherapy patients. However, targeted pharmaceutical interventions for radiation-induced senescence are currently scarce. Our findings showcase that nicotinamide riboside(NR) effectively alleviates radiation-induced intestinal senescence, offering crucial implications for utilizing NR as a pharmacological agent to combat intestinal DEARE.

The aim of this study was to investigate the ability of NR to reduce radiation induced intestinal senescence and explore its related mechanisms.

Male C57BL/6J mice were randomly divided into CON, IR, and IR + NR groups. The mice in the IR and IR + NR groups were subjected to a 6.0 Gy γ-ray total body exposure. After 8 weeks, the mice in the IR + NR group received NR via gavage at a dose of 400 mg/kg/d for 21 days. Then the mice were used for sample collection.

Our results demonstrate that NR can significantly mitigate radiation-induced intestinal senescence. Furthermore, our findings indicate that NR can mitigate oxidative damage, restore the normal function of intestinal stem cells, regulate the disruption of the intestinal symbiotic ecosystem and address metabolic abnormalities. In addition, the underlying mechanisms involve the activation of SIRT6, SIRT7 and the inhibition of the mTORC1 pathway by NR.

In conclusion, our results reveal the substantial inhibitory effects of NR on radiation-induced intestinal senescence. These findings offer valuable insights into the potential therapeutic use of NR as a pharmacological agent for alleviating intestinal DEARE.

Neuroinflammation contributes to the loss of dopamine neurons and motor dysfunctions in Parkinson's disease (PD). How cell metabolism regulates neuroinflammation by modulating epigenetic modifications is largely unknown. In this study, we found that the expression of phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first step of the de novo serine synthesis pathway was mainly expressed in astrocytes and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) injection triggered the upregulation of PHGDH in astrocytes in substantia nigra. PHGDH inhibition or knockdown reduced proinflammatory cytokine production in primary astrocytes after LPS (lipopolysaccharide) stimulation which was not due to suppressed inflammatory signaling transduction. Mechanistically, PHGDH promotes proinflammatory cytokine transcription by sustaining nicotinamide adenine dinucleotide (NADH) accumulation to facilitate histone acetylation of cytokine promoters. Moreover, PHGDH inhibition-induced inflammatory response decreased neurotoxicity in vitro and alleviated astrocytes-mediated neuroinflammation and neurotoxicity in an MPTP mice model. This study reveals the role and mechanism of PHGDH-mediated serine synthesis in promoting the inflammatory response of astrocytes which may provide a potential target for neurological diseases involving neuroinflammation.

By dissecting metabolic and epigenetic features imposed by ageing in cardiomyocyte conversion from fetal and adult mouse fibroblasts, Santos et al. describe that metabolic modulation can enhance direct cardiac reprogramming.

Keratoconus is a bilateral and asymmetric degenerative eye disease that causes corneal thinning and bowing, leading to irregular astigmatism and vision loss. Although environmental and genetic factors contribute to the disease's development, the exact cause and underlying pathological mechanism remain unknown. In this review, we comprehensively explore the latest pathophysiological mechanisms of keratoconus, focusing on oxidative damage and inflammation. Senescence emerges as a key driver of keratoconus pathogenesis. Understanding these common elements enhances our understanding of the disease and paves the way for innovative therapeutic approaches to keratoconus.

Maimendong decoction (MMDD) originates from the ancient Chinese medical text Synopsis of the Golden Chamber and is a well-established remedy for treating lung diseases. It has demonstrated efficacy in the long-term clinical management of idiopathic pulmonary fibrosis (IPF); however, its underlying mechanisms remain unclear.

This study investigates whether MMDD alleviates IPF by reducing type 2 alveolar epithelial cell (AEC2) senescence and enhancing mitochondrial autophagy. It also explores whether these effects are mediated through the PTEN-induced putative kinase 1 (PINK1)/Parkinson juvenile disease protein 2 (Parkin) pathway.

An IPF mouse model was established with bleomycin (BLM). Mice were administered MMDD, pirfenidone (PFD), or saline for 7 or 28 days. Body weight, lung coefficient, and lung appearance were monitored, and lung tissue pathology was assessed. The expression levels of p53, p21, p16, SA-β-gal activity, and senescence-associated secretory phenotype (SASP) markers were measured. Ultrastructural changes in AEC2 mitochondria were analyzed using transmission electron microscopy. Protein levels of autophagy markers sequestosome-1 and light chain 3 were assessed. The protein levels of PINK1, Parkin, and phosphorylated Parkin were further assessed using network pharmacology analysis and molecular docking technology.

MMDD alleviated BLM-induced IPF by improving body weight, lung appearance, and histopathological features. It reduced AEC2 senescence markers, including p53, p21, p16, SA-β-gal, and SASP, while enhancing mitochondrial autophagy and repairing mitochondrial damage. Network pharmacology and molecular docking identified PINK1 as a major target, and Western blot (WB) analysis confirmed that MMDD regulates the PINK1/Parkin signaling pathway in the treatment of IPF.

MMDD regulates the PINK1/Parkin signaling pathway, alleviates AEC2 senescence, and enhances mitochondrial autophagy, providing significant therapeutic potential for IPF treatment.

Neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's disease are increasing globally and represent a significant cause of age-related death in the population. Recent studies emphasize the strong association between environmental stressors, particularly dietary factors, and brain health and neurodegeneration unsatisfactory outcomes. Despite ongoing efforts, the efficiency of current treatments for NDDs remains wanting. Considering this, nootropic foods with neuroprotective effects are of high interest as part of a possible long-term therapeutic strategy to improve brain health and alleviate NDDs. However, since it is a new and emerging area in food and neuroscience, there is limited information on mechanisms and challenges to consider for this to be a successful intervention. Here, we seek to address these gaps by presenting a comprehensive review of possible pathways or mechanisms including mutual interactions governing nootropic food metabolism, linkages of the pathways with NDDs, intake, and neuroprotective properties of nootropic foods. We also discuss in-depth intervention with nootropic compounds and dietary patterns in NDDs, providing a detailed exploration of their mechanisms of action. Additionally, we analyze the demand, challenges, and future directions for successful development of nootropic foods targeting NDDs.

Cellular senescence, a stable state of cell cycle arrest induced by various stressors or genomic damage, is recognized as a hallmark of cancer. It exerts a context-dependent dual role in cancer initiation and progression, functioning as a tumor suppressor and promoter. The complexity of senescence in cancer arises from its mechanistic diversity, potential reversibility, and heterogeneity. A key mediator of these effects is the senescence-associated secretory phenotype (SASP), a repertoire of bioactive molecules that influence tumor microenvironment (TME) remodeling, modulate cancer cell behavior, and contribute to therapeutic resistance. Given its intricate role in cancer biology, senescence presents both challenges and opportunities for therapeutic intervention. Strategies targeting senescence pathways, including senescence-inducing therapies and senolytic approaches, offer promising avenues for cancer treatment. This review provides a comprehensive analysis of the regulatory mechanisms governing cellular senescence in tumors. We also discuss emerging strategies to modulate senescence, highlighting novel therapeutic opportunities. A deeper understanding of these processes is essential for developing precision therapies and improving clinical outcomes.

Cellular senescence, a characteristic feature of the aging process, is induced by diverse stressors. In recent years, glaucoma has emerged as a blinding ocular disease intricately linked to cellular senescence. The principal pathways implicated are oxidative stress, mitochondrial dysfunction, DNA damage, autophagy impairment, and the secretion of various senescence- associated secretory phenotype factors. Research on glaucoma-associated cellular senescence predominantly centers around the increased resistance of the aqueous humor outflow pathway, which is attributed to the senescence of the trabecular meshwork and Schlemm's canal. Additionally, it focuses on the mechanisms underlying retinal ganglion cell senescence in glaucoma and the corresponding intervention measures. Given that cell senescence represents an irreversible phase preceding cell death, an in-depth investigation into its mechanisms in the pathogenesis and progression of glaucoma, particularly by specifically blocking the signal transduction of cell senescence, holds the potential to decrease the outflow resistance of aqueous humor. This, in turn, could provide a novel avenue for safeguarding the optic nerve in glaucoma.

Osteoarthritis (OA) is a prevalent joint disease characterized by pain, disability, and loss of physical function, posing a challenge to public health. However, molecular mechanisms of OA pathogenesis have not been fully described. We report that tripartite motif containing 15 (TRIM15) is a regulator in chondrocyte senescence and OA. Our study revealed heightened expression of TRIM15 in chondrocytes of senescent cartilage from patients with OA and in aged wild-type mice. Using gain- and loss-of-function studies, we found that TRIM15 facilitated human chondrocyte senescence. Conditional deletion of Trim15 in mouse chondrocytes severely impaired skeletal growth, partially because of impaired embryonic chondrocyte senescence. Compared with conditionally knocked out Col2a1-CreERT2/Trim15flox/flox mice, Trim15flox/flox control mice exhibited accelerated OA phenotypes, increased senescence markers, and senescence-associated secretory phenotype during aging. Mechanistically, TRIM15 bound with yes-associated protein (YAP) and mediated K48-linked YAP ubiquitination at K254, which interrupted the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. Dysregulation of TRIM15-YAP and transcriptional coactivator with PDZ-binding motif (TAZ) signaling promoted OA progression in both the surgery-induced and natural aging-induced mouse OA model. Intra-articular injection of adeno-associated virus 5 (AAV5)-Trim15 shRNA decelerated OA progression in mice. In particular, YAP and TAZ protein amounts were increased in chondrocytes of patients with OA. Our preclinical results demonstrated that the AAV5-TRIM15 shRNA treatment protected human OA explants against degeneration through inhibiting chondrocyte senescence. Together, our findings underscore the potential of targeting TRIM15 in reshaping the aging cartilage microenvironment and suggest a promising therapeutic avenue for OA.

The coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, our understanding of SARS-CoV-2-induced inflammation in alveolar epithelial cells remains very limited. The contributions of intracellular insulin-like growth factor binding protein-2 (IGFBP2) to SARS-CoV-2 pathogenesis are also unclear. In this study, we have uncovered a critical role for IGFBP2, specifically in alveolar epithelial type 2 cells (AEC2), in the immunopathogenesis of COVID-19. Using bulk RNA sequencing, we show that IGFBP2 mRNA expression is significantly downregulated in primary AEC2 cells isolated from fibrotic lung regions from patients with COVID-19-acute respiratory distress syndrome (ARDS) compared to those with idiopathic pulmonary fibrosis (IPF) alone or IPF with a history of COVID-19. Using multicolor immunohistochemistry, we demonstrated that IGFBP2 and its selective ligands IGF1 and IGF2 were significantly reduced in AEC2 cells from patients with COVID-ARDS, IPF alone, or IPF with COVID history than in those from age-matched donor controls. Further, we demonstrated that lentiviral expression of Igfbp2 significantly reduced mRNA expression of proinflammatory cytokines-Tnf-α, Il1β, Il6, Stat3, Stat6 and chemokine receptors-Ccr2 and Ccr5-in mouse lung epithelial cells challenged with SARS-CoV-2 spike protein injury (S2; 500 ng/mL). Finally, we demonstrated higher levels of cytokines-TNF-α; IL-6 and chemokine receptor-CCR5 in AEC2 cells from COVID-ARDS patients compared to the IPF alone and the IPF with COVID history patients. Altogether, these data suggest that anti-inflammatory properties of IGFBP2 in AEC2 cells and its localized delivery may serve as potential therapeutic strategy for patients with COVID-19.

