In pigs, the effect of sex on production and reproductive traits has been largely reported, however, whether sex exerts its influence through regulating mitochondrial function is still unclear. In this study, we constructed 15 male cells and 15 female fibroblasts derived from 35-day and 50-day fetuses, newborn piglets and 1-year-old pigs to identify the sex effect on mitochondrial functions. Results indicated significant differences on cellular and molecular characteristics between male and female cells, including energy metabolic trait, mitochondrial DNA (mtDNA) replication and transcription, and mRNA expressions of mitochondrial biogenesis genes and mitoprotease genes. Referring to sex, males exhibited significantly higher oxygen consumption rate productions, levels of reactive oxygen species (ROS) and mtDNA copy numbers than those with females in muscle and ear fibroblasts. And the expressions of mtDNA, mitochondrial biogenesis genes (POLG, PPARGC1A, TFAM and TWNK) and XPNPEP3 were higher in males than females in ear fibroblasts derived from 1-year-old adult pigs (EFA cells). While, the cell proliferation and expressions of genes related to ROS metabolism were not influenced by sex. The results highlight the effect of sex on mitochondrial function and gene expression, and provide important data for a comprehensive understanding of the mechanisms underlying sex regulation of energy metabolism-related traits in pigs.

Metabolic disturbances in late gestation contributes to oxidative stress and mitochondrial dysfunction in the placenta, leading to intrauterine growth retardation (IUGR), all of which are associated with reduced nicotinamide adenine dinucleotide (NAD+) levels. This study aimed to investigate the effects of maternal supplementation of β-nicotinamide mononucleotide (NMN), a nutraceutical NAD+ precursor, on IUGR rate and its underlying mechanisms. A total of 24 sows were randomly divided into either the control or NMN group, with each sow in the NMN group receiving 0.2 g of NMN per day. The results demonstrated that NMN supplementation significantly reduced the IUGR rate and increased NAD+ levels in the placenta of sows. Furthermore, NMN supplements upregulated mRNA and protein expressions of key mitochondrial regulators, such as PGC-1α, declined oxidative stress and apoptosis, and improved lipid metabolism in the placenta. These effects were linked to the upregulation of p-AMPK and the downregulation expression of p-mTOR. Taken together, this study indicates that maternal NMN supplementation reduces the IUGR rate by improving mitochondria function, enhancing lipid metabolism, and declining oxidative stress in the placenta.

Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.

A detailed understanding of aging biology and the development of anti-aging therapeutic strategies remain imperative yet inherently challenging due to the protracted nature of aging. Cellular senescence arises naturally through replicative exhaustion and is accelerated by clinical treatments or environmental stressors. The accumulation of senescent cells-defined by a loss of mitogenic potential, resistance to apoptosis, and acquisition of a pro-inflammatory secretory phenotype-has been implicated as a key driver of chronic disease, tissue degeneration, and organismal aging. Recent studies have highlighted the therapeutic promise of senolytic drugs, which selectively eliminate senescent cells. Compelling results from preclinical animal studies and ongoing clinical trials underscore this potential. However, the clinical translation of senolytics requires further pharmacological validation to refine selectivity, minimize toxicity, and determine optimal dosing. Equally important is the evaluation of senolytics' potential to restore tissue structure and function by reducing the senescent cell burden. In vitro tissue culture models offer a powerful platform to advance these efforts. This review summarizes the current landscape of in vitro systems used for inducing cellular senescence-referred to as "senescence assays"-and for screening senolytic drugs-referred to as "senolytic assays". We conclude by discussing key challenges to improving mechanistic insight, predictive accuracy, and clinical relevance in senolytic drug development, as well as emerging applications of senolytic therapies.

Cancer chemotherapy and radiotherapy are rarely successful in eliminating the entire tumor population, often leaving behind a subpopulation of senescent cells that can contribute to disease recurrence. These senescent tumor cells also secrete various chemokines and cytokines that may be tumor promoting and immunosuppressive. Recognition of the deleterious impact of therapy-induced senescence has led to the preclinical development of senolytic compounds that eliminate senescent cells, representing a potential strategy to enhance the efficacy of conventional and targeted anticancer therapy. However, it remains uncertain whether this strategy can or will be translated to the clinic. This review provides a summary of the recent preclinical literature supporting the use of senolytics as an adjunct for cancer treatment, discusses the limitations associated with their use in the current preclinical models, and provides perspectives on the clinical development of senolytics in cancer treatment regimens. Overall, preclinical studies support the potential of senolytics to enhance efficacy and prolong the antitumor activity of current standard-of-care cancer therapies that promote senescence. However, further work is needed to develop optimal senolytic agents with the appropriate combination of properties for clinical testing, specifically, activity in the context of therapy-induced senescence with acceptable tolerability.

Modulating cancer-related chronic inflammation (CCI) is essential to reverse the immunosuppressive tumor microenvironment (TME) for improved therapeutic outcomes. However, the complexity and dynamism of inflammatory processes within the TME pose formidable challenges. Here, we identify senescent tumor cells as a novel "nest"-like target and design a tailored nanotuner that transforms these cells from adversaries to allies in TME remodeling. Specifically, this nanotuner targets metabolic abnormalities and initiates cascading artificial reactions via chemiluminescence resonance energy transfer mechanisms, which trigger self-initiated and self-sustaining photodynamic processes for boosted 1O2, converting cellular senescence into pyroptosis. Such conversion fosters multifaceted immune activation, including blocking CCI networks, downregulating PD-L1, and enhancing dendritic cell maturation and T-cell recruitment in tumors. Assessments in two tumor models further demonstrate its durable antitumor effects against primary and distant solid tumors when combined with a PD-1 blockade. This work provides a paradigm shift for novel insights into tumor development and immunoregulatory tactics.

