Cordycepin alleviates hepatic fibrosis in association with the inhibition of glutaminolysis to promote hepatic stellate cell senescence.

Cordycepin (CRD) is an active component derived from Cordyceps militaris, which possesses multiple biological activities and uses in liver disease. However, whether CRD improves liver fibrosis by regulating hepatic stellate cell (HSC) activation has remained unknown. The study aims further to clarify the activities of CRD on liver fibrosis and elucidate the possible mechanism. Our results demonstrated that CRD significantly relieved hepatocyte injury and inhibited HSC activation, alleviating hepatic fibrogenesis in the Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC)-induced mice model. In vitro, CRD exhibited dose-dependent repress effects on HSC proliferation, migration, and pro-fibrotic function in TGF-ß1-activated LX-2 and JS-1 cells. The functional enrichment analysis of RNA-seq data indicated that the pathway through which CRD alleviates HSC activation involves cellular senescence and cell cycle-related pathways. Furthermore, it was observed that CRD accumulated the number of senescence-associated a-galactosidase positive cells and the levels of senescencemarker p21, and provoked S phasearrestof activated HSC. Remarkably, CRD treatment abolished TGF-ß-induced yes-associated protein (YAP) nuclear translocation that acts upstream of glutaminolysis in activated HSC. On the whole, CRD significantly inhibited glutaminolysis of activated-HSC and induced cell senescence through the YAP signaling pathway, consequently alleviating liver fibrosis, which may be a valuable supplement for treating liver fibrosis.

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice.

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 µM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 µM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.

Endogenous sulfur dioxide deficiency as a driver of cardiomyocyte senescence through abolishing sulphenylation of STAT3 at cysteine 259.

OBJECTIVE: Cardiomyocyte senescence is an important contributor to cardiovascular diseases and can be induced by stressors including DNA damage, oxidative stress, mitochondrial dysfunction, epigenetic regulation, etc. However, the underlying mechanisms for the development of cardiomyocyte senescence remain largely unknown. Sulfur dioxide (SO2) is produced endogenously by aspartate aminotransferase 2 (AAT2) catalysis and plays an important regulatory role in the development of cardiovascular diseases. The present study aimed to explore the effect of endogenous SO2 on cardiomyocyte senescence and the underlying molecular mechanisms. APPROACH AND RESULTS: We interestingly found a substantial reduction in the expression of AAT2 in the heart of aged mice in comparison to young mice. AAT2-knockdowned cardiomyocytes exhibited reduced SO2 content, elevated expression levels of Tp53, p21Cip/Waf, and p16INk4a, enhanced SA-ß-Gal activity, and elevated level of γ-H2AX foci. Notably, supplementation with a SO2 donor ameliorated the spontaneous senescence phenotype and DNA damage caused by AAT2 deficiency in cardiomyocytes. Mechanistically, AAT2 deficiency suppressed the sulphenylation of signal transducer and activator of transcription 3 (STAT3) facilitated its nuclear translocation and DNA-binding capacity. Conversely, a mutation in the cysteine (Cys) 259 residue of STAT3 blocked SO2-induced STAT3 sulphenylation and subsequently prevented the inhibitory effect of SO2 on STAT3-DNA-binding capacity, DNA damage, and cardiomyocyte senescence. Additionally, cardiomyocyte (cm)-specific AAT2 knockout (AAT2cmKO) mice exhibited a deterioration in cardiac function, cardiomegaly, and cardiac aging, whereas supplementation with SO2 donors mitigated the cardiac aging and remodeling phenotypes in AAT2cmKO mice. CONCLUSION: Downregulation of the endogenous SO2/AAT2 pathway is a crucial pathogenic mechanism underlying cardiomyocyte senescence. Endogenous SO2 modifies STAT3 by sulphenylating Cys259, leading to the inhibition of DNA damage and the protection against cardiomyocyte senescence.

Lycium barbarum polysaccharide's protective effects against PM2.5-induced cellular senescence in HUVECs.

Fine particulate matter (PM2.5) exposure is strongly associated with vascular endothelial senescence, a process implicated in cardiovascular diseases. While there is existing knowledge on the impact of Lycium barbarum polysaccharide (LBP) on vascular endothelial damage, the protective mechanism of LBP against PM2.5-induced vascular endothelial senescence remains unclear. In this study, we investigated the impact of PM2.5 exposure on vascular endothelial senescence and explored the intervention effects of LBP in human umbilical vein endothelial cells (HUVECs). We found that PM2.5 exposure dose-dependently reduced cell viability and proliferation in HUVECs while increasing the production of reactive oxygen species (ROS), malondialdehyde (MDA), and hydrogen peroxide (H2O2). Additionally, PM2.5 exposure inhibited the activity of superoxide dismutase (SOD). Notably, PM2.5 exposure induced autophagy impairments and cellular senescence. However, LBP mitigated PM2.5-induced cell damage. Further studies demonstrated that correcting autophagy impairment in HUVECs reduced the expression of the senescence markers P16 and P21 induced by PM2.5. This suggests the regulatory role of autophagy in cellular senescence and the potential of LBP in improving HUVECs senescence. These findings provide novel insights into the mechanisms underlying PM2.5-induced cardiovascular toxicity and highlight the potential of LBP as a therapeutic agent for improving vascular endothelial health.

Resveratrol Shows Potent Senescence Reversal in Experimental Cellular Models of Particular Matter 2.5-induced Cellular Senescence in Human Dermal Papilla Cells.

BACKGROUND/AIM: Particular matter 2.5 (PM2.5) pollution is associated with senescence induction. Since the impact of PM2.5 on stem cell senescence and potential compounds capable of reversing this process are largely unknown, this study aimed to examine the senescence effects of PM2.5 on dermal papilla (DP) stem cells. Additionally, we explored the reversal of these effects using natural product-derived substances, such as resveratrol (Res) or Emblica fruits, soybean, and Thunbergia Laurifolia (EST) extract. MATERIALS AND METHODS: Cell senescence was determined using the ß-Galactosidase (SA-ß-gal) assay. The senescence-associated secretory phenotype (SASP) was detected using real-time RT-PCR. For senescence markers, the mRNA and protein levels of p21 and p16 were measured using real-time RT-PCR and immunofluorescence analysis. RESULTS: Subtoxic concentration of PM2.5 (50 µg/ml) induced senescence in DP cells. Resveratrol (50, 100 µM) and plant extracts (400, 800 µg/ml) reversed PM2.5-induced cell senescence. Treatment with Res or EST significantly decreased SA-ß-gal staining in PM2.5-treated cells. Furthermore, Res and EST decreased the mRNA levels of SASP, including IL1α, IL7, IL8, and CXCL1. DP cells exposed to PM2.5 exhibited an increase in p21 and p16 mRNA and protein levels, which could be reversed by the addition of Res or EST. Res and EST could reduce p21 and p16 in senescent cells approximately 3- and 2-fold, respectively, compared to untreated senescent cells. CONCLUSION: PM2.5 induced senescence in human DP stem cells. Res and EST extract potentially reverse the senescence phenotypes of such cells.

Therapeutic effect of dietary ingredients on cellular senescence in animals and humans: A systematic review.

BACKGROUND: Cellular senescence has been regarded as a therapeutic target for ageing and age-related diseases. Several senotherapeutic agents have been proposed, including compounds derived from natural products which hold the translational potential to promote healthy ageing. This systematic review examined the association of dietary ingredients with cellular senescence in animals and humans, with an intent to identify dietary ingredients with senotherapeutic potential. METHODS: This systematic review was registered at PROSPERO International prospective register of systematic reviews (Reg #: CRD42022338885). The databases PubMed and Embase were systematically searched for key terms related to cellular senescence, senescence markers, diets, nutrients and bioactive compounds. Intervention and observational studies on human and animals investigating the effects of dietary ingredients via oral administration on cellular senescence load were included. The SYRCLE's risk of bias tool and Cochrane risk of bias tool v2.0 were used to assess the risk of bias for animal and human studies respectively. RESULTS: Out of 5707 identified articles, 83 articles consisting of 78 animal studies and 5 human studies aimed to reduce cellular senescence load using dietary ingredients. In animal studies, the most-frequently used senescence model was normative ageing (26 studies), followed by D-galactose-induced models (17 studies). Resveratrol (8 studies), vitamin E (4 studies) and soy protein isolate (3 studies) showed positive effects on reducing the level of senescence markers such as p53, p21, p16 and senescence-associated ß-galactosidase in various tissues of physiological systems. In three out of five human studies, ginsenoside Rg1 had no positive effect on reducing senescence in muscle tissues after exercise. The risk of bias for both animal and human studies was largely unclear. CONCLUSION: Resveratrol, vitamin E and soy protein isolate are promising senotherapeutics studied in animal models. Studies testing dietary ingredients with senotherapeutic potential in humans are limited and translation is highly warranted.

Vitamin D3 inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing.

Vitamin D3 replacement in older insufficient adults significantly improves their antigen-specific varicella zoster virus (VZV) cutaneous immunity. However, the mechanisms involved in this enhancement of cutaneous immunity are not known. Here, we show for the first time that vitamin D3 blocks the senescence-associated secretory phenotype (SASP) production by senescent fibroblasts by partially inhibiting the p38 MAPK pathway. Furthermore, transcriptomic analysis of skin biopsies from older subjects after vitamin D3 supplementation shows that vitamin D3 inhibits the same inflammatory pathways in response to saline as the specific p38 inhibitor, losmapimod, which also enhances immunity in the skin of older subjects. Vitamin D3 supplementation therefore may enhance immunity during ageing in part by blocking p38 MAPK signalling and in turn inhibit SASP production from senescent cells in vivo.

NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.

Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.

Environmental aluminum oxide inducing neurodegeneration in human neurovascular unit with immunity.

Aluminum oxide nanoparticle (AlNP), a ubiquitous neurotoxin highly enriched in air pollution, is often produced as an inevitable byproduct in the manufacturing of industrial products such as cosmetics and metal materials. Meanwhile, ALNP has emerged as a significant public health concern due to its potential association with neurological diseases. However, the studies about the neurotoxic effects of AlNP are limited, partially due to the lack of physiologically relevant human neurovascular unit with innate immunity (hNVUI). Here, we employed our AlNP-treated hNVUI model to investigate the underlying mechanism of AlNP-driven neurodegeneration. First, we validated the penetration of AlNP across a blood-brain barrier (BBB) compartment and found AlNP-derived endothelial cellular senescence through the p16 and p53/p21 pathways. Our study showed that BBB-penetrating AlNP promoted reactive astrocytes, which produced a significant level of reactive oxygen species (ROS). The astrocytic neurotoxic factors caused neuronal damage, including the synaptic impairment, the accumulation of phosphoric-tau proteins, and even neuronal death. Our study suggests that AlNP could be a potential environmental risk factor of neurological disorders mediated by neuroinflammation.

The function of Bazhen decoction in rescuing progeroid cell senescence via facilitating G-quadruplex resolving and telomere elongation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Bazhen decoction is one of the most extensively used Traditional Chinese medicine (TCM) prescriptions for treatment of aging related diseases. However, due to the complexity of the components, the pharmacological mechanism of Bazhen decoction is still limited. AIM OF THE STUDY: In this study, with the aim of helping the clinical precision medicine of TCM, we try out a systematic analysis for dissecting the molecular mechanism of complicated TCM prescription: Bazhen decoction. We identify the pharmacological mechanism of Bazhen decoction in telomere elongation as revealed by systematic analysis. MATERIALS AND METHODS: By RNA sequencing and transcriptome analysis of Bazhen decoction treated wild type cells, we reveal the transcriptome profile induced by Bazhen decoction. We utilized the cells derived from Werner syndrome (WS) mice, which is known to be dysfunctional in telomere elongation due to the deficiency of DNA helicase Wrn. By Western blot, qPCR, Immunofluorescence, flow cytometry, telomere FISH, and SA-ß-Gal staining, we verify the transcriptome data and confirm the pharmacological function of Bazhen decoction and its drug containing serum in telomere elongation and reversing progeroid cell senescence. RESULTS: We reveal that Bazhen decoction may systematically regulate multiple anti-aging pathways, including stem cell regulation, protein homeostasis, cardiovascular function, neuronal function, anti-inflammation, anti-DNA damage induced stress, DNA helicase activity and telomere lengthening. We find that Bazhen decoction and its drug containing serum could up-regulate multiple DNA helicases and telomere regulating proteins. The increased DNA helicases promote the resolving of G-quadruplex (G4) structures, and facilitate DNA replication and telomere elongation. These improvements also endow the cellular resistance to DNA damages induced by replication stress, and rescue the WS caused cellular senescence. CONCLUSIONS: Together these data suggest that Bazhen decoction up-regulate the expression of DNA helicases, thus facilitate G4 resolving and telomere maintenance, which rescue the progeroid cellular senescence and contribute to its anti-aging properties. Our data reveal a new molecular mechanism of Bazhen decoction in anti-aging related diseases via elongating telomere, this may shed light in the application of Bazhen decoction in multiple degenerative diseases caused by telomere erosion.

Salvianolic acid B protects against pulmonary fibrosis by attenuating stimulating protein 1-mediated macrophage and alveolar type 2 cell senescence.

Idiopathic pulmonary fibrosis (IPF), as the most common idiopathic interstitial pneumonia, is caused by a complex interaction of pathological mechanisms. Interestingly, IPF frequently occurs in the middle-aged and elderly populations but rarely affects young people. Salvianolic acid B (SAB) exerts antioxidant, antiinflammatory, and antifibrotic bioactivities and is considered a promising drug for pulmonary disease treatment. However, the pharmacological effects and mechanisms of SAB on cellular senescence of lung cells and IPF development remain unclear. We used bleomycin (BLM)-induced pulmonary fibrosis mice and different lung cells to investigate the antisenescence impact of SAB and explain its underlying mechanism by network pharmacology and the Human Protein Atlas database. Here, we found that SAB significantly prevented pulmonary fibrosis and cellular senescence in mice, and reversed the senescence trend and typical senescence-associated secretory phenotype (SASP) factors released from lung macrophages and alveolar type II (AT2) epithelial cells, which further reduced lung fibroblasts activation. Additionally, SAB alleviated the epithelial-mesenchymal transition process of AT2 cells induced by transforming growth factor beta. By predicting potential targets of SAB that were then confirmed by chromatin immunoprecipitation-qPCR technology, we determined that SAB directly hampered the binding of transcription factor stimulating protein 1 to the promoters of SASPs (P21 and P16), thus halting lung cell senescence. We demonstrated that SAB reduced BLM-induced AT2 and macrophage senescence, and the subsequent release of SASP factors that activated lung fibroblasts, thereby dual-relieving IPF. This study provides a new scientific foundation and perspective for pulmonary fibrosis therapy.

Jianpi Huayu Decoction suppresses cellular senescence in colorectal cancer via p53-p21-Rb pathway: Network pharmacology and in vivo validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Huayu Decoction (JHD) is an herbal prescription in traditional Chinese medicine based on Sijunzi Decoction to treat patients with colorectal cancer (CRC). Its effects on the inhibition of CRC cell proliferation and tumor growth are promising; however, its multicomponent nature makes a complete understanding of its mechanism challenging. AIM OF THE STUDY: To explore the therapeutic targets and underlying molecular pathways of JHD in CRC treatment using network pharmacology techniques and in vivo validation. MATERIALS AND METHODS: The active ingredients and targets of JHD were identified, compound-target interactions were mapped, and enrichment analyses were conducted. We identified the hub targets of JHD-induced cellular senescence in CRC. The binding affinities between compounds and targets were evaluated through molecular docking. Subsequently, we conducted bioinformatic analyses to compare the expression of hub targets between colorectal tissue and normal tissue. Finally, in vivo experiments were carried out utilizing a xenograft model to assess the effects of JHD on cellular senescence biomarkers. RESULTS: Network pharmacology revealed 129 active ingredients in JHD that were associated with 678 targets, leading to the construction of compound-target and target-pathway networks. Enrichment analyses highlighted key pathways including cellular senescence. Based on this, hub targets associated with cellular senescence were determined and validated. Molecular docking indicated favorable interactions between the active components and hub targets. Gene expression and survival analysis in CRC tissue were consistent with the potential roles of hub genes. Animal experiments showed that JHD triggered cellular senescence and suppressed the growth of CRC by regulating the p53-p21-Rb signaling pathway. CONCLUSIONS: This research adopted network pharmacology, bioinformatics, and animal experiments to unveil that JHD induces cellular senescence in CRC by influencing the p53-p21-Rb pathway and senescence-associated secretory phenotypes, highlighting its potential as a CRC treatment.

Traditional herbs: mechanisms to combat cellular senescence.

Cellular senescence plays a very important role in the ageing of organisms and age-related diseases that increase with age, a process that involves physiological, structural, biochemical and molecular changes in cells. In recent years, it has been found that the active ingredients of herbs and their natural products can prevent and control cellular senescence by affecting telomerase activity, oxidative stress response, autophagy, mitochondrial disorders, DNA damage, inflammatory response, metabolism, intestinal flora, and other factors. In this paper, we review the research information on the prevention and control of cellular senescence in Chinese herbal medicine through computer searches of PubMed, Web of Science, Science Direct and CNKI databases.

Pharmacological modulation of vascular ageing: A review from VascAgeNet.

Vascular ageing, characterized by structural and functional changes in blood vessels of which arterial stiffness and endothelial dysfunction are key components, is associated with increased risk of cardiovascular and other age-related diseases. As the global population continues to age, understanding the underlying mechanisms and developing effective therapeutic interventions to mitigate vascular ageing becomes crucial for improving cardiovascular health outcomes. Therefore, this review provides an overview of the current knowledge on pharmacological modulation of vascular ageing, highlighting key strategies and promising therapeutic targets. Several molecular pathways have been identified as central players in vascular ageing, including oxidative stress and inflammation, the renin-angiotensin-aldosterone system, cellular senescence, macroautophagy, extracellular matrix remodelling, calcification, and gasotransmitter-related signalling. Pharmacological and dietary interventions targeting these pathways have shown potential in ameliorating age-related vascular changes. Nevertheless, the development and application of drugs targeting vascular ageing is complicated by various inherent challenges and limitations, such as certain preclinical methodological considerations, interactions with exercise training and sex/gender-related differences, which should be taken into account. Overall, pharmacological modulation of endothelial dysfunction and arterial stiffness as hallmarks of vascular ageing, holds great promise for improving cardiovascular health in the ageing population. Nonetheless, further research is needed to fully elucidate the underlying mechanisms and optimize the efficacy and safety of these interventions for clinical translation.

Discovery of Salidroside as a Novel Non-Coding RNA Modulator to Delay Cellular Senescence and Promote BK-Dependent Apoptosis in Cerebrovascular Smooth Muscle Cells of Simulated Microgravity Rats.

Cardiovascular aging has been reported to accelerate in spaceflights, which is a great potential risk to astronauts' health and performance. However, current exercise routines are not sufficient to reverse the adverse effects of microgravity exposure. Recently, salidroside (SAL), a valuable medicinal herb, has been demonstrated to display an important role for prevention and treatment in cardiovascular and other diseases. In the present work, Sprague-Dawley rats with four-week tail-suspension hindlimb-unloading were used to simulate microgravity effects on the cardiovascular system. We found that intragastrical administration of SAL not only significantly decreased the expressions of senescence biomarkers, such as P65 and P16, but also obviously increased the expressions of BK-dependent apoptotic genes, including the large-conductance calcium-activated K+ channel (BK), Bax, Bcl-2, and cleaved caspase-3, in vascular smooth muscle cells (VSMCs) in vivo and in vitro. In addition, relative non-coding RNAs were screened, and a luciferase assay identified that SAL increased apoptosis by activating LncRNA-FLORPAR, inhibiting miR-193, and then triggering the activity of the BK-α subunit. Our work indicated that SAL is a novel non-coding RNA modulator for regulating the LncRNA-FLORPAR sponging miR-193 pathway, which significantly promoted BK-dependent apoptosis and delayed cerebrovascular aging-like remodeling during simulated microgravity exposure. Our findings may provide a new approach to prevent cardiovascular aging in future spaceflights.

Yoga maintains Th17/Treg cell homeostasis and reduces the rate of T cell aging in rheumatoid arthritis: a randomized controlled trial.

The pathogenesis of rheumatoid arthritis (RA) is characterized by a Th17/Treg cell imbalance. A pro-inflammatory cytokine milieu that promotes the continued proliferation of Th17 cells is related to the development of autoinflammation. In RA, T cells have several hallmarks of cellular aging, and they accumulate DNA damage, predisposing to the occurrence of mutations and epigenetic alterations. Since the onset, progression, and treatment response are influenced by a variety of external stressors and environmental factors, this study aimed to evaluate the impact of 8-week yoga practice on disease severity, T cell subsets, markers of T cell ageing and inflammation, epigenetic alterations and gene expression patterns in active RA patients on standard disease-modifying anti-rheumatic drugs (DMARDs). A total of 64 participants with active RA were randomized into 2 groups, yoga group (n = 32) or non-yoga group (n = 32); that were assessed for disease severity, at baseline and after 8 week duration, for Disease Activity Score (DAS28-ESR), T cell subsets [Th17 (CD3+ CD4+ IL17+ RORγt+) cells and Treg (CD3+ CD4+ CD25+ CD127-Foxp3+) cells], markers of T cell aging [aged Th17 cells (CD3+ CD4+ IL17+ RORγt+ CD28-) and aged Treg cells (CD3+ CD4+ CD25+ CD127-Foxp3+ CD28-)], pro-inflammatory markers [IL-6, and IL-17], anti-inflammatory markers [TGF-ß, and IL-10], epigenetic alterations [5-methyl cytosine, 5-hydroxymethyl cytosine, and HDAC1] and gene expression patterns [RORγt, FoxP3, IL-17, IL-6, TGF-ß, CXCL2, CXCR2, and JUN]. In yoga group, there was a significant improvement in DAS28-ESR scores at the end of 8-weeks of yoga program. The Th17 cells and aged T cell subsets showed a significant decline whereas Treg cell population showed a significant elevation in yoga group. There were significant improvements observed in epigenetic markers as well as inflammatory markers post 8-weeks of yoga practice. The yoga group showed downregulation of RORγt, IL-17, IL-6, CXCL2, CXCR2, and upregulation of FoxP3 and TGF-ß transcripts. Yoga enables the maintenance of immune-homeostasis as evident by increased Treg cell population and reduced Th17 cell population. Yoga reduces the rate of immunological aging in T cells, as seen by the reduction in population of aged Th17 cells and aged Treg cells. Yoga positively modifies transcriptome and epigenome by normalization of various inflammatory markers, gene expression patterns and epigenetic alterations. Taken together, yoga reduces RA severity, and aids in immune-modulation and hence can be beneficial as an adjunct therapy.

Pannexin 1 Modulates Angiogenic Activities of Human Endothelial Colony-Forming Cells Through IGF-1 Mechanism and Is a Marker of Senescence.

BACKGROUND: We examined the role of Panxs (pannexins) in human endothelial progenitor cell (EPC) senescence. METHODS: Young and replication-induced senescent endothelial colony-forming cells (ECFCs) derived from human circulating EPCs were used to examine cellular activities and senescence-associated indicators after transfection of short interference RNA specific to Panx1 or lentivirus-mediated Panx1 overexpression. Hind limb ischemia mice were used as in vivo angiogenesis model. Protein and phospho-kinase arrays were used to determine underlying mechanisms. RESULTS: Panx1 was the predominant Panx isoform in human ECFCs and upregulated in both replication-induced senescent ECFCs and circulating EPCs from aged mice and humans. Cellular activities of the young ECFCs were enhanced by Panx1 downregulation but attenuated by its upregulation. In addition, reduction of Panx1 in the senescent ECFCs could rejuvenate cellular activities with reduced senescence-associated indicators, including senescence-associated ß-galactosidase activity, p16INK4a (cyclin-dependent kinase inhibitor 2A), p21 (cyclin-dependent kinase inhibitor 1), acetyl-p53 (tumor protein P53), and phospho-histone H2A.X (histone family member X). In mouse ischemic hind limbs injected senescent ECFCs, blood perfusion ratio, salvaged limb outcome, and capillary density were all improved by Panx1 knockdown. IGF-1 (insulin-like growth factor 1) was significantly increased in the supernatant from senescent ECFCs after Panx1 knockdown. The enhanced activities and paracrine effects of Panx1 knockdown senescent ECFCs were completely inhibited by anti-IGF-1 antibodies. FAK (focal adhesion kinase), ERK (extracellular signal-regulated kinase), and STAT3 (signal transducer and activator of transcription 3) were activated in senescent ECFCs with Panx1 knockdown, in which the intracellular calcium level was reduced, and the activation was inhibited by supplemented calcium. The increased IGF-1 in Panx1-knockdown ECFCs was abrogated, respectively, by inhibitors of FAK (PF562271), ERK (U0126), and STAT3 (NSC74859) and supplemented calcium. CONCLUSIONS: Panx1 expression is upregulated in human ECFCs/EPCs with replication-induced senescence and during aging. Angiogenic potential of senescent ECFCs is improved by Panx1 reduction through increased IGF-1 production via activation of the FAK-ERK axis following calcium influx reduction. Our findings provide new strategies to evaluate EPC activities and rejuvenate senescent EPCs for therapeutic angiogenesis.

Peficitinib ameliorates 5-fluorouracil-induced intestinal damage by inhibiting aging, inflammatory factors and oxidative stress.

5-Fluorouracil (5-FU) is a conventional and effective drug for colorectal cancer patients, and it is an important part of combined chemotherapy and adjuvant chemotherapy. Chemotherapy intestinal mucositis (CIM) is a severe side effect caused by 5-FU that, induces cancer treatment failure and affects patients' quality of life. The mechanism of 5-FU-induced CIM is related to normal cell senescence induced by 5-FU. Peficitinib, a Janus Kinase (JAK) inhibitor, treats inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, the therapeutic role and underlying mechanism of peficitinib in CIM remain unclear. The main objective of our research was to investigate the effects of peficitinib on 5-FU-induced senescence and intestinal damage in human umbilical vein endothelial (HUVEC) cells, human intestinal epithelial (HIEC) cells and BABL/C mice. The results showed that 5-FU caused intestinal damage by inducing aging and increasing inflammation and oxidative stress. Peficitinib alleviated aging by reducing senescence-beta-galactosidase (SA-ß-gal) activity and the protein levels of aging indicators (p53, p21, p16). Moreover, peficitinib reversed the changes in senescence-associated secretory phenotype (SASP) expression caused by 5-FU. Besides, 5-FU induced release of inflammatory factors and oxidative stress indicators was reversed by peficitinib. Additionally, the combination of peficitinib and 5-FU reinforced the anticancer curative intent of 5-FU in two colorectal cancer cell lines (HCT116 cells and SW620 cells). In conclusion, peficitinib alleviates mucositis by alleviating aging, reducing inflammatory accumulation and oxidative stress and enhancing the antitumor activity of 5-FU.

The mechanism of Qijing Mingmu decoction on cellular senescence of conjunctivochalasis.

BACKGROUND: Qijing Mingmu decoction (QJMM), a compound Chinese medicine preparation, which consists of Lycium barbarum, Polygonatum, Ophiopogon japonicus, Poria cocos, Glycyrrhiza, Eclipta prostrata and Ligusticum striatum, has been confirmed to be effective for the treatment of conjunctivochalasis (CCH) in clinic and reduce cellular senescence. However, the underlying mechanism is still unknown. Our previous study revealed that p38-mediated cellular senescence contributed to the pathogenesis of CCH. METHODS: To explore whether p38 might be the potential therapeutic target of QJMM for CCH, CCH fibroblasts were treated with QJMM granule and then the effect of QJMM granule on the expression and promoter activity of p38α was determined by western blot and dual luciferase reporter gene assay, respectively. Meanwhile, the influence of QJMM granule on cell proliferation, oxidative stress, cellular senescence and the expression of the cellular senescence-associated genes were measured by corresponding methods. RESULTS: QJMM granule significantly decreased the protein expression of p38α and p-p38α in CCH fibroblasts in a dose-dependent manner and inhibited p38α promoter activity. QJMM granule as well as the p38 inhibitor SB203580 reduced the level of reactive oxygen species and increased the activity of superoxide dismutase in CCH fibroblasts. QJMM granule and SB203580 promoted cell proliferation and reduced the percentage of SA-ß-Gal-positive cells. The mRNA and protein expression of p53 and p21 was remarkably down-regulated by QJMM granule as well as SB203580 and that of SMP30 was up-regulated in CCH fibroblasts. CONCLUSIONS: Our findings demonstrated that QJMM granule was effective for alleviating cellular senescence of CCH fibroblasts by p38 MAPK signaling and the followed p53/p21 signaling.

Identification of resibufogenin, a component of toad venom, as a novel senolytic compound in vitro and for potential skin rejuvenation in male mice.

Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin. A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.