Myocardial infarction is a cardiovascular disease that poses a serious threat to human health. The traditional view is that adult mammalian cardiomyocytes have almost no regenerative ability, but recent studies have shown that they have regenerative potential under specific conditions. This article comprehensively describes the research progress of post-infarction cardiomyocyte regeneration, including the characteristics of cardiomyocytes and post-infarction changes, regeneration mechanisms, influencing factors, potential therapeutic strategies, challenges and future development directions, and deeply discusses the specific pathways and targets included in the regeneration mechanism, aiming to provide new ideas and methods for the treatment of myocardial infarction.

Aging is a biological process along with systemic and multiple organ dysfunction. It is more and more recognized that aging is a systemic disease instead of a single-organ functional disorder. Systemic aging plays a profound role in multiple diseases including neurodegenerative diseases, cardiovascular diseases, and malignant diseases. Aged organs communicate with other organs and accelerate aging. Skeletal muscle, heart, bone marrow, skin, and liver communicate with each other through organ-organ crosstalk. The crosstalk can be mediated by metabolites including lipids, glucose, short-chain fatty acids (SCFA), inflammatory cytokines, and exosomes. Metabolic disorders including hyperglycemia, hyperinsulinemia, and hypercholesterolemia caused by chronic diseases accelerate hallmarks of aging. Systemic aging leads to the destruction of systemic hemostasis, causes the release of inflammatory cytokines, senescence-associated secretory phenotype (SASP), and the imbalance of microbiota composition. Released inflammatory factors further aggregate senescence, which promotes the aging of multiple solid organs. Targeting senescence or delaying aging is emerging as a critical health strategy for solving age-related diseases, especially in the old population. In the current review, we will delineate the mechanisms of organ crosstalk in systemic aging and age-related diseases to provide therapeutic targets for delaying aging.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in the aging population. Evidence showing the presence of cellular senescence in retinal pigment epithelium (RPE) of patients with AMD is growing. Senescent RPE play a pivotal role in its pathogenesis. The senescent RPE suffers from structural and functional alterations and disruption of the surrounding microenvironment due to the development of the senescence-associated secretory phenotype, which contributes to metabolic dysfunctions and inflammatory responses in the retina. Senotherapeutics, including senolytics, senomorphics and others, are novel treatments targeting senescent cells and are promising treatments for AMD. As senotherapeutic targets are being developed, it is promising that the burden of AMD could be decreased.

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.

This study explores the complex mechanisms between Rheumatoid Arthritis (RA) and cellular senescence, with a focus on the role of four key genes (MMP1, CCL7, CXCL1, HK3) identified through transcriptome analysis in the GEO database. These genes are closely related to IL-17 signalling and the pathogenesis of RA. In a macrophage senescence model induced by hydrogen peroxide (H2O2) and bleomycin (BLM), quantitative real-time PCR (qRT-PCR) and Western blot confirmed the significant upregulation of these genes and an increase in the secretion of the cytokine IL-17, which promotes an inflammatory environment for the polarization of macrophages to M1. When co-cultured with mouse synovial fibroblasts (MSF), MSF showed enhanced vitality and increased invasiveness, indicating a key role for these genes in the progression of RA. Additionally, HK3, less reported in RA, when its expression is knocking down, lactate secretion and lactylation modification at lysine 14 of histone H3 in macrophages were reduced, leading to a change in macrophage polarity. The study concludes that the altered polarity of senescent macrophages drives the proliferation and invasion of MSF, significantly promoting the development of RA and providing insights into the pathophysiology of RA.

Cardiovascular health (CVH) is closely associated with ageing. This study aimed to investigate the association between cardiometabolic index (CMI), a novel indicator of cardiometabolic status, and biological ageing.

Cross-sectional data were obtained from participants with comprehensive CMI and biological age data in the National Health and Nutrition Examination Survey from 2011 to 2018. Biological age acceleration (BioAgeAccel) is calculated as the differences between biological age and chronological age, and that biological age is derived from a model incorporating eight biomarkers. Weighted multivariable regression, sensitivity analysis, and smoothing curve fitting were performed to explore the independent association between CMI and the acceleration of biological age. Subgroup and interaction analyses were performed to investigate whether this association was consistent across populations.

In 4282 subjects ≥ 20 years of age, there was a positive relationship between CMI and biological age. The BioAgeAccel increased 1.16 years for each unit CMI increase [1.16 (1.02, 1.31)], and increased 0.99 years for per SD increase in CMI [0.99 (0.87, 1.11)]. Participants in the highest CMI quartile had a BioAgeAccel that was 2.49 years higher than participants in the lowest CMI quartile [2.49 (2.15, 2.83)]. In stratified studies, the positive correlation between CMI and biological age acceleration was not consistent across strata. This positive correlation was stronger in female, diabetes, and non-hypertension populations.