Senescence in stem cells and progenitor cells can be particularly detrimental because these cells are essential for tissue renewal and overall organismal homeostasis. In mesenchymal stromal cells (MSCs), which comprise a heterogeneous mix of stem cells, progenitors, fibroblasts, and other stromal cells, senescence poses a significant challenge, as it impairs their ability to support tissue repair and maintenance. This decline in regenerative capacity can contribute to aging-related diseases, impaired wound healing, and degenerative disorders. One hallmark of senescence is resistance to apoptosis, mediated by activation of anti-apoptotic pathways. Consequently, senotherapeutics have emerged as a promising strategy to selectively eliminate senescent cells and promote healthy aging. Plant secondary metabolites, notably polyphenols and terpenes, exhibit diverse effects on living organisms and have served as medicinal agents.

In this study, we investigated four terpenes-carvacrol, thymol, eugenol, and lycopene-for their senolytic potential in human senescent MSCs.

We found that these compounds induce apoptosis through both caspase-dependent and caspase-independent mechanisms, involving the activation of BAX, cytochrome c release, and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei. Importantly, terpene-induced apoptosis was associated with a significant increase in reactive oxygen species, and pre-incubation with glutathione partially rescued cell viability, confirming oxidative stress as a central trigger. Moreover, we identified SRC pathway modulation as a critical determinant of the senescence-to-apoptosis shift, highlighting a key regulatory switch in terpene action.

These findings provide a detailed mechanistic dissection of terpene-induced senolysis and underscore their potential as promising candidates for senotherapeutics targeting senescent cells.

The process of allogeneic chondrocyte implantation entails obtaining donor chondrocytes, culturing them in a medium enriched with growth factors, and then introducing them-either individually or in conjunction with biocompatible scaffolds-into areas of cartilage damage. While promising, this approach is hindered by mitochondrial dysfunction in the implanted chondrocytes.

This research introduced an innovative approach by creating a new type of scaffold derived from Decellularized Umbilical Cord Wharton's Jelly (DUCWJ) extracted from human umbilical cords. The scaffold was manufactured using procedures involving decellularization and lyophilization. The resulting scaffold demonstrated superior characteristics, including high porosity, hydrophilic properties, and excellent biocompatibility. To enhance its function, SS31 peptides, known for their mitochondrial-protective properties, were chemically bonded to the scaffold surface, creating an SS31@DUCWJ system. This system aims to protect chondrocytes and regulate the mitochondrial respiratory chain (MRC), thereby improving cartilage repair mediated by allogeneic chondrocyte implantation.

In vitro studies have shown that SS31 effectively attenuates metabolic dysfunction, extracellular matrix degradation, oxidative stress, inflammation, and mitochondrial damage induced by serial cell passages. Complementary in vivo experiments showed that the SS31@DUCWJ scaffold promoted regeneration of healthy articular cartilage in femoral condylar defects in rabbits.

This SS31-modified porous decellularized scaffold represents an innovative biomaterial with anti-inflammatory properties and targeted mitochondrial regulation. It offers a promising new approach for treating articular cartilage injuries.

Our study was the first to successfully load the mitochondrial protectant SS31 onto a DUCWJ hydrogel scaffold for localized drug delivery. This method is highly efficacious in repairing cartilage defects and offers a promising new avenue for the treatment of such conditions.

The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.

The Shennong Bencao Jing (Shennong's Classic of Materia Medica) records that Panax ginseng C. A. Mey (ginseng) 'lightens the body and prolongs life'. Many investigations have documented that ginseng exerts neuroprotective effects by mitigating the aging of the brain. However, a comprehensive review of the impacts of ginseng on brain aging remains lacking.

This study aims to review the advances in ginseng research regarding its role in delaying brain aging, focusing on its bioactive constituents, underlying mechanisms and potential side effects. The findings provide scientific pieces of evidence to support the medical utilization of ginseng in the delaying senescence and the management of aging-related diseases.

This review includes studies on ginseng and brain aging in humans, retrieved from English-language research articles published between 2017 and the present in the PubMed and Web of Science databases. The work focused on ginseng, brain aging, and aging-related diseases, utilizing keywords such as "Ginseng", "Brain aging", "central nervous system", "intracellular homeostasis", "peripheral system", etc. RESULTS: Ginseng comprises a varied spectrum of biologically bioactive constituents, such as ginsenosides, Maillard reaction products, ginseng polysaccharides, volatile oils, amino acids, proteins, etc. These components work to contribute to their significant medicinal value. Based on the traditional Chinese medicine (TCM) theory that "the heart and brain are interconnected, the liver and brain are mutually supportive, the brain and spleen are related, the brain and lung are linked, and the brain and kidney work in harmony," we summarize that ginseng may sustain neural homeostasis through both central and peripheral perspectives. Additionally, the potential toxic side effects of ginseng are minimal.

Ginseng and its bioactive constituents exhibit considerable promise in delaying brain aging and treating neurodegenerative diseases. Future research should prioritize exploring the direct targets of ginseng and its active ingredients, and work toward establishing precise drug-target-efficacy relationships. This approach will facilitate the translation of these findings into clinically viable therapeutic approaches.

Cellular senescence plays a pivotal role in aging and stress response mechanisms. Controlling cellular senescence is essential for developing novel techniques to prevent aging or aging-related diseases and promote a healthy lifespan. This study explores the efficiency of cold atmospheric microplasma (CAM) for controlling cellular senescence in yeast Saccharomyces cerevisiae. Reactive oxygen and nitrogen species (RONS) generated by CAM influence key processes, such as the regulation of oxidative stress, alterations in membrane potential, and senescence-related epigenetic modifications. As a marker of cellular senescence, the expression of β-galactosidase was assessed in response to different plasma treatments. At a frequency of 1 kHz and a discharge voltage of 5 kVp-p, a significant reduction in β-galactosidase activity was observed in cells treated for 10 s and 30 s compared to the control, indicating a reduction in cellular senescence. Additionally, cell viability, metabolic activity, and plasma membrane potential were also found to be higher for the treated cells compared to the control under the same conditions. This study confirms that a physiologically tolerable level of ROS and RNS is sufficient for cellular signaling, but not for damage induction. The findings from this study provide insights on the potential of microplasma as a tool for controlling cellular senescence and the development of therapeutic innovations involving eukaryotic cells.

