Latest advances in aging research and drug discovery.
Bakula Daniela,Ablasser Andrea,Aguzzi Adriano,Antebi Adam,Barzilai Nir,Bittner Martin-Immanuel,Jensen Martin Borch,Calkhoven Cornelis F,Chen Danica,Grey Aubrey D N J de,Feige Jerome N,Georgievskaya Anastasia,Gladyshev Vadim N,Golato Tyler,Gudkov Andrei V,Hoppe Thorsten,Kaeberlein Matt,Katajisto Pekka,Kennedy Brian K,Lal Unmesh,Martin-Villalba Ana,Moskalev Alexey A,Ozerov Ivan,Petr Michael A,Reason ,Rubinsztein David C,Tyshkovskiy Alexander,Vanhaelen Quentin,Zhavoronkov Alex,Scheibye-Knudsen Morten
Aging
An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6 annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7 annual ARDD exhibition will transpire 2-4 of September, 2020, in Basel.
10.18632/aging.102487
Engineering the human pluripotent stem cell microenvironment to direct cell fate.
Biotechnology advances
Human pluripotent stem cells (hPSCs), including both embryonic stem cells and induced pluripotent stem cells, offer a potential cell source for research, drug screening, and regenerative medicine applications due to their unique ability to self-renew or differentiate to any somatic cell type. Before the full potential of hPSCs can be realized, robust protocols must be developed to direct their fate. Cell fate decisions are based on components of the surrounding microenvironment, including soluble factors, substrate or extracellular matrix, cell-cell interactions, mechanical forces, and 2D or 3D architecture. Depending on their spatio-temporal context, these components can signal hPSCs to either self-renew or differentiate to cell types of the ectoderm, mesoderm, or endoderm. Researchers working at the interface of engineering and biology have identified various factors which can affect hPSC fate, often based on lessons from embryonic development, and they have utilized this information to design in vitro niches which can reproducibly direct hPSC fate. This review highlights culture systems that have been engineered to promote self-renewal or differentiation of hPSCs, with a focus on studies that have elucidated the contributions of specific microenvironmental cues in the context of those culture systems. We propose the use of microsystem technologies for high-throughput screening of spatial-temporal presentation of cues, as this has been demonstrated to be a powerful approach for differentiating hPSCs to desired cell types.
10.1016/j.biotechadv.2013.03.002
Ginsenoside Rg1 improves pathological damages by activating the p21‑p53‑STK pathway in ovary and Bax‑Bcl2 in the uterus in premature ovarian insufficiency mouse models.
He Lianli,Wang Xiaojuan,Cheng Daigang,Xiong Zhengai,Liu Xiaoyun
Molecular medicine reports
The aim of the present study was to investigate the effects of the ginsenoside Rg1 on D‑galactose (D‑gal)‑induced mouse models of premature ovarian insufficiency (POI) and the related mechanisms. C57BL/6 female mice were randomly grouped into the following: i) D‑gal [subcutaneously (s.c.) 200 mg/kg/d D‑gal for 42 days]; ii) Rg1 [intraperitoneally (i.p.) 20 mg/kg/d Rg1 for 28 days]; iii) D‑gal + Rg1 (s.c. 200 mg/kg/d D‑gal for 42 days followed by i.p. 20 mg/kg/d Rg1 for 28 days); and iv) saline groups (equivalent volume of saline s.c. and i.p.). Hematoxylin and eosin staining and electron microscopy were used to analyze uterine and ovarian morphology. Expression levels of senescence factors (p21, p53 and serine/threonine kinase), secretion of pro‑inflammatory cytokines [interleukin (IL)‑6, tumor necrosis factor (TNF)‑α and IL‑1β] and the activities of oxidation biomarkers [superoxide dismutase (T‑SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH‑px)] were analyzed. The results showed that mice in the Rg1 + D‑gal group had significantly higher uterine and ovarian weight compared with those in the D‑gal group. Uterus morphology was also improved, based on the comparison between the D‑gal group and the Rg1 + D‑gal group. In addition, the Rg1 treatment after D‑gal administration significantly decreased the expression of senescence‑associated factors, enhanced the activities of anti‑oxidant enzymes total T‑SOD and GSH‑px in addition to reducing TNF‑α, IL‑1β, MDA and IL‑6 (based on the comparison between the D‑gal group and the Rg1 + D‑gal group). In conclusion, the present study suggested that the ginsenoside Rg1 improved pathological damages in the ovary and uterus by increasing anti‑oxidant and anti‑inflammatory abilities whilst reducing the expression of senescence signaling pathways in POI mouse models.
10.3892/mmr.2020.11675
Ginsenoside Rg1 Decreases Oxidative Stress and Down-Regulates Akt/mTOR Signalling to Attenuate Cognitive Impairment in Mice and Senescence of Neural Stem Cells Induced by D-Galactose.
Chen Linbo,Yao Hui,Chen Xiongbin,Wang Ziling,Xiang Yue,Xia Jieyu,Liu Ying,Wang Yaping
Neurochemical research
Adult hippocampal neurogenesis plays a pivotal role in learning and memory. The suppression of hippocampal neurogenesis induced by an increase of oxidative stress is closely related to cognitive impairment. Neural stem cells which persist in the adult vertebrate brain keep up the production of neurons over the lifespan. The balance between pro-oxidants and anti-oxidants is important for function and surviving of neural stem cells. Ginsenoside Rg1 is one of the most active components of Panax ginseng, and many studies suggest that ginsenosides have antioxidant properties. This research explored the effects and underlying mechanisms of ginsenoside Rg1 on protecting neural stem cells (NSCs) from oxidative stress. The sub-acute ageing of C57BL/6 mice was induced by subcutaneous injection of D-gal (120 mg kg day) for 42 day. On the 14th day of D-gal injection, the mice were treated with ginsenoside Rg1 (20 mg kg day, intraperitoneally) or normal saline for 28 days. The study monitored the effects of Rg1 on proliferation, senescence-associated and oxidative stress biomarkers, and Akt/mTOR signalling pathway in NSCs. Compared with the D-gal group, Rg1 improved cognitive impairment induced by D-galactose in mice by attenuating senescence of neural stem cells. Rg1 also decreased the level of oxidative stress, with increased the activity of superoxide dismutase and glutathione peroxidase in vivo and in vitro. Rg1 furthermore reduced the phosphorylation levels of protein kinase B (Akt) and the mechanistic target of rapamycin (mTOR) and down-regulated the levels of downstream p53, p16, p21 and Rb in D-gal treated NSCs. The results suggested that the protective effect of ginsenoside Rg1 on attenuating cognitive impairment in mice and senescence of NSCs induced by D-gal might be related to the reduction of oxidative stress and the down-regulation of Akt/mTOR signaling pathway.
10.1007/s11064-017-2438-y
Ginsenoside Rg1 enhances the resistance of hematopoietic stem/progenitor cells to radiation-induced aging in mice.
Chen Cui,Mu Xin-yi,Zhou Yue,Shun Ke,Geng Shan,Liu Jun,Wang Jian-wei,Chen Jie,Li Tin-yu,Wang Ya-Ping
Acta pharmacologica Sinica
AIM:To investigate the effects of ginsenoside Rg1 on the radiation-induced aging of hematopoietic stem/progenitor cells (HSC/HPCs) in mice and the underlying mechanisms. METHODS:Male C57BL/6 mice were treated with ginsenoside Rg1 (20 mg·kg(-1)·d(-1), ip) or normal saline (NS) for 7 d, followed by exposure to 6.5 Gy X-ray total body irradiation. A sham-irradiated group was treated with NS but without irradiation. Sca-1(+) HSC/HPCs were isolated and purified from their bone marrow using MACS. DNA damage was detected on d 1. The changes of anti-oxidative activities, senescence-related markers senescence-associated β-galactosidase (SA-β-gal) and mixed colony-forming unit (CFU-mix), P16(INK4a) and P21(Cip1/Waf1) expression on d 7, and cell cycle were examined on d 1, d 3, and d 7. RESULTS:The irradiation caused dramatic reduction in the number of Sca-1(+) HSC/HPCs on d 1 and the number barely recovered until d 7 compared to the sham-irradiated group. The irradiation significantly decreased SOD activity, increased MDA contents and caused DNA damage in Sca-1(+) HSC/HPCs. Moreover, the irradiation significantly increased SA-β-gal staining, reduced CFU-mix forming, increased the expression of P16(INK4a) and P21(Cip1/Waf1) in the core positions of the cellular senescence signaling pathways and caused G1 phase arrest of Sca-1(+) HSC/HPCs. Administration of ginsenoside Rg1 caused small, but significant recovery in the number of Sca-1(+) HSC/HPCs on d 3 and d 7. Furthermore, ginsenoside Rg1 significantly attenuated all the irradiation-induced changes in Sca-1(+) HSC/HPCs, including oxidative stress reaction, DNA damage, senescence-related markers and cellular senescence signaling pathways and cell cycle, etc. CONCLUSION:Administration of ginsenoside Rg1 enhances the resistance of HSC/HPCs to ionizing radiation-induced senescence in mice by inhibiting the oxidative stress reaction, reducing DNA damage, and regulating the cell cycle.
10.1038/aps.2013.136
Protective Effect of Ginsenoside Rg1 on Hematopoietic Stem/Progenitor Cells through Attenuating Oxidative Stress and the Wnt/β-Catenin Signaling Pathway in a Mouse Model of d-Galactose-induced Aging.
Li Jing,Cai Dachuan,Yao Xin,Zhang Yanyan,Chen Linbo,Jing Pengwei,Wang Lu,Wang Yaping
International journal of molecular sciences
Stem cell senescence is an important and current hypothesis accounting for organismal aging, especially the hematopoietic stem cell (HSC). Ginsenoside Rg1 is the main active pharmaceutical ingredient of ginseng, which is a traditional Chinese medicine. This study explored the protective effect of ginsenoside Rg1 on Sca-1⁺ hematopoietic stem/progenitor cells (HSC/HPCs) in a mouse model of d-galactose-induced aging. The mimetic aging mouse model was induced by continuous injection of d-gal for 42 days, and the C57BL/6 mice were respectively treated with ginsenoside Rg1, Vitamin E or normal saline after 7 days of d-gal injection. Compared with those in the d-gal administration alone group, ginsenoside Rg1 protected Sca-1⁺ HSC/HPCs by decreasing SA-β-Gal and enhancing the colony forming unit-mixture (CFU-Mix), and adjusting oxidative stress indices like reactive oxygen species (ROS), total anti-oxidant (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and malondialdehyde (MDA). In addition, ginsenoside Rg1 decreased β-catenin and c-Myc mRNA expression and enhanced the phosphorylation of GSK-3β. Moreover, ginsenoside Rg1 down-regulated advanced glycation end products (AGEs), 4-hydroxynonenal (4-HNE), phospho-histone H2A.X (r-H2A.X), 8-OHdG, p16(Ink4a), Rb, p21(Cip1/Waf1) and p53 in senescent Sca-1⁺ HSC/HPCs. Our findings indicated that ginsenoside Rg1 can improve the resistance of Sca-1⁺ HSC/HPCs in a mouse model of d-galactose-induced aging through the suppression of oxidative stress and excessive activation of the Wnt/β-catenin signaling pathway, and reduction of DNA damage response, p16(Ink4a)-Rb and p53-p21(Cip1/Waf1) signaling.
10.3390/ijms17060849
Ginsenoside Rg1 Improves Differentiation by Inhibiting Senescence of Human Bone Marrow Mesenchymal Stem Cell via GSK-3 and -Catenin.
Stem cells international
OBJECTIVES:To demonstrate the effect of Ginsenoside Rg1 on the differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). Subsequently, a rational mechanism for the detection of Rg1 which affects mesenchymal stem cell differentiation was explored. METHODS:Flow cytometry is used for cell identification. The differentiation ability of hBM-MSCs was studied by differentiation culture. SA--gal staining is used to detect cell senescence levels. Western blot and immunofluorescence were used to determine protein expression levels. RT-qPCR is used to detect mRNA expression levels. RESULTS:Rg1 regulates the differentiation of hBM-MSCs. Differentiation culture analysis showed that Rg1 promoted cells to osteogenesis and chondrogenesis. Western blot results showed that Rg1 regulated the overactivation of the -catenin signaling pathway and significantly adjusted the phosphorylation of GSK-3. GSK-3 inhibitor (Licl) significantly increased Rg1-induced phosphorylation of GSK-3, which in turn reduced Rg1-induced differentiation of hBM-MSCs. CONCLUSION:Ginsenoside Rg1 can reduce the excessive activation of the Wnt pathway in senescent cells by inhibiting the phosphorylation of GSK-3 and regulate the mesenchymal stem cell differentiation ability.
10.1155/2020/2365814
Neuroprotective effects of ginseng protein on PI3K/Akt signaling pathway in the hippocampus of D-galactose/AlCl3 inducing rats model of Alzheimer's disease.
Li Hongyan,Kang Tingguo,Qi Bin,Kong Liang,Jiao Yanan,Cao Yang,Zhang Jianghua,Yang Jingxian
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Alzheimer disease (AD) is a progressive neurodegenerative disease, with progressive memory loss, cognitive deterioration, