Delay Cell Senescence Research Articles

Supplemented collagen peptide composition improves skin aging, elasticity, and tissue regeneration in zebrafish

A supplemented collagen peptide composition (SCPC) containing microbe-fermented collagen peptide, collagen tripeptide, elastin peptide, and sodium hyaluronate was investigated to determine its effects on skin aging, skin elasticity, and tissue regeneration in zebrafish. β-Galactosidase activity was inhibited, while telomerase activity was elevated, by exposure to 0.977 μL/mL of SCPC in an H2O2-induced aging zebrafish model, indicating that SCPC can delay cell senescence. Expression of the collagen I gene col1a1a was up-regulated by exposure to 62.5 μL/mL of SCPC, indicating that SCPC can improve skin elasticity. Regrowth of the injured caudal fin was enhanced by exposure to only 0.122 μL/mL of SCPC. These improvements to skin aging, elasticity, and tissue regeneration in zebrafish suggest that this SCPC has potential as a functional food with beneficial effects on skin health and aging resistance in humans.

Taurine rescues intervertebral disc degeneration by activating mitophagy through the PINK1/Parkin pathway

Intervertebral disc degeneration (IDD) is a common cause of low back pain and disability. Recent studies have highlighted the critical role of mitochondrial dysfunction in the progression of IDD. In this study, we investigated the therapeutic potential of taurine in delaying IDD through the activation of mitophagy via the PINK1/Parkin pathway. Our in vitro and in vivo experiments demonstrate that taurine treatment significantly enhances mitophagy, reduces oxidative stress, delays cell senescence, and promotes the removal of damaged mitochondria in nucleus pulposus cells (NPC). Additionally, taurine-mediated activation of the PINK1/Parkin pathway leads to improved mitochondrial homeostasis and slows the progression of disc degeneration. These findings provide new insights into the protective effects of taurine and highlight its potential as a therapeutic agent for IDD.

Mechanism of Bazi Bushen capsule in delaying the senescence of mesenchymal stem cells based on network pharmacology and experimental validation

Ageing is becoming an increasingly serious problem; therefore, there is an urgent need to find safe and effective anti-ageing drugs. AimsTo investigate the effects of Bazi Bushen capsule (BZBS) on the senescence of mesenchymal stem cells (MSCs) and explore its mechanism of action. MethodsNetwork pharmacology was used to predict the targets of BZBS in delaying senescence in MSCs. For in vitro studies, MSCs were treated with D-gal, BZBS, and NMN, and cell viability, cell senescence, stemness-related genes, and cell cycle were studied using cell counting kit-8 (CCK-8) assay, SA-β-galactosidase (SA-β-gal) staining, Quantitative Real-Time PCR (qPCR) and flow cytometry (FCM), respectively. Alkaline phosphatase (ALP), alizarin red, and oil red staining were used to determine the osteogenic and lipid differentiation abilities of MSCs. Finally, the expression of senescence-related genes and cyclin-related factors was detected by qPCR and western blotting. ResultsNetwork pharmacological analysis suggested that BZBS delayed cell senescence by interfering in the cell cycle. Our in vitro studies suggested that BZBS could significantly increase cell viability (P < 0.01), decrease the quantity of β-galactosidase+ cells (P < 0.01), downregulate p16 and p21 (P < 0.05, P < 0.01), improve adipogenic and osteogenic differentiation, and upregulate Nanog, OCT4 and SOX2 genes (P < 0.05, P < 0.01) in senescent MSCs. Moreover, BZBS significantly reduced the proportion of senescent MSCs in the G0/G1 phase (P < 0.01) and enhanced the expression of CDK4, Cyclin D1, and E2F1 (P < 0.05, P < 0.01, respectively). Upon treatment with HY-50767A, a CDK4 inhibitor, the upregulation of E2F1 was no longer observed in the BZBS group. ConclusionsBZBS can protect MSCs against D-gal-induced senescence, which may be associated with cell cycle regulation via the Cyclin D1/CDK4/E2F1 signalling pathway.

Anemonin ameliorates human diploid fibroblasts 2BS and IMR90 cell senescence by PARP1-NAD+-SIRT1 signaling pathway

ObjectiveAging becomes the most predominant risk factor for all age‐associated pathological conditions with the increase of life expectancy and the aggravation of social aging. Slowing down the speed of aging is considered an effective way to improve health, but so far, effective anti-aging methods are relatively lacking. MethodsAnemonin (ANE) was screened from eight existing small-molecule compounds by cell viability assay. The function of ANE was determined by the analysis of cell proliferation, β -galactosidase (SA-β -Gal) activity, cell cycle, SASP secretion, NAD+/NADH ratio, and other aging-related indicators. The targets of ANE were predicted by Drug Target Prediction System (DTPS) and Swiss Targe Prediction System. The effect of ANE on PARP-1-NAD+-SIRT1 signaling pathway was assessed by quantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot, PARP1, NAD+ and SIRT1 activity detection. ResultsANE can delay cell senescence; PARP1 is one of the targets of ANE and plays a crucial role in ANE anti-aging; ANE release more NAD+ by inhibiting PARP1 activity, thereby conversely promoting the function of SIRT1 and delay cell senescence. ConclusionsOur study indicates that ANE can delay cellular senescence through the PARP1-NAD+-SIRT1 signaling pathway, which may be considered as an effective anti-aging strategy.

Spermidine Retarded the Senescence of Multipotent Mesenchymal Stromal Cells In Vitro and In Vivo through SIRT3-Mediated Antioxidation.

Multipotent mesenchymal stromal cells (MSCs) expand in vitro and undergo replicative senescence, thereby restricting their clinical utilization. Thus, an effective strategy is required to impede MSC senescence. Since spermidine (SPD) supplementation can prolong the lifespan of yeast by inhibiting oxidative stress, spermidine is a potential option for delaying MSC senescence. In this study, to test our hypothesis, we first isolated primary human umbilical cord mesenchymal stem cells (hUCMSCs). Subsequently, the appropriate SPD dose was administered during continuous cell cultivation. Next, we evaluated the antisenescence effects by SA-β-gal staining, Ki67 expression, reactive oxygen species (ROS) levels, adipogenic or osteogenic ability, senescence-associated markers, and DNA damage markers. The results revealed that early SPD intervention significantly delays the replicative senescence of hUCMSCs and constrains premature H2O2-induced senescence. Additionally, by silencing SIRT3, the SPD-mediated antisenescence effects disappear, further demonstrating that SIRT3 is necessary for SPD to exert its antisenescence effects on hUCMSCs. Besides, the findings of this study also suggest that SPD in vivo protects MSCs against oxidative stress and delays cell senescence. Thus, MSCs maintain the ability to proliferate and differentiate efficiently in vitro and in vivo, which reflects the potential clinical utilization of MSCs in the future.

Long noncoding RNA MAGI2-AS3 regulates the H2O2 level and cell senescence via HSPA8

The redox homeostasis system regulates many biological processes, intracellular antioxidant production and redox signaling. However, long noncoding RNAs (lncRNAs) involved in redox regulation have rarely been reported. Herein, we reported that downregulation of MAGI2-AS3 decreased the superoxide level in Human fibroblasts (Fbs), a replicative aging model, as detected by the fluorescent probes dihydroethidium (DHE) and MitoSOX™ Red. RNA pulldown combined with mass spectrometry showed that HSPA8 is a novel interacting protein of MAGI2-AS3, which was further confirmed by photoactivatable ribonucleoside–enhanced crosslinking and immunoprecipitation (PAR-CLIP). Downregulation of MAGI2-AS3 decreased the hydrogen peroxide (H2O2) content by stabilizing the HSPA8 protein level via inhibiting the protesome degradation of HSPA8. Further evidence showed that MAGI2-AS3 interacted with the C-terminal domain (CTD) of HSPA8. Downregulation of MAGI2-AS3 delayed cell senescence, while this antiaging effect was abolished by HSPA8 knockdown. The underlying molecular mechanism by which MAGI2-AS3 knockdown inhibited cell senescence was mediated via suppression of the ROS/MAP2K6/p38 signaling pathway. Taken together, these findings revealed that downregulation of lncRNA MAGI2-AS3 decreased the H2O2 content and delayed cell senescence by stabilizing the HSPA8 protein level, identifying a potential antiaging application.

RhEPO Upregulates the PPARγ Pathway in Long-term Cultured Primary Nerve Cells via PI3K/Akt to Delay Cell Senescence.

Previous studies have confirmed that both recombinant human erythropoietin (rhEPO) and peroxisome proliferator-activated receptors γ (PPARγ) activator pioglitazone can protect senescent nerve cells, and their mechanisms involve enhancing cell antioxidant capacity and reducing cell apoptosis. However, whether the PPARγ pathway is involved in the rhEPO anti-aging process in neuronal cells is still unclear. In this study, to explore the relationship between rhEPO and the PPARγ pathway at the cellular level, primary nerve cells cultured for 22days were used to simulate the natural aging process of nerve cells. Starting on the 11th day of culture, rhEPO, LY294002, and GW9662 were added for treatment. Immunochemical methods and SA-β-gal staining were used to observe the changes in cellular antioxidant capacity and the fraction of senescent cells. The results showed that PPARγ blockade retarded the effect of rhEPO on the cellular antioxidant capacity and altered the fraction of senescent cells. It was confirmed that PPARγ was involved in rhEPO's anti-aging process in neuronal cells. Real-time fluorescent quantitative RT-PCR, Western blotting, and immunofluorescence staining were used to observe the changes in PPARγ pathway-related factors in nerve cells after rhEPO treatment. The results showed that rhEPO significantly upregulated the expression of PPARγ coactivator-1α (PGC-1α), PPARγ, and nuclear PPARγ in cells but did not affect the level of phosphorylated PPARγ protein, confirming that rhEPO has the ability to upregulate the PPARγ pathway. PI3K/Akt and PPARγ pathway blockade experiments were used to explore the relationships among rhEPO, PI3K/Akt, and PPARγ. The results showed that after PPARγ blockade, rhEPO had no significant effect on the PI3K/Akt pathway-related factor p-Akt, while after PI3K/Akt blockade, rhEPO's effects on PPARγ-related factors (PGC-1α, PPARγ, and nuclear PPARγ) were significantly decreased. It is suggested that rhEPO delays the PI3K/Akt pathway in the process of neuronal senescence, which is located upstream of PPARγ regulation. In conclusion, this study confirmed that rhEPO can upregulate the expression of PGC-1α and PPARγ in cells and the level of PPARγ protein in the nucleus to enhance the antioxidant capacity of cells and delay the senescence of nerve cells through the PI3K/Akt pathway. These findings will provide ideas for finding new targets for neuroprotection research and will also provide a theoretical basis and experimental evidence for rhEPO anti-aging research in neural cells.

Erdosteine prevents contrast-induced renal oxidative stress damage in mice

Purpose: To investigate the protective effect of erdosteine on contrast-induced renal oxidative stress in mice.&#x0D; Methods: C57BL/6 mice were injected intraperitoneally with contrast medium to establish an acute kidney injury model (AKI). Renal function, blood urea nitrogen (BUN) and serum creatinine (SCr) were determined. Also, oxidative stress, lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD) and reduced glutathione (GSH) were evaluated. And the renal tissue structure was examined by light microscopy, while Western blot (WB) and Real-time polymerase chain reaction (RT-PCR) were used to determine the expressions of senescence-related factor, Nrf-2 and downstream antioxidant factor.&#x0D; Results: Erdosteine improved the renal structure of mice and significantly decreased serum BUN and SCr levels. In addition, erdosteine promoted the expression of antioxidant enzymes SOD1, SOD2, GPX1 and GPX3 in renal tissues, decreased the content of ROS, and inhibited the content of LDH and MDA in serum. Also, WB and RT-PCR results showed that erdosteine activated Nrf2 pathway, thereby alleviating contrast-induced renal injury.&#x0D; Conclusion: Erdosteine inhibits contrast-induced renal oxidative stress in mice and delays cell senescence by activating Nrf2 pathway. This will be of great significance in the treatment of contrast-induced nephropathy.

Fabrication of Resveratrol-Loaded Scaffolds and Their Application for Delaying Cell Senescence In Vitro.