CMI is positively correlated with biological ageing in adults in the United States. Prospective studies with larger sample sizes are required to validate our findings.

The Mesenchymal Stem Cell (MSC) is a multipotent progenitor cell with known differentiation potential towards various cell lineage, making it an appealing candidate for regenerative medicine. One major contributing factor to age-related MSC dysfunction is cellular senescence, which is the hallmark of relatively irreversible growth arrest and changes in functional properties. GATA4, a zinc-finger transcription factor, emerges as a critical regulator in MSC biology. Originally identified as a key regulator of heart development and specification, GATA4 has since been connected to several aspects of cellular processes, including stem cell proliferation and differentiation. Accumulating evidence suggests that the involvement of GATA4-nuclear signalizing in the process of MSC senescence-related traits may contribute to age-induced alterations in MSC behavior. GATA4 emerged as the central player in MSC senescence, interacting with several signaling pathways. Studies have shown that GATA4 expression is reduced with age in MSCs, which is associated with increased expression levels of senescence markers and impaired regenerative potential. At the mechanistic level, GATA4 regulates the expression of genes involved in cell cycle regulation, DNA repair, and oxidative stress response, thereby influencing the senescence phenotype in MSCs. The findings underscore the critical function of GATA4 in MSC homeostasis and suggest a promising new target to restore stem cell function during aging and disease. A better understanding of the molecular mechanisms that underlie GATA4 mediated modulation of MSC senescence would provide an opportunity to develop new therapies to revitalize old MSCs to increase their regenerative function for therapeutic purposes in regenerative medicine.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1-2% of people over age 65. The risk of developing PD dramatically increases with advanced age, indicating that aging is likely a driving factor in PD neuropathogenesis. Several age-associated biological changes are also hallmarks of PD neuropathology, including mitochondrial dysfunction, oxidative stress, and neuroinflammation. Accumulation of senescent cells is an important feature of aging that contributes to age-related diseases. How age-related cellular senescence affects brain health and whether this phenomenon contributes to neuropathogenesis in PD is not yet fully understood. In this review, we highlight hallmarks of aging, including mitochondrial dysfunction, loss of proteostasis, genomic instability and telomere attrition in relation to well established PD neuropathological pathways. We then discuss the hallmarks of cellular senescence in the context of neuroscience and review studies that directly examine cellular senescence in PD. Studying senescence in PD presents challenges and holds promise for advancing our understanding of disease mechanisms, which could contribute to the development of effective disease-modifying therapeutics. Targeting senescent cells or modulating the senescence-associated secretory phenotype (SASP) in PD requires a comprehensive understanding of the complex relationship between PD pathogenesis and cellular senescence.

A complete understanding of aging is a critical first step in treating age-related diseases and postponing aging dysfunction in the context of an aging global population. Aging in organisms is driven by related molecular alterations that gradually occur in many organs. There has previously been a wealth of knowledge of how cells behave as they age, but when aging is investigated as a disease, the discovery and selection of aging biomarkers and how to diagnose the aging of the organism are crucial. Here, we provide a summary of the state of the field and suggest future potential routes for research on organ senescence markers. We reviewed research on biomarkers of risk of aging from the perspective of organ aging and summarized the biomarkers currently used on three scales. We emphasize that the combination of traditional markers with emerging multifaceted biomarkers may be a better way to diagnose age-related diseases.

As a complex chronic gynecological disorder characterized by multifaceted etiology involving genetics, environment, immunity and inflammation, endometriosis (EM) has long been a significant concern for women of reproductive age worldwide. This review aimed to comprehensively examine the interplay between epigenetics and oxidative stress (OS) in the pathogenesis of EM. Through the integration of cutting-edge research, the response of OS signals to epigenetic modifications was explored. The microbiome exerts an influence on this causal regulatory relationship, and these mechanisms collectively contribute to the pathophysiology of EM. Specifically, this article highlighted the roles of epigenetics and OS in EM and underscored the importance of the microbiome as a regulatory link. A discussion was also held on the future directions of biomarkers and precision medicine, including the application prospects of epigenetic and OS markers in the diagnosis and treatment decision-making of EM, and innovations in therapeutic strategies like targeting epigenetic modifications and antioxidant therapies. Moreover, this review emphasized the potential of multi-omics integrated analysis to deepen the understanding of the disease, guide future therapeutic strategies and promote personalized medicine.

Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.

Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention. Mitochondrial malate dehydrogenase (MDH2), an enzyme in the TCA cycle, was identified as an anti-aging target through activity-based protein profiling in present study. The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts. Glibenclamide (Gli), a classic anti-glycemic drug, was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner. The anti-aging effects of Gli were also further validated in vivo, as it extended the lifespan and reduced the frailty index of naturally aged mice. Liver specific Mdh2 knockdown eliminated Gli's beneficial effects in naturally aged mice, reducing p16INK4a expression and hepatic fibrosis. Mechanistically, MDH2 inhibition or knockdown disrupted central carbon metabolism, then enhanced the methionine cycle flux, and subsequently promoted histone methylation. Notably, the tri-methylation of H3K27, identified as a crucial methylation site in reversing cellular senescence, was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown. Taken together, these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation. Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development, but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.

Epigenetic factors influence inflammaging and geriatric disorders such as sarcopenia and frailty. It is necessary to develop a biomarker/panel of biomarkers for fast and easy diagnostics. Currently, hard-to-access equipment is required to diagnose sarcopenia. The development of a biomarker/panel of biomarkers will prevent many older adults from being excluded from the diagnostic process.

In this study, we analyzed selected gene expression profiles, namely, SIRT1, SIRT3, SIRT6, DNMT3A, FOXO1, FOXO3A, and ELAVL1, in whole blood. The study included 168 subjects divided into five groups: patients hospitalized at the Geriatrics Clinic and Polyclinic with sarcopenia, frailty syndrome, or without those disorders (geriatric control), and non-hospitalized healthy controls (HC) aged 25 to 30 years and over 50 years.

We revealed a lower mRNA level of FOXO3A (p<0.001) in sarcopenic patients compared to the geriatric controls. Furthermore, we detected upregulation of DNMT3A (p=0.003) and SIRT3 (p=0.015) in HC over 50 years old compared to HC aged 25 to 30 years. Interestingly, we observed 2 cluster formations during the gene expression correlation analysis (SIRT1, SIRT3, DNMT3A, and FOXO1, ELAVL1). We also noted correlations of clinical parameters with mRNA levels in the sarcopenic patients group, such as vitamin D level with SIRT1 (r=0.64, p=0.010), creatine kinase with SIRT3 (r=-0.58, p=0.032) and DNMT3A (r=-0.59, p=0.026), creatinine with DNMT3A (r=0.57, p=0.026), erythrocyte sedimentation rate (ESR) with FOXO3A (r=0.69, p=0.004), and lactate dehydrogenase (LDH) with FOXO3A (r=-0.86, p=0.007). In the frailty syndrome group, we noted a correlation of appendicular skeletal muscle mass (ASMM) with ELAVL1 (r=0.59, p=0.026) mRNA level. In the geriatric controls, we observed a correlation of serum iron with FOXO3A mRNA level (r=-0.79, p=0.036).

Our study revealed FOXO3A as a potential biomarker of sarcopenia. Furthermore, we observed a high expression of epigenetic factors (DNMT3A and SIRT3) in older adults.

p16INK4a is a crucial tumor suppressor and regulator of cellular senescence, forming a molecular bridge between aging and cancer. Dysregulated p16INK4a expression is linked to both premature aging and cancer progression, where non-coding RNAs (ncRNAs) such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and small interfering RNAs (siRNAs) play key roles in modulating its function. These ncRNAs interact with p16INK4a through complex post-transcriptional and epigenetic mechanisms, influencing pathways critical to senescence and tumor suppression. In this review, we explore ncRNAs, including ANRIL, MIR31HG, UCA1, MALAT1, miR-24, miR-30, and miR-141, which collectively regulate p16INK4a expression, promoting or inhibiting pathways associated with cancer and aging. ANRIL and MIR31HG modulate p16INK4a silencing via interactions with polycomb repressive complexes (PRC), while miRNAs such as miR-24 and miR-30 target p16INK4a to influence cellular proliferation and senescence. This regulatory interplay underscores the therapeutic potential of ncRNA-targeted strategies to restore p16INK4a function. We summarize recent studies supporting that ncRNAs that control p16INK4a may be diagnostic biomarkers and therapeutic targets for age-related diseases and cancer.

The DNA methylation-based epigenetic clocks are increasingly recognized for their precision in predicting aging and its health implications. Although prior research has identified connections between accelerated epigenetic aging and multiple sclerosis, the chronological and causative aspects of these relationships are yet to be elucidated. Our research seeks to clarify these potential causal links through a bidirectional Mendelian randomization study.

This analysis employed statistics approaches from genome-wide association studies related to various epigenetic clocks (GrimAge, HannumAge, PhenoAge, and HorvathAge) and multiple sclerosis, utilizing robust instrumental variables from the Edinburgh DataShare (n = 34,710) and the International Multiple Sclerosis Genetics Consortium (including 24,091 controls and 14,498 cases). We applied the inverse-variance weighted approach as our main method for Mendelian randomization, with additional sensitivity analyses to explore underlying heterogeneity and pleiotropy.

Using summary-based Mendelian randomization, we found that HannumAge was associated with multiple sclerosis (OR = 1.071, 95%CI:1.006-1.140, p = 0.033, by inverse-variance weighted). The results suggest that an increase in epigenetic age acceleration of HannumAge promotes the risk of multiple sclerosis. In reverse Mendelian randomization analysis, no evidence of a clear causal association of multiple sclerosis on epigenetic age acceleration was identified.

Our Mendelian randomization analysis revealed that epigenetic age acceleration of HannumAge was causally associated with multiple sclerosis, and provided novel insights for further mechanistic and clinical studies of epigenetic age acceleration-mediated multiple sclerosis.

Ageing results in diminished adaptability, as well as declines in physiological and psychological functions and resilience. The epigenetic clock 'Phenotypic Age' (PhenoAge) represents 'preclinical ageing'. Phenotypic Age Acceleration (PhenoAgeAccel) is defined as the residual from a linear regression model predicting PhenoAge on the basis of chronological age. Abdominal subcutaneous adipose tissue, visceral adipose tissue, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and high-density lipoprotein cholesterol (HDL-C) have all been shown to correlate with ageing; however, the connections between these factors and PhenoAge are still insufficiently investigated.

Data for this study were sourced from the National Health and Nutrition Examination Survey (2015-2018), comprising 2580 participants. Complex survey designs were considered. To examine the association between body fat area and PhenoAgeAccel, logistic regression was applied. Additionally, subgroup analysis was used to identify variations in population characteristics. The dose‒response relationship between body fat area and PhenoAgeAccel was determined via restricted cubic spline analysis. Mediation and interaction analyses were further employed to investigate the roles of the HOMA-IR and HDL-C in this association.

In nonelderly adults, the relationships between body fat area and PhenoAgeAccel differed chronological age. For abdominal subcutaneous fat area (SFA), this relationship was nonlinear in individuals aged 18-44 years and 45-59 years, with thresholds of 2.969 m² and 3.394 m², respectively. In contrast, a nonlinear relationship of visceral fat area (VFA) with PhenoAgeAccel was observed in individuals aged 18-44 years, while this relationship was linear in individuals aged 45-59 years, with thresholds of 0.769 m² and 1.220 m², respectively. Mediation effect analysis revealed that the HOMA-IR had a more pronounced mediation effect in individuals aged 18-44 years, accounting for 13.4% of the relationship between VFA and PhenoAgeAccel and 6.9% of the relationship between SFA and PhenoAgeAccel. Conversely, HDL-C had a greater mediating effect in individuals aged 45-59 years, accounting for 21.7% of the relationship between VFA and PhenoAgeAccel and 11.6% of the relationship between abdominal SFA and PhenoAgeAccel. HOMA-IR ≥ 2.73 or VFA > 0.925 m², as well as HOMA-IR ≥ 2.73 or abdominal SFA > 3.137 m², accelerated PhenoAge, whereas 1.60 < HDL-C ≤ 3.90 mmol/L combined with abdominal SFA ≤ 3.137 m² or VFA ≤ 0.925 m² decelerated PhenoAge.

In this study, the nonlinear relationships among abdominal SFA, VFA, and PhenoAgeAccel were elucidated, while characteristic thresholds across different age groups were identified. The results of this study emphasize the complex influence of fat distribution on the ageing process and refine the roles of HOMA-IR and HDL-C in various age cohorts. These findings provide a biological basis for future screening for accelerated ageing and appropriate intervention in high-risk populations and offer valuable insights for guiding personalized clinical interventions and health management strategies.

Cellular senescence is understood to be a biological process that is defined as irreversible growth arrest and was originally recognized as a tumor-suppressive mechanism that prevents further propagation of damaged cells. More recently, cellular senescence has been shown to have a dual role in prevention and tumor promotion. Senescent cells carry a senescence-associated secretory phenotype (SASP), which is altered by secretory factors including pro-inflammatory cytokines, chemokines, and other proteases, leading to the alteration of the tissue microenvironment. Though senescence would eventually halt the growth of cancerous potential cells, SASP contributes to the tumor environment by promoting inflammation, matrix remodeling, and tumor cell invasion. The paradox of tumor prevention/promotion is particularly relevant to the bone niche tumor microenvironment, where longer-lasting, chronic inflammation promotes tumor formation. Insights into a mechanistic understanding of cellular senescence and SASP provide the basis for targeted therapies, such as senolytics, which aim to eliminate senescent cells, or SASP inhibitors, which would eliminate the tumor-promoting effects of senescence. These therapeutic interventions offer significant clinical implications for treating cancer and healthy aging.

Cancer's epigenetic landscape, a labyrinthine tapestry of molecular modifications, has long captivated researchers with its profound influence on gene expression and cellular fate. This review discusses the intricate mechanisms underlying cancer epigenetics, unraveling the complex interplay between DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. We navigate through the tumultuous seas of epigenetic dysregulation, exploring how these processes conspire to silence tumor suppressors and unleash oncogenic potential. The narrative pivots to cutting-edge technologies, revolutionizing our ability to decode the epigenome. From the granular insights of single-cell epigenomics to the holistic view offered by multi-omics approaches, we examine how these tools are reshaping our understanding of tumor heterogeneity and evolution. The review also highlights emerging techniques, such as spatial epigenomics and long-read sequencing, which promise to unveil the hidden dimensions of epigenetic regulation. Finally, we probed the transformative potential of CRISPR-based epigenome editing and computational analysis to transmute raw data into biological insights. This study seeks to synthesize a comprehensive yet nuanced understanding of the contemporary landscape and future directions of cancer epigenetic research.

Atherosclerosis is a chronic inflammatory disease developing and progressing in the presence of risk factors including hyperlipidemia, hypercholesterolemia, and chronic inflammation, among others. Atherosclerosis commonly precipitates as ischemic events, transient ischemic attacks, and myocardial infarction. Saturated fatty acids are risk factors; however, their association with epigenetics in the pathophysiology of atherosclerosis is not clearly understood. The preclinical and clinical trials associating atherosclerosis with epigenetics are scarcely documented, and most of the studies reported the use of drugs inhibiting methylation and histone modification to improve atherosclerosis. This narrative review aims to discuss various aspects and the association between a high-fat diet, epigenetic reprogramming, and atherosclerosis.

A literature search with the keywords high-fat diet, epigenetics, and atherosclerosis, alone or in combination, was conducted to search for articles in the English language. Duplicate articles were removed, and articles related to the subject of this review article were included in this review.

A review of the literature suggests that a high-fat diet with saturated fatty acids is a risk factor for atherosclerosis, but this association is multifactorial, and epigenetics play a critical role. However, the connecting link and the underlying molecular and cellular mechanisms are not clearly understood yet and warrant more research.

A high-fat diet rich in saturated fatty acids is a risk factor for atherosclerosis involving epigenetic reprogramming and altered gene expression. The existing preclinical and clinical trials support the role of epigenetics and reversing it using drugs to attenuate atherosclerosis, but definitive evidence warrants larger clinical trials. Further, a high-fat diet in pregnant mothers can manifest as cardiovascular disease in offspring; caution must be taken in pregnant mothers for their diet and nutrients.

Immunosenescence, the slow degradation of immune function over time that is a hallmark and driver of aging, makes older people much more likely to be killed by common infections (such as flu) than young adults, but it also contributes greatly to rates of chronic inflammation in later life. Such micro nutrients are crucial for modulating effective immune responses and their deficiencies have been associated with dysfunctional immunity in the elderly. In this review, we specifically focused on the contribution of major micro nutrients (Vitamins A, D and E, Vitamin C; Zinc and Selenium) as immunomodulators in ageing population especially related to inflame-ageing process including autoimmunity. This review will cover these hologenomic interactions, including how micro nutrients can modulate immune cell function and/or cytokine production to benefit their hosts with healthy mucous-associated immunity along with a sustainable immunologic homeostasis. For example, it points out the modulatory effects of vitamin D on both innate and adaptive immunity, with a specific focus on its ability to suppress pro-inflammatory cytokines synthesis while enhancing regulatory T-cell function. In the same context, also zinc is described as important nutrient for thymic function and T-cell differentiation but exhibits immunomodulatory functions by decreasing inflammation. In addition, the review will go over how micro nutrient deficiencies increase systemic chronic low-grade inflammation and, inflammaging as well as actually enhance autoimmune pathologies in old age. It assesses the potential role of additional targeted nutritional supplementation with micro nutrients to counteract these effects, promoting wider immune resilience in older adults. This review collates the current evidence and highlights the role of adequate micro nutrient intake on inflammation and autoimmunity during ageing, providing plausible origins for nutritional interventions to promote healthy immune aging.

Sepsis, a systemic inflammatory condition, is a leading cause of mortality due to cardiovascular injury. Sepsis and cellular senescence are closely related, yet the specific mechanisms are still unclear. This study aims to identify a novel therapeutic target for mitigating sepsis-induced myocardial injury.

We initially assessed serum inflammatory markers and myocardial injury indicators in septic mice. This involved observing inflammatory cell infiltration in ventricular muscle tissue, assessing cardiac function, and recording electrocardiograms. We examined the expression of connexin 40 (Cx40) and connexin 43 (Cx43) and analyzed mitochondrial structures in ventricular tissues. A conditional heart-specific Nppb knockout mouse model was then developed in mice to evaluate these changes. Ventricular tissues were analyzed via mRNA sequencing to identify differentially expressed genes (DEGs), which were cross-referenced with senescence-related genes to identify key hub genes. The expression and distribution of hub genes were subsequently analyzed by single-cell analysis. Finally, the expression of the senescence-related gene CCL2, along with cardiac structure and function, was validated in a conditional heart-specific Nppb knockout sepsis mouse model.

Myocardial injury severity positively correlated with serum brain natriuretic peptide (BNP) in septic mice. Conditional heart-specific Nppb knockout improved myocardial injury outcomes in mice with sepsis. The DEGs identified in the conditional heart-specific Nppb knockout model overlapped with senescence-related genes, identifying seven upregulated genes associated with inflammation, cardiac contraction and apoptotic pathways. Single-cell analysis confirmed high CCL2 levels and an increased macrophage presence correlating with sepsis progression. Conditional heart-specific Nppb knockout reduced CCL2 levels, which were associated with improved cardiac structure and function.

This study confirms that conditional heart-specific Nppb knockout reduces CCL2 expression, thereby ameliorating myocardial injury in septic mice. Targeting Nppb to regulate the senescence-related gene CCL2 may represent an effective strategy for treating myocardial injury in septic patients.

Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.

One of the important markers affecting aging processes is the increase in inflammatory markers. Many chronic diseases are associated with inflammation and chronic inflammation increases with aging. Inflammation can change with dietary components. Foods, compounds and nutrients that have anti-inflammatory or proinflammatory properties attract attention. According to the Dietary Inflammatory Index, positive scores are obtained if the nutrient has a proinflammatory effect on cytokines, and negative scores are obtained if it has an anti-inflammatory effect.

A higher proinflammatory diet is associated with cardiometabolic diseases, neurodegenerative disease, cancers and musculoskeletal health and related mortality. In this study, its relationship with type 2 diabetes mellitus, obesity, metabolic syndrome, musculoskeletal diseases, dementia, depression and cancer, which are more common in older adults and known to be associated with inflammation, was examined. Although studies involving under 65 years old are more prevalent, research involving older adults and Dietary Inflammatory Index (DII) is more limited. It is known that chronic inflammation increases with aging. Diet is one of the factors affecting inflammation. In the light of these investigations, the topics of anti-inflammatory nutrition and DII for the treatment of inflammation-related diseases in older adults are strong and open to development topics of discussion. Despite the significant interest in the potential positive effects of anti-inflammatory nutrition on diseases, contributing to clearer evidence of its protective effects on health necessitates further randomized controlled trials, in vivo, in vitro, cell, animal, human and case-control studies for better risk assessment.

Aging has profound effects on the body, most notably an increase in the prevalence of several diseases. An important aging hallmark is the presence of senescent cells that no longer multiply nor die off properly. Another characteristic is an altered immune system that fails to properly self-surveil. In this multi-player aging process, cellular senescence induces a change in the secretory phenotype, known as senescence-associated secretory phenotype (SASP), of many cells with the intention of recruiting immune cells to accelerate the clearance of these damaged senescent cells. However, the SASP phenotype results in inducing secondary senescence of nearby cells, resulting in those cells becoming senescent, and improper immune activation resulting in a state of chronic inflammation, called inflammaging, in many diseases. Senescence in immune cells, termed immunosenescence, results in further dysregulation of the immune system. An interdisciplinary approach is needed to physiologically assess aging changes of the immune system at the cellular and tissue level. Thus, the intersection of biomaterials, microfluidics, and spatial omics has great potential to collectively model aging and immunosenescence. Each of these approaches mimics unique aspects of the body undergoes as a part of aging. This perspective highlights the key aspects of how biomaterials provide non-cellular cues to cell aging, microfluidics recapitulate flow-induced and multi-cellular dynamics, and spatial omics analyses dissect the coordination of several biomarkers of senescence as a function of cell interactions in distinct tissue environments. An overview of how senescence and immune dysregulation play a role in organ aging, cancer, wound healing, Alzheimer's, and osteoporosis is included. To illuminate the societal impact of aging, an increasing trend in anti-senescence and anti-aging interventions, including pharmacological interventions, medical procedures, and lifestyle changes is discussed, including further context of senescence.

The increasing environmental presence of nanoplastics (NPs) has raised concerns about their potential impact on biological systems. We investigated the repercussions of polymethyl methacrylate (PMMA) NPs exposure on normal gastric epithelial cells and revealed a pronounced increase in senescence-associated β-galactosidase activity and G1 phase cell cycle arrest. Our study demonstrated a dose-dependent increase in reactive oxygen species (ROS) and DNA damage, underscoring the pivotal role of ROS in PMMA NPs-mediated effects, a novel contribution to the existing body of knowledge dominated by polystyrene particles. Furthermore, we explored the influence of PMMA NPs on DNA damage response mechanisms, highlighting the significant inhibition of nonhomologous end-joining (NHEJ). Our findings help to elucidate the consequent genomic instability, as evidenced by increased chromosomal aberrations and micronuclei formation. By connecting these cellular manifestations to organism-level effects, we hypothesize that PMMA NPs play a critical role in aging processes. Our work revealed an activated cGAS-STING signaling pathway after PMMA NPs exposure, which correlated with aging-related inflammation and behavioral changes in mice. Importantly, our study provides comprehensive evidence of PMMA NPs-induced premature aging in gastric epithelial cells, shedding light on the molecular intricacies underlying DNA damage, repair impairment, and inflammation. Our research prompts heightened caution regarding the risks of NPs exposure and calls for further investigation into the broader implications of these environmental pollutants on aging processes in higher organisms.

In the face of cell damage, cells can initiate a response ranging from survival to death, the balance being crucial for tissue homeostasis and overall health. Cell death, in both accidental and regulated forms, plays a fundamental role in maintaining tissue homeostasis. Among the regulated mechanisms of cell death, ferroptosis has garnered attention for its iron-dependent phospholipid (PL) peroxidation and its implications in aging and age-related disorders, as well as for its therapeutic relevance. In this review, we provide an overview of the mechanisms, regulation, and physiological and pathological roles of ferroptosis. We present new insights into the relationship between ferroptosis, cellular senescence and aging, emphasizing how alterations in ferroptosis pathways contribute to aging-related tissue dysfunction. In addition, we examine the therapeutic potential of ferroptosis in aging-related diseases, offering innovative insights into future interventions aimed at mitigating the effects of aging and promoting longevity.

Ulcerative Colitis (UC) is an inflammatory disorder characterized by chronic intestinal inflammation and immune dysregulation. Despite a clear association between cellular senescence and chronic inflammation and immune dysregulation, the mechanisms underlying cellular senescence in UC remain unclear. We screened differentially expressed genes (DEGs) associated with cellular senescence in multiple UC datasets, performed immune infiltration analysis, and constructed clinical diagnostic models. Additionally, we investigated the relationship between key genes related to cellular senescence and disease remission in UC patients undergoing biologic therapy, validating their expression in a single-cell dataset. We identified six DEGs associated with cellular senescence (TWIST1, IGFBP5, MME, IFNG, ME1, FOS). Immune infiltration results indicated strong correlations of four of these genes with immune cells and pathways. Through WGCNA, GO, and KEGG analyses, we found that gene modules strongly associated with the expression of hub genes in cellular senescence were enriched in inflammation-related pathways. In the single-cell dataset, the expression of these six key genes exhibited similarities with Immune infiltration results. Additionally, we constructed a nomogram using these six genes for diagnosing UC, demonstrating good diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant association between changes in the expression levels of these cell genes and disease remission in UC patients undergoing biologic therapy. This study utilizes bioinformatic analysis and machine learning to identify and analyze features associated with cellular senescence in multiple UC datasets. It provides insights into the role of cellular senescence in the premature onset of intestinal aging in UC and offers new perspectives for exploring novel therapeutic targets.