Breast cancer has now become the most prevalent cancer worldwide. Existing therapeutic agents are generally accompanied by significant side effects. Here, we highlight Saikosaponin A (SSA), a promising natural metabolite characterized by low toxicity, demonstrating significant efficacy against breast cancer through the induction of cellular senescence.

The antitumor property of SSA was determined via MTT colorimetric assay, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, colony formation, and propidium iodide (PI) staining in vitro, as well as xenograft in vivo model. A network approach was used to predict potential targets of SSA reevant for a potential anti-tumor effect and verified through senescence-associated β-galactosidase (SA-β-gal), flow-cytometry analysis, RT-PCR, Western blotting, and immuno-histochemistry assay.

SSA significantly suppressed proliferation and triggered cell cycle arrest of SUM159PT and MDA-MB-231 cells. Revealed by network analysis, cellular senescence, and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway were implemented in the anti-tumor effects of SSA. SSA-stimulated senescence was associated with increased ROS production, distinct senescence-associated secretory phenotype (SASP), and restricted PI3K/Akt signaling, as well as p21 and p53 accumulation. Furthermore, SSA displayed inhibitory effects on tumor growth with minimal toxicity in animal studies, accompanied by activated biomarkers of cellular senescence and decreased expression of p-Akt and p-PI3K.

Taken together, based on the preliminary results of network analysis and further experimental validation, this study revealed that SSA significantly induced cell cycle arrest and senescence, and the inhibition of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.

Extracellular vesicles (EVs) derived from human organoids are phospholipid bilayer-bound nanoparticles that carry therapeutic cargo. However, the low yield of EVs remains a critical bottleneck for clinical translation. Vertical-Wheel bioreactors (VWBRs), with unique design features, facilitate the scalable production of EVs secreted by human blood vessel organoids (BVOs) under controlled shear stress, using aggregate- and microcarrier-based culture systems.

Human induced pluripotent stem cell-derived BVOs cultured as aggregates or on Synthemax II microcarriers within VWBRs (40 and 80 rpm) were compared to static controls. The organoids were characterized by metabolite profiling, flow cytometry, and gene expression of EV biogenesis markers. EVs were characterized by nanoparticle tracking analysis, electron microscopy, and Western blotting. Lipidomics provided insights into EV lipid composition, while functional assays assessed the impact of EVs in a D-galactose-induced senescence model.

VWBR cultures showed more aerobic metabolism and higher expression of EV biogenesis genes compared to the static control. EVs from different conditions were comparable in size, but the yields were significantly higher for microcarrier and dynamic cultures than static aggregates. Lipidomic profiling revealed minimal variation (< 0.36%) in total lipid content; however, distinct differences were identified in lipid chain lengths and saturation levels, affecting key pathways such as sphingolipid and neurotrophin signaling. Human BVO EVs demonstrated the abilities of reducing oxidative stress and increasing cell proliferation in vitro.

Human BVOs differentiated in VWBRs (in particular 40 rpm) produce 2-3 fold higher yield of EVs (per mL) than static control. The bio manufactured EVs from VWBRs have exosomal characteristics and therapeutic cargo, showing functional properties in in vitro assays. This innovative approach establishes VWBRs as a scalable platform for producing functional EVs with defined lipid profiles and therapeutic potential, paving the way for future in vivo studies.

Curcumin is a natural polyphenol extracted from plants that can interact with various molecular targets, including antioxidant, antibacterial, anticancer, and anti-aging activities. Due to its variety of pharmacological activities and large margin pf safety, curcumin has been used in the prevention and treatment of various diseases, such as Alzheimer's, heart, and rheumatic immune diseases. To develop curcumin eye drops that can be used as antioxidant and antibacterial agents after phacoemulsification, we have designed a nano-based drug delivery system to improve curcumin bioavailability and duration of action. We successfully prepared zeolitic imidazolate framework-8 (ZIF-8) coated with chitosan-liposome (Cur@ZIF-8/CS-Lip) for curcumin delivery. It can release curcumin for over 20 hin vitroand exhibits excellent biosafety, antioxidant, and antibacterial activities. Therefore, we hypothesized that Cur@ZIF-8/CS-Lip could reduce the incidence of oxidative stress and infection after cataract surgery.

This research aimed to investigate the potential of Pogostemon cablin Benth's ethanolic extract (PCEE) as an antiaging agent.

We treated 3T3-L1 cells induced by doxorubicin with PCEE and assessed them with antiaging markers such as GLB-1 gene and telomere length with polymerase chain reaction (PCR), or reactive oxygen species (ROS) accumulation with 2,7-dichlorofluorescein diacetate (DCFHDA).

This study demonstrates that PCEE can inhibit ROS accumulation, decrease the expression level of the senescence-associated β-galactosidase (SA-β-gal) gene, GLB-1, and maintain telomere length in doxorubicin-induced 3T3-L1 cells.

These studies reveal that PCEE is a promising antiaging agent. An in vivo approach should be conducted for further research.

With the growing demand for food safety and nutrition, the challenge of ensuring the quality of cooked meat products while reducing the accumulation of AGEs during processing needs urgent attention. In this study, the patterns of AGEs production, detection methods, quality contribution, and molecular mechanisms of its inhibition by natural plant-based extracts (NPBE) in cooked meat products were comprehensively reviewed. NPBE can effectively reduce the accumulation of AGEs in meat by binding to AGEs precursors and reducing glycosylation sites. It has also been shown to significantly remove off-flavour, and inhibit protein carbonylation. The potential for synergistic inhibition of AGE formation using NPBE and exogenous physical field treatments such as pulsed electric fields, microwave irradiation, thermal cycling of air, and ultrasound was emphasized, as well as the urgent need for the development of portable AGE detectors integrated with artificial intelligence and big data analytical models. This study indicates the future research direction for inhibiting the generation of AGEs in cooked meat products, which can promote and guide the practical application of NPBE in cooked meat products.

Previous studies have highlighted the in vitro and in vivo anti-aging potential of Streptococcus thermophilus prompting us to investigate the biomolecular mechanisms underlying its effects. We evaluated the reparative ability of S. thermophilus lysate in a hydrogen peroxide (H2O2)-induced senescence model of human dermal fibroblasts (HDFs). Cell proliferation, cell number, and senescence level were evaluated by IncuCyte® Live Cell Imager system, trypan blue dye exclusion test and β-galactosidase activity, respectively. We analyzed p21, prolyl 4-hydroxylase A1, intracellular collagen I, nuclear factor E2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB) and heme oxygenase-1 expression through western blot. Extracellular levels of collagen I, interleukin-1β, and IL-6 were assessed by ELISA. The oxidative stress markers were assayed using standard methods. The direct antioxidant activity of probiotic was quantified using multiple techniques. The presence of antioxidant genes in probiotic was detected via PCR assay. Probiotic lysate exposure increased the proliferation rate, counteracted the aging by reducing β-galactosidase activity and p21 levels, promoted collagen I synthesis and neutralized oxidative stress by activating Nrf2. The probiotic lysate inhibited the NF-κB pathway with pro-inflammatory marker downregulation. Notably, we revealed that probiotic exhibited strong free radical scavenging ability, iron-chelating properties, and significant ferric reducing power in a concentration-dependent manner. We identified seven genes with antioxidant function in its genome. Our results show that S. thermophilus lysate is efficacious in suppressing the biomolecular events associated with H2O2-induced cellular aging, thus supporting the reparative action of S. thermophilus, helpful in treating skin aging.

Senescence associated secretory phenotype (SASP) contributes to age-related pathology, however the role of SASP in Chronic Kidney Disease (CKD) is unclear. Here, we employ a variety of omic techniques to show that senescence signatures can separate CKD patients into distinct senescence endotypes (Sendotype).

Using specific numbers of senescent proteins, we clustered CKD patients into two distinct sendotypes based on proteomic expression. These clusters were evaluated with three independent criteria assessing inter and intra cluster distances. Differential expression analysis was then performed to investigate differing proteomic expression between sendotypes.

These clusters accurately stratified CKD patients, with patients in each sendotype having different clinical profiles. Higher expression of these proteins correlated with worsened disease symptomologies. Biological signalling pathways such as TNF, Janus kinase-signal transducers and activators of transcription (JAK-STAT) and NFKB were differentially enriched between patient sendotypes, suggesting potential mechanisms driving the endotype of CKD.

Our work reveals that, combining clinical features with SASP signatures from CKD patients may help predict whether a patient will have worsening or stable renal trajectory. This has implications for the CKD clinical care pathway and will help clinicians stratify CKD patients accurately.

Senescent proteins are upregulated in severe patients compared to mild patients Senescent proteins can stratify patients based on disease severity High expression of senescent proteins correlates with worsening renal trajectories.

To enhance the biocompatibility and drug delivery efficiency of graphene oxide (GO), poly(ethylene glycol) (PEG), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), or its triblock copolymer PEG-PHBV-PEG (PPP) were used to chemically modify GO. However, it is still unknown whether non-toxic polymer-modified GO mediates muscle toxicity or triggers intramuscular inflammation. This study aims to investigate the biological reactivity and inflammation/immune response induced by PEG, PHBV, or PPP modified GO when injected into the tibialis anterior (TA) muscle of mice prior to drug loading. The results showed that after muscle exposure, the coating of biocompatible polymers on GO is more likely to provoke muscle necrosis. Muscle regeneration was found to occur earlier and more effectively in muscle treated with hydrophilic PEG-GO and PPP-GO compared to muscle treated with hydrophobic PHBV-GO. When observing the transient muscle macrophage invasion of three modified GOs, PHBV-GO caused severe muscle necrosis in the early stage, induced a delayed peak of macrophage aggregation, and caused severe inflammatory progression. All three kinds of modified GO induced T cell aggregation to varying degrees, but PEG-GO induced early mass muscle recruitment of CD4+ T cells and was more sensitive to cytotoxic T cells. Based on the higher biocompatibility of PPP-GO in muscles, PPP-GO was implanted into the muscles of old or adult mice. Compared to adult mice, aged mice are more vulnerable to the stress from PPP-GO, as demonstrated by a delayed inflammatory response and muscle regeneration.

The incidence of inflammatory bowel disease among the elderly has significantly risen in recent years, posing a growing socioeconomic burden to aging societies. Moreover, non-gastrointestinal diseases, also prevalent in this demographic, have been linked to intestinal barrier dysfunction, thus highlighting the importance of investigating aged-mediated changes within the human gut. While gastrointestinal pathology often involves an impaired gut barrier, the impact of aging on the human gastrointestinal barrier function remains unclear. To explore the effect of senescence, a key hallmark of aging, on gut barrier integrity, we established and evaluated an in vitro gut-on-a-chip model tailored to investigate barrier changes by the integration of an impedance sensor. Here, a microfluidic gut-on-a-chip system containing integrated membrane-based electrode microarrays is used to non-invasively monitor epithelial barrier formation and senescence-mediated changes in barrier integrity upon treating Caco-2 cells with 0.8 μg mL-1 doxorubicin (DXR), a chemotherapeutic which induces cell cycle arrest. Results of our microfluidic human gut model reveal a DXR-mediated increase in impedance and cell hypertrophy as well as overexpression of p21, and CCL2, indicative of a senescent phenotype. Combined with the integrated electrodes, monitoring ∼57% of the cultivation area in situ and non-invasively, the developed chip-based senescent-gut model is ideally suited to study age-related malfunctions in barrier integrity.

Aging is associated with immunosenescence, a decline in immune functions, but also with inflammaging, a chronic, low-grade inflammation, contributing to immunosenescence. Monocytes and macrophages belong to the innate immune system and aging has a profound impact on these cells, leading to functional changes and most importantly, to the secretion of pro-inflammatory cytokines and thereby contributing to inflammaging. Rheumatoid arthritis (RA) is an autoimmune disease and age is an important risk factor for developing RA. RA is associated with the early development of age-related co-morbidities like cardiovascular manifestations and osteoporosis. The immune system of RA patients shows signs of premature aging like age-inappropriate increased production of myeloid cells, accelerated telomeric erosion, and the uncontrolled production of pro-inflammatory cytokines. In this review we discuss the influence of aging on monocytes and macrophages during healthy aging and premature aging in rheumatoid arthritis.