In this research, resveratrol (RSV)-loaded scaffolds have been prepared to control the release of resveratrol and used to delay hepatic stellate cell (HSC) senescence in vitro. The functional carboxyl group-COOH is first introduced to the surface of poly(ε-caprolactone/d,l-lactide) (P(CL-DLLA)) under the coadministration of ultra-violet (UV) treatment and photo initiator and then resveratrol are conjugated onto the surface of the modified scaffolds through esterification. The characterization of the structure of RSV-AA-P(CL-DLLA) shows that resveratrol has been successfully conjugated onto the modified surface. Cell growth exhibits a higher level of cell viability and much more obvious agglomeration on the surface of the synthetic RSV-AA-P(CL-DLLA). Meanwhile the activity of senescence-associated β-galactosidase (SA-β-gal) and reactive oxygen species (ROS) is downgulated for cells on RSV-AA-P(CL-DLLA), which suggests that cell senescence is delayed on RSV-AA-P(CL-DLLA). And then it is attested that cells have a lower level of p53 but SIRT1 expression is upregulated on RSV-AA-P(CL-DLLA), which might be related to resveratrol release from RSV-AA-P(CL-DLLA). It also suggested cell senescence on RSV-AA-P(CL-DLLA) has been regulated by p53 and the SIRT1 signaling pathway. In all, the present study shows that RSV-AA-P(CL-DLLA) can be successfully prepared to promote cell growth and delay cell senescence and could be used for cell-based therapy in tissue engineering.

Baicalein Delays H2O2-Induced Astrocytic Senescence through Inhibition of Senescence-Associated Secretory Phenotype (SASP), Suppression of JAK2/STAT1/NF-κB Pathway, and Regulation of Leucine Metabolism.

Baicalein is an active ingredient extracted from the dried roots of the Scutellaria baicalensis Georgi. It has been demonstrated to improve memory impairment in multiple animal models; however, the underlying mechanisms remain ambiguous. The accumulation of senescent astrocytes and senescence-associated secretory phenotype (SASP) secreted by senescent astrocytes has been deemed as potential contributors to neurodegenerative diseases. Therefore, this study explored the protective effects of baicalein against astrocyte senescence and investigated the molecular mechanisms and metabolic mechanisms of baicalein against astrocyte senescence. Our results demonstrated that treatment with baicalein protects T98G cells from H2O2-induced damage, delays cell senescence, inhibits the secretion of SASP (IL-6, IL-8, TNF-α, CXCL1, and MMP-1), and inhibits SASP-related pathways NF-κB and JAK2/STAT1. 1H NMR metabolomics analysis and correlation analysis revealed that leucine was significantly correlated with SASP factors. Further study demonstrated that supplement with leucine could restrain SASP secretion, and baicalein could significantly increase leucine level through down-regulation of BCAT1 and up-regulation of SLC7A5 expression. The above results revealed that baicalein exerted protective and antisenescence effects in H2O2-induced T98G cells possibly through inhibition of SASP, suppression of JAK2/STAT1/NF-κB pathway, and regulation of leucine metabolism. Consistent results were obtained in primary astrocytes of newborn SD rats, which suggests that baicalein significantly increases viabilities, delays senescence, inhibits IL-6 secretion, and increases leucine level in H2O2-induced primary astrocytes.

MicroRNA-340-5p increases telomere length by targeting telomere protein POT1 to improve Alzheimer's disease in mice.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder which is the primary cause of dementia in the elderly. Telomere attrition has been proposed as a hallmark of aging. Our study aimed to explore the mechanism of the protection of telomere 1 (POT1) in regulating telomere length and affecting cellular senescence in AD. The AD mouse model was established by d-galactose and aluminum chloride,and the water maze test and dark avoidance test were used to detect the behaviors of mice and confirm the success of AD mouse model. AD cell model was established with HT22 cells induced by Aβ42 oligomers. POT1 expression in the AD model was detected by quantitative real-time polymerase chain reaction. Cellular telomere length in hippocampal tissue was analyzed by telomere restriction fragment. Localization of intracellular POT1, telomerase, and telomeres was analyzed by immunofluorescence and fluorescence in situ hybridization. Dual-luciferase assay was used to validate the targeted binding relationship between microRNA-340-5p(miR-340-5p) and POT1. After inhibiting POT1 expression, the symptoms of AD in mice were improved. Aβ1-42 deposition was reduced, whereas telomere length and telomerase activity was increased. Dual-luciferase assay verified the binding relationship between miR-340-5p and POT1. An increase in miR-340-5p expression could alleviate cellular senescence and AD symptoms. miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms. This study made a conclusion that miR-340-5p increased cellular telomere length and delayed cell senescence by inhibiting POT1 expression to improve AD symptoms in mice.

Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence.

Our previous studies found that deletion of nuclear receptor interacting protein 1 (Nrip1) extended longevity in female mice and delayed cell senescence. The current study investigates the role of NRIP1 in regulating functions of adipose-derived mesenchymal stem cells (ADMSCs) and explores the mechanisms of NRIP1 in skin aging. We first verified the skin aging phenotypes in young (6 months) and old (20 months) C57BL/6J (B6) mice and found deletion of Nrip1 can delay skin aging phenotypes, including reduced thickness of dermis and subcutaneous white adipose tissue (sWAT), as well as the accumulation of senescent cells in sWAT. In ADMSCs isolated from sWAT, we found that deletion of Nrip1 could decrease cell proliferation, prevent cell apoptosis, and suppress adipogenesis. Interestingly, deletion of Nrip1 also reduced cell senescence and maintain cell quiescence of ADMSCs. Moreover, the expressions of genes associated with senescence (p21, and p53), inflammation (p65, IL6, and IL1a), and growth factor (mTOR, Igf1) were reduced in Nrip1 knockout ADMSCs, as well as in siNrip1-treated ADMSCs. Suppression of Nrip1 by siNrip1 also decreased the expressions of mTOR, p-mTOR, p65, and p-p65 in ADMSCs. Reduced expressions of p65 and p-p65 were also confirmed in the skin of Nrip1 knockout mice. These findings suggest that NRIP1 plays an important role in delaying skin aging by reducing ADMSCs senescence and maintaining ADMSCs quiescence.

Alleviation of the doxorubicin-induced nephrotoxicity by fasudil in vivo and in vitro

ObjectiveTreatment with the chemotherapeutic agent, doxorubicin (DOX), is limited by side effects. We have previously demonstrated that fasudil, a Rho/ROCK inhibitor, has antioxidant, anti-inflammatory and anti-apoptotic effects in contrast-induced acute kidney injury model. The present study to investigated the possible protective effect of fasudil, on DOX-induced nephrotoxicity. Materials and methodIn vivo: Forty male C57BL/6 male mice were randomly divided into 4 groups: Control group, DOX treatment group (DOX group), DOX + low dose fasudil (DOX + L group), DOX + high dose fasudil (DOX + H group). Mice in 2–4 groups received DOX (2.5 mg/kg, i.p.) once a week for 8 weeks. The 3 and 4 group were given 2 mg/kg/d or 10 mg/kg/d fasudil before DOX injection. respectively. Meanwhile, the control group received saline. At the end of week eight, blood samples were collected for biochemical testing. The kidneys were removed for histological, immunohistochemical, Western blot, quantitative real-time PCR (qRT-PCR), and molecular detection. In vitro: NRK-52E cells were treated with 40 uM fasudil for 12 h, then incubated with 1 uM DOX for 24 h. Cells then collected for qRT-PCR and Western blot. ResultsIn vivo, fasudil treatment ameliorated DOX-induced immunofluorescence reaction of DNA damage-related factors (8-OHdG), decreased the expression of Bax, Caspase-3, p16, p21 and p53, and increased the expression of protein of Bcl-2, Bmi-1 and Sirt-1. In the mouse model, administration of fasudil significantly ameliorated DOX-induced kidney damage, suppressed cell apoptosis and senescence, ameliorated redox imbalance and DNA damage. At the same time, DOX produced obvious kidney damage revealed by kidney functions changes: increased serum creatinine (SCr) and blood urea nitrogen (BUN) concentrations. In addition, kidney tissue staining in the DOX group showed abnormal structure and fibroproliferative disorders. And DOX could promote the oxidation and senescence of kidney cells, leading to increased expression of 8-OHdG and senescence and apoptosis-related factors. On the contrary, fasudil treatment can effectively inhibit redox imbalance and DNA damage caused by DOX, and inhibit cell senescence and apoptosis. Fasudil can inhibit excessive activation of Rho/ROCK signaling pathway, thereby improving kidney tissue fibrosis and recovery kidney function. ConclusionFasudil has a protective effect on DOX-induced nephrotoxicity in mice and NRK-52E cells, which can inhibit oxidative stress and DNA damage, inhibit apoptosis, and delays cell senescence by inhibiting RhoA/Rho kinase (ROCK) signaling pathway.

Regulation of left atrial fibrosis induced by mitral regurgitation by SIRT1

SIRT1 (silent information regulator 1) is a histone deacetylase. It can sense the energy level in cells and delay cell senescence, leading to resistance to external stress and improving metabolism. Mitral regurgitation (MR) is a common disease in cardiac surgery. However, there are no previous studies on SIRT1 and left atrial fibrosis caused by MR. In this study, we aimed to explore the regulatory effect of SIRT1 on left atrial fibrosis induced by MR. We used Guizhou miniature pigs to establish an MR model and a sham operation model after anaesthesia induction and respiratory intubation, and these model animals were followed for 30 months after the surgery. The differential distribution and expression of SIRT1 and collagen I in the left atrium was determined by immunofluorescence and Western blotting. Furthermore, we treated NIH3T3 fibroblasts (CFs) with resveratrol and Angiotensin II (Ang II) to analyse the specific mechanism involved in the development of myocardial fibrosis. The results showed that the MR model was successfully constructed. There were 8 pigs in the MR group and 6 pigs in the control group. In both the animal experiments and the cell experiments, the expression of collagen I in the MR group was increased significantly compared to that in the control group, while the expression of SIRT1 was decreased.

Studies on the effect of a Fupenzi glycoprotein on the fibrillation of bovine serum albumin and its antioxidant activity

In this study, the effect of a glycoprotein obtained from Fupenzi (FPZ) (Rubus chingii Hu.) on the fibrillation of bovine serum album (BSA) was investigated by multi-spectroscopic methods and transmission electron microscopy. Moreover, the cytotoxicity of the glycoprotein and the effect of it on H2O2-induced cell viability were investigated by cell counting kit and β-galactosidase kit, respectively. The experimental results indicated that the glycoprotein showed very low toxicity to NRK-52E cells and could obviously delay cell senescence and improve cell viability. Moreover, the glycoprotein could effectively inhibit the formation of BSA fibrils and destroy the stability of preformed BSA fibrils in a concentration-dependent manner. Generally, antioxidant capacities are thought to be related to the anti-amyloidogenic activity of inhibitors; therefore, to reveal the inhibitory mechanism, the anti-oxidative property of the glycoprotein was examined by DPPH and ABTS assays. The results demonstrated that FPZ glycoprotein had a remarkable antioxidant activity and the IC50 values of DPPH and ABTS were 0.249mgmL-1 and 0.092mgmL-1, respectively. This work suggested that the FPZ glycoprotein had the potential to be designed a new therapeutic agent for attenuating aging and preventing the age-related diseases.

Sirtuin-1 and Its Relevance in Vascular Calcification.

Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.

Myocyte enhancer factor 2A delays vascular endothelial cell senescence by activating the PI3K/p-Akt/SIRT1 pathway.

Myocyte enhancer factor 2A (MEF2A) dysfunction is closely related to the occurrence of senile diseases such as cardiocerebrovascular diseases, but the underlying molecular mechanism is unclear. Here, we studied the effects of MEF2A on the senescent phenotype of vascular endothelial cells (VEC) and downstream signaling pathway, and the association between plasma MEF2A levels and coronary artery disease (CAD). Results showed that MEF2A silencing promoted cell senescence and down-regulated PI3K/p-AKT/Sirtuin 1 (SIRT1) expression. MEF2A overexpression delayed cell senescence and up-regulated PI3K/p-AKT/SIRT1. Hydrogen peroxide (H2O2) treatment induced cellular senescence and down-regulated the expression of MEF2A and PI3K/p-AKT/SIRT1. MEF2A overexpression inhibited cellular senescence and the down-regulation of PI3K/p-AKT/SIRT1 induced by H2O2. Further study revealed that MEF2A directly up-regulated the expression of PIK3CA and PIK3CG through MEF2 binding sites in the promoter region. Pearson correlation and logistic regression analysis showed that the plasma level of MEF2A was negatively correlated with CAD, and with age in the controls. These results suggested that MEF2A can directly up-regulate PI3K gene expression, and one of the molecular mechanisms of delaying effect of MEF2A on VEC cell senescence was SIRT1-expression activation through the PI3K/p-Akt pathway. Moreover, the plasma MEF2A levels may be a potential biomarker for CAD risk prediction.

Silibinin Alleviates the Learning and Memory Defects in Overtrained Rats Accompanying Reduced Neuronal Apoptosis and Senescence.

Excessive physical exercise (overtraining; OT) increases oxidative stress and induces damage in multiple organs including the brain, especially the hippocampus that plays an important role in learning and memory. Silibinin, a natural flavonoid derived from milk thistle of Silybum marianum, has been reported to exert neuroprotective effect. In this study, rats were subjected to overtraining exercise, and the protective effects of silibinin were investigated in these models. Morris water maze and novel object recognition tests showed that silibinin significantly attenuated memory defects in overtrained rats. At the same time, the results of Nissl, TUNEL and SA-β-gal staining showed that silibinin reversed neuronal loss caused by apoptosis, and delayed cell senescence of the hippocampus in the overtrained rats, respectively. In addition, silibinin decreased malondialdehyde (MDA) levels which is associated with reactive oxygen species (ROS) generation. Silibinin prevented impairment of learning and memory caused by excessive physical exercise in rats, accompanied by reduced apoptosis and senescence in hippocampus cells.

Soluble α-Klotho in Liver Cirrhosis and Alcoholism.

Alpha Klotho is a transmembrane protein that serves as co-receptor for FGF23. Ectodomain of membrane bound α Klotho may be shed by membrane bound proteases (activated, among other factors, by tumor necrosis factor (TNF)-α) generating the soluble form of the protein (sKl) that functions as a hormone by itself. It modulates calcium influx into cells, blunts IGF-1/Insulin signaling, promotes synthesis of antioxidants, generally slows down tumor progression, delays cell senescence, is neuroprotective and promotes oligodendrocyte maturation and myelin synthesis, and muscle rejuvenation. It may be involved in inflammation and exerts antifibrogenic effects. Some of these pathways may become altered in alcoholism or liver cirrhosis, but data are scattered and scarce and an update is required. Literature survey. Alcohol consumption in non-alcoholics is inversely related to sKl, but alcoholic cirrhotics showed higher-than-normal sKl values in association with liver function derangement. In hepatoma cells, the intensity of Klotho staining was related to faster tumor progression and a shortened life span. Among severe alcoholic cirrhotics sKl is directly related to serum TNF-α levels, and, inversely, to brain atrophy. Given the antioxidant, anti-inflammatory, and antifibrogenic effects of Klotho, perhaps the increase in cirrhosis (and in other inflammatory conditions, such as sepsis or cancer) reflects an attempt to regulate increased inflammation, but clinical and experimental research is urgently needed in this field.

Nucleophagy Plays a Major Role in Human Diseases.

Nucleophagy is a selective autophagy, which selectively removes damaged or non-essential nuclear material from a cell by the autophagy pathway. Additionally, nucleophagy is crucial for promoting cell longevity and ensure body proper function. Increasing evidence has shown that nucleophagy may play a major role in such human diseases as degenerative disorders, tumorigenesis, malnutrition and metabolic disorders, parakeratosis and psoriasis. Studies indicated that nucleophagy can improve degenerative disorders by delaying premature cell senescence, prevent malnutrition and metabolic disorder via maintaining nuclear structure and releasing nutrients for energy production, and alleviate parakeratosis and psoriasis. But the activation of nucleophagy appears to be a double-edged sword. Some studies indicated that overexpression of lamin B1 delays cell senescence. During the process of nucleophagy, appropriate nucleophagy can drive RAS-induced cell senescence and DNA damage-induced cell senescence so as to restrain cell proliferation. Besides, appropriate nucleophagy can degrade excessive amount of DNA content in polyploid tumor cells. Hence, selective nucleophagy may effectively protect cells from tumorigenesis and maintain cell and tissue integrity. However, excessive nucleophagy can attack normal cells and lead to an unforeseen cytotoxicity. In this paper, some signal pathways of nucleophagy occurrence were explained and the role of nucleophagy in these human diseases was analyzed. Our review indicates that nucleophagy may be a potential target in human diseases.