Targeting senescent cells and the factors that accelerate this pathological state has recently emerged as a novel field in medicinal chemistry. As attention shifts to synthetic substances, studies on natural agents are often overlooked. In this paper, we present a detailed computational modeling study that encompasses quantum mechanics and molecular dynamics to elucidate the senotherapeutic activity of fisetin, a natural flavonoid. The mitochondrial environment, serving as a proxy for senescence, received special attention. Throughout the study, fisetin's outstanding geroprotective properties-exhibiting significant potential against ⋅OOH, O2⋅-, and ⋅OH radicals, surpassing those of Trolox or ascorbate-were identified. Furthermore, fisetin demonstrated a high capacity to restore oxidatively damaged biomolecules to their pristine forms, thereby renewing the functionality of proteins and amino acids. The senolytic properties were examined in terms of Bcl-2 and Bcl-xL inhibition. The results indicated that fisetin not only binds effectively to these proteins but also, with appropriate modifications, may exhibit specific selectivity toward either target. This study highlights fisetin's remarkable activity in these areas and provides a molecular description of the underlying processes, paving the way for future research.

Prolonged exposure to ultraviolet B (UVB) light leads to the accumulation of reactive oxygen species (ROS), a key contributor to skin aging. Previous studies have demonstrated that UVB exposure results in a deficiency in the expression of TIMP3 in keratinocytes. The objective of this study was to investigate the specific role of TIMP3 in keratinocytes. UVB-treated HaCaT cells were utilized to establish a cellular photoaging model. We found that UVB significantly increased levels of ROS, promoted senescence and ferroptosis, and inhibited the expression of TIMP3 in HaCaT. This inhibition was notably alleviated by Fer-1, a ferroptosis inhibitor. In addition, the knockdown of TIMP3 in HaCaT enhanced senescence by inducing the ferroptosis. Mechanistically, UVB exposure also led to a decrease in the expression of KLF4, a transcription factor that regulated TIMP3 expression. Futhermore, UVB-induced reduced expression of KLF4 and TIMP3 in vivo. Our results suggest that deletion of the KLF4/TIMP3 axis promotes HaCaT cell senescence by facilitating the progression of ferroptosis. TIMP3 may serve as an effective therapeutic target for preventing skin photoaging.

Myotonic dystrophy type 1 (DM1) is considered a progeroid disease (i.e., causing premature aging). This hypervariable disease affects multiple systems, such as the musculoskeletal, central nervous, gastrointestinal, and others. Despite advances in understanding the underlying pathogenic mechanism of DM1, numerous gaps persist in our understanding, hindering elucidation of the heterogeneity and severity of its symptoms. Accumulating evidence indicates that the toxic intracellular RNA accumulation associated with DM1 triggers cellular senescence. These cells are in a state of irreversible cell cycle arrest and secrete a cocktail of cytokines, referred to as a senescence-associated secretory phenotype (SASP), that can have harmful effects on neighboring cells and more broadly. We hypothesize that cellular senescence contributes to the pathophysiology of DM1, and clearance of senescent cells is a promising therapeutic approach for DM1. We will discuss the therapeutic potential of different senotherapeutic drugs, especially senolytics that eliminate senescent cells, and senomorphics that reduce SASP expression.

Intervertebral disc degeneration (IVDD) is one of the most common musculoskeletal disorders in middle-aged and elderly people, and lower back pain (LBP) is the main clinical symptom [1, 2], which often causes significant pain and great economic burden to patients [3]. The current molecular mechanisms of IVDD include extracellular matrix degradation, cellular pyroptosis, apoptosis, necrotic apoptosis, senescence, and the newly discovered ferroptosis [4, 5], among which ferroptosis, as a new hot spot of research, has a non-negligible role in IVDD. Ferroptosis is an iron-dependent cell death caused by lipid peroxide accumulation [6]. Its main mechanism is cell death caused by lipid peroxidation by oxygen radicals due to iron overload and inhibition of pathways such as SLC7A11-GSH-GPX4. Currently, more and more studies have found a close relationship between IVDD and ferroptosis [7]. In the process of ferroptosis, the most important factors are abnormal iron metabolism, increased ROS, lipid peroxidation, and abnormal proteins such as GSH, GPX4, and system XC-. Our group has previously elucidated the pathogenesis of IVDD in terms of extracellular matrix degradation, myeloid cell senescence and pyroptosis, apoptosis, and inflammatory immunity. Therefore, this time, we will use ferroptosis as an entry point to discover the new mechanism of IVDD and provide guidance for clinical treatment.

Cellular senescence is a state of irreversible cell growth arrest. As such, senescence induction is viewed as an efficacious countermeasure in cancer treatment. Flap endonuclease 1 (FEN1) has been reported to participate in tumor growth, metastasis and immunomodulation. However, the role of FEN1 in cellular senescence of breast cancer and its molecular mechanism remains unclear.

In vitro assessments of breast cancer cell senescence and apoptosis were conducted using CCK-8 assay, cell cycle assay, senescence-associated β-galactosidase (SA-β-gal) staining, and cleaved caspase-3 staining. Western blot, dihydroethidium (DHE) staining, RNA-sequencing, quantitative real-time polymerase chain reaction (qRT-PCR), rescue experiments, and dual-luciferase reporter assay were performed to explore the potential target of FEN1. Co-Immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP)-qPCR assay, and immunostaining were used to evaluate the interaction between FEN1 and Pre-B-cell leukemia homeobox transcription factor 1 (PBX1). A xenograft mouse model was employed to validate the effect of FEN1 on breast cancer cell senescence and apoptosis.

Functional analysis demonstrated that FEN1 suppressed both senescence and apoptosis of breast cancer cells in vitro, while in vivo experiments demonstrated moderate therapeutic effects. Further studies indicated that FEN1 deficiency promoted the aforementioned effects by increasing intracellular reactive oxygen species (ROS) levels. RNA-sequencing and qRT-PCR assays revealed that FEN1 knockdown enhanced the expressions of several senescence-associated secretory phenotype (SASP) factors and resulted in decreased PBX1 level. The rescue experiments by PBX1 overexpression verified that PBX1 mediated the senescence and apoptosis of breast cancer cells induced by FEN1 inhibition. In detail, FEN1 downregulation inhibited the transcription activity of PBX1, which was partially restored by itself overexpression. Of note, FEN1 directly interacted with PBX1. Furthermore, immunostaining illustrated the colocalization of FEN1 and PBX1 in breast cancer cells and tissues. In our local breast cancer cohort, a positive correlation was identified between the expression levels of FEN1 and PBX1.

Knockdown of FEN1 facilitates breast cancer cell senescence through PBX1 down-regulation mediating increase in intracellular ROS levels. This study reveals FEN1 as a negative regulator of cellular senescence and provides support for pro-senescence cancer therapy. Given that FEN1 knockdown exhibited only moderate in vivo effects, these findings underscore the necessity of combining it with senolytic therapy to enhance therapeutic efficacy.

In response to various stressors, cells can enter a state called cellular senescence which is characterized by irreversible cell cycle arrest and a senescence-associated secretory phenotype (SASP). The progressive accumulation of senescent glial cells in the central nervous system (CNS) with aging suggests a potential role for senescence as driver of aging and inflammation in the brain. As the main immune cell population residing in the CNS, microglia are thought to play a pivotal role in the progression of age-associated neuroinflammation. Furthermore, due to their slow turnover, microglia are highly susceptible to undergoing cellular senescence. However, current understanding of age-related changes in microglia and their impact on brain aging is limited. Due to the challenge in accessing human primary microglia and the lack of models to adequately recapitulate aging, this knowledge is predominantly limited to rodent studies. Here, we chemically induced senescence in a human immortalized microglia cell line with a cocktail of senescence-inducing molecules. We demonstrate that chemically induced senescent microglia adopt a proinflammatory phenotype, have reduced phagocytic activity, and impaired calcium activity. Our results show that chemically induced senescence can mimic features of cellular aging and can provide insight into the impact of aging and cellular senescence on human microglia.

Age-related hearing loss is characterized by senescent inner ear hair cells (HCs) and reduced autophagy. Despite the improved understanding of these processes, detailed molecular mechanisms underlying cochlear HC senescence remain unclear. Transcription Factor EB (TFEB), a key regulator of genes associated with autophagy and lysosomes, crucially affects aging-related illnesses. However, intricate regulatory networks that influence TFEB activity remain to be thoroughly elucidated. The findings revealed that RONIN (THAP11), through its interaction with host cell factor C1 (HCF1/HCFC1), modulated the transcriptional activity of Tfeb, thus contributing to the mitigation (D-galatactose [D-gal]) senescent HC loss. Specifically, RONIN overexpression improved autophagy levels and lysosomal activity and attenuated changes associated with the senescence of HCs triggered by D-gal. These findings highlight the possibility of using RONIN as a viable therapeutic target to ameliorate presbycusis by enhancing the TFEB function.

Yeast TIM8 was initially identified as a homolog of human TIMM8A/DDP1, which is associated with human deafness-dystonia syndrome. Tim8p is located in the mitochondrial intermembrane space and forms a hetero-oligomeric complex with Tim13p to facilitate protein transport through the TIM22 translocation system. Previous research has indicated that TIM8 is not essential for yeast survival but does affect the import of Tim23p in the absence of the Tim8-Tim13 complex. Previous research on TIM8 has focused mainly on its involvement in the mitochondrial protein transport pathway, and the precise biological function of TIM8 remains incompletely understood. In this study, we provide the first report that yeast TIM8 is associated with the endoplasmic reticulum (ER) stress response and chronological senescence. We found that deletion of TIM8 leads to both oxidative stress and ER stress in yeast cells while increasing resistance to the ER stress inducer tunicamycin (TM), which is accompanied by an enhanced basic unfolded protein response (UPR). More importantly, TIM8 deficiency can lead to a shortened chronological lifespan (CLS) but does not affect the replicative lifespan (RLS). Moreover, we found that improving the antioxidant capacity further increased TM resistance in the tim8Δ strain. Importantly, we provide evidence that the knockdown of TIMM8A in ARPE-19 human retinal pigment epithelium cells can also induce ER stress, suggesting the potential function of the TIM8 gene in ER stress is conserved from budding yeast to higher eukaryotes. In summary, these results suggest novel roles for TIM8 in maintaining ER homeostasis and CLS maintenance.

Aging is a general biological process inherent in all living organisms. It is characterized by progressive cellular dysfunction. For many years, aging has been widely recognized as a highly effective mechanism for suppressing the progression of malignant neoplasms. However, in recent years, increasing evidence suggests a "double-edged" role of aging in cancer development. According to these data, aging is not only a tumor suppressor that leads to cell cycle arrest in neoplastic cells, but also a cancer promoter that ensures a chronic proinflammatory and immunosuppressive microenvironment. In this regard, in our review, we discuss recent data on the destructive role of senescent cells in the pathogenesis of cancer. We also identify for the first time correlations between the modulation of the senescence-associated secretory phenotype and the antitumor effects of naturally occurring molecules.

Background: Aging is a complex biological process characterized by the accumulation of molecular and cellular damage over time, often driven by oxidative stress. This oxidative stress is particularly detrimental to the testes, where it causes degeneration, reduced testosterone levels, and compromised fertility. D-galactose (D-gal) is commonly used to model aging as it induces oxidative stress, mimicking age-related cellular and molecular damage. Testicular aging is of significant concern due to its implications for reproductive health and hormonal balance. This research examines the protection by thymoquinone (TQ) or thymoquinone-loaded chitosan nanoparticles (NCPs) against D-galactose (D-gal)-induced aging in rat testes, focusing on biochemical, histological, and molecular changes. Aging, which is driven largely by oxidative stress, leads to significant testicular degeneration, reducing fertility. D-gal is widely used to model aging due to its ability to induce oxidative stress and mimic age-related damage. TQ, a bioactive ingredient of Nigella sativa, has earned a reputation for its anti-inflammatory, anti-apoptotic, and antioxidant characteristics, but its therapeutic application is limited by its poor bioavailability. Methods: Thymoquinone was loaded into chitosan nanoparticles (NCPs) to enhance its efficacy, and this was hypothesized to improve its stability and bioavailability. Four groups of male Wistar rats participated in the study: one for the control, one for D-gal, one for D-gal + TQ, and the last one for D-gal + NCP. Results: The results exhibited that D-gal substantially increased oxidative injury, reduced testosterone levels, and caused testicular damage. Treatment with TQ and NCPs significantly reduced oxidative stress, improved antioxidant enzyme levels, and restored testosterone levels, with NCPs showing a stronger protective effect than TQ alone. A histological analysis confirmed that NCPs better preserved testicular structure and function. Additionally, the NCP treatment upregulated the expression of key genes of oxidative stress resistance, mitochondrial function, and reproductive health, including SIRT1, FOXO3a, and TERT. Conclusions: The findings suggest that NCPs offer enhanced protection against aging-related testicular damage compared with TQ alone, which is likely due to the improved bioavailability and stability provided by the nanoparticle delivery system. This research emphasizes the potential of NCPs as a more effective therapeutic strategy for mitigating oxidative stress and age-related reproductive dysfunction. Future research should further explore the mechanisms underlying these protective effects.

Viral infections remain a major concern, as existing treatments often yield inadequate responses or lead to the development of antiviral resistance in some cases. Fucoidan extracted from Undaria pinnatifida (F) is a natural sulphated polysaccharide that exhibits antiviral action. Despite its potential, the biomedical application of F is limited due to its difficult administration through trans-mucosal, skin, or oral ingestion. The most effective way to solve these problems is to propose novel methods of administration aiming to ensure better contact between the biopolymers and pathogens, leading to their inactivation. In this work, the synthesis of films based on chitosan (Ch)-coupled F is reported, aiming to generate a synergic effect between both biopolymers in terms of their antiviral and antioxidant capability. Biocomposites were prepared by a sonochemical method. They were characterized to infer structural properties, functionality, and possible F-Ch interactions by using Zeta potential, FTIR, and XRD techniques. The biocomposites showed excellent film-forming ability. They also exhibited improved antioxidant activity with respect to F and Ch individually and proved to be non-cytotoxic. These results demonstrate, for the first time, the antiviral activity of F:Ch biocomposites against bovine coronavirus and human viruses (adenovirus, poliovirus, herpes simplex, and respiratory syncytial virus), which could be applied in film form to prevent or treat viral infections.

According to the Shen Nong Herbal Classic, Ginseng (Panax ginseng C.A. Meyer) is documented to possess life-prolonging effects and is extensively utilized in traditional Chinese medicine for the treatment of various ailments such as qi deficiency, temper deficiency, insomnia, and forgetfulness. Ginseng is commonly employed for replenishing qi and nourishing blood, fortifying the body and augmenting immunity; it has demonstrated efficacy in alleviating fatigue, enhancing memory, and retarding aging. Furthermore, it exhibits a notable ameliorative impact on age-related conditions including cardiovascular diseases and neurodegenerative disorders. One of its active constituents - ginsenoside Rg2 (G-Rg2) - exhibits potential therapeutic efficacy in addressing these ailments.

The aim of this review is to explore the traditional efficacy of ginseng in anti-aging diseases and the modern pharmacological mechanism of its potential active substance G-Rg2, in order to provide strong theoretical support for further elucidating the mechanism of its anti-aging effect.

This review provides a comprehensive analysis of the traditional efficacy of ginseng and the potential mechanisms underlying the anti-age-related disease properties of G-Rg2, based on an extensive literature review up to March 12, 2024, from PubMed, Web of Science, Scopus, Cochrane, and Google Scholar databases. Potential anti-aging mechanisms of G-Rg2 were predicted using network pharmacology and molecular docking analysis techniques.

In traditional Chinese medicine theory, ginseng has been shown to improve aging-related diseases with a variety of effects, including tonifying qi, strengthening the spleen and stomach, nourishing yin, regulating yin and yang, as well as calming the mind. Its potential active ingredient G-Rg2 has demonstrated significant therapeutic potential in age-related diseases, especially central nervous system and cardiovascular diseases. G-Rg2 exhibited a variety of pharmacological activities, including anti-apoptotic, anti-inflammatory and antioxidant effects. Meanwhile, the network pharmacological analyses and molecular docking results were consistent with the existing literature review, further validating the potential efficacy of G-Rg2 as an anti-aging agent.

The review firstly explores the ameliorative effects of ginseng on a wide range of age-related diseases based on TCM theories. Secondly, the article focuses on the remarkable significance and value demonstrated by G-Rg2 in age-related cardiovascular and neurodegenerative diseases. Consequently, G-Rg2 has broad prospects for development in intervening in aging and treating age-related health problems.

Aging is associated with a marked increase in cardiovascular diseases, such as myocardial infarction (MI). Cellular senescence is also a crucial factor in the development of age-related MI. Matrix metalloproteinases (MMPs) interaction with cellular senescence is a critical determinant of MI development and outcomes, most notably in the aged heart. After experiencing a heart attack, senescent cells exhibit a Senescence-Associated Secretory Phenotype (SASP) and are involved in tissue regeneration and chronic inflammation. MMPs are necessary for extracellular matrix proteolysis and have a biphasic effect, promoting early heart healing and detrimental change if overexpressed shortly. This review analyses the complex connection between senescence and MMPs in MI and how it influences elderly cardiac performance. Critical findings suggest that increasing cellular senescence in aged hearts elevates MMP activity and aggravates extended ventricular remodeling and dysfunction. Additionally, we explore potential therapeutics that address MMPs and senescence to enhance old MI patient myocardial performance and regeneration.

To investigate the role of lupeol in mitigating chondrocyte senescence in osteoarthritis (OA) by regulating autophagy through the sirtuin 3 (SIRT3)/mechanistic target of rapamycin kinase (mTOR) pathway.

Knee articular chondrocytes from primary-generation mice were isolated and divided into different groups, including a control group, a lupeol group (given 2.5, 5, 10, 20, and 40 μmol/L lupeol), a tert-butyl hydrogen peroxide (TBHP) group (receiving 50 μmol/L TBHP), TBHP + lupeol group, TBHP + lupeol + chloroquine (CQ) group (receiving 20 μmol/L CQ, an autophagy inhibitor), TBHP + lupeol + si-NC group, and TBHP + lupeol + si-SIRT3 group. Cell proliferation, reactive oxygen species (ROS) levels, and apoptosis were determined by CCK-8, DCFH-DA probe, and flow cytometry. Cell senescence was evaluated by β-gal staining. Western blot was used to determine the expressions of SIRT3, mTOR, senescence marker proteins (p21 and p16), extracellular matrix (ECM) degradation-related proteins (aggrecan, collagen Ⅱ, ADAMTS5, and MMP13), and autophagy-related proteins (LC3BⅠ, LC3BⅡ, and P62). RT-qPCR was used to determine the mRNA levels of senescence-associated secretory phenotypes (SASP), including IL-6, Cxcl10, MCP1, and MMP3. The expression of LC3 was detected by immunofluorescence. Autophagosomes were observed by transmission electron microscopy. A total of 30 male wild-type C57BL/6 mice were divided into different groups (n = 10), including a Sham group, an OA group, and an OA + lupeol group receiving 50 mg/(kg·d) lupeol via gastric gavage. Cartilage damage was evaluated by safranin O-fast green staining.

Based on the results of cell viability assay, 20 μmol/L lupeol treatment for 24 h was identified as the optimal intervention concentration and duration. Compared with that in the TBHP group, cell viability was elevated in the TBHP + lupeol group (P < 0.05); ROS production, the proportion of β-gal-positive cells, the protein expression levels of p21 and p16, and the mRNA levels of SASP were decreased (P < 0.05); the protein levels of aggrecan and collagen Ⅱ were elevated and the protein levels of ADAMTS5 and MMP13 were decreased (P < 0.05); apoptosis was reduced (P < 0.05); P62 protein levels were reduced and the LC3BⅡ/LC3BⅠ ratio, the intensity of LC3B fluorescence spots, and the number of autophagosomes were increased (P < 0.05); the expression level of SIRT3 was elevated and the level of mTOR phosphorylation was reduced (P < 0.05) in the TBHP+Lupeol group. CQ treatment effectively abolished the promotion effects of lupeol on cell viability and autophagy, and the inhibitory effects of lupeol on ROS level, cell senescence, ECM degradation, and apoptosis (P < 0.05). Silencing of SIRT3 reversed the inhibitory effect of lupeol on mTOR phosphorylation level and the promotion effect of lupeol on autophagy (P < 0.05). In the in vivo experiment, compared with the OA group, the OA + lupeol group showed reduced cartilage degeneration and lower scores for the Osteoarthritis Research Society International grading system (P < 0.05). The OA + lupeol group also showed up-regulated SIRT3 expression, reduced mTOR phosphorylation level, increased LC3BⅡ/LC3BⅠ ratio, reduced MMP13 protein level, and reduced mRNA level of SASP (P < 0.05).

Lupeol alleviates chondrocyte senescence in osteoarthritis by regulating autophagy through the SIRT3/mTOR pathway.

Reactive oxygen species (ROS) are natural by-products of oxygen metabolism. As signaling molecules, ROS can regulate various physiological processes in the body. However excessive ROS may be a major cause of inflammatory diseases. In the field of neurological diseases, ROS cause neuronal apoptosis and neurodegeneration, which severely impede neuroregeneration. Currently, ROS-scavenging biomaterials are considered as a promising therapeutic strategy for neurological injuries due to their ability to scavenge excessive ROS at defects and modulate the oxidative stress microenvironment. This review provides an overview of the generation and sources of ROS, briefly describes the dangers of generating excessive ROS in nervous system diseases, and highlights the importance of scavenging excessive ROS for neuroregeneration. We have classified ROS-scavenging biomaterials into three categories based on the different mechanisms of ROS clearance. The applications of ROS-responsive biomaterials for neurological diseases, such as spinal cord injury, brain injury, and peripheral nerve injury, are also discussed. Our review contributes to the development of ROS-scavenging biomaterials in the field of neural regeneration.

The capacity for tissue repair during wound healing declines with age. A chronic low but systemic inflammatory status, often called "inflammaging", is considered a key factor that contributes to impaired tissue regeneration. This phenomenon has been substantiated by an increased number of immune cells in wound-tissue of old mice. Although immune cells coordinate an inflammatory response by their secretome the composition of the wound milieu has not been examined. In young (2 months) and old (18 months) female mice, excision wounds were induced using a punch biopsy device, i.e., the healing progress occurred through secondary intention. The closure rate was analyzed for 7 days. At days 1, 3 and 7 post-surgery, wound specimen were investigated for immunohistochemical detection of granulocytes, M1-macrophages and mesenchymal stem cells of the skin. The concentrations of inflammatory cytokines and regenerative growth factors were determined in tissue homogenates by ELISA. The carbonyl assay was used to determine protein oxidation. In old mice, the wound closure was delayed between days 1 and 3 post-surgery, as was the peak of immune cell infiltration. There was no age effect on the concentration of inflammatory cytokines, but wounds of young animals contained higher number of mesenchymal stem cells and increased levels of growth factors. Protein oxidation was increased with age. The present study suggests that a reduced regenerative capacity rather than an enhanced inflammatory score affected the tissue regeneration process in old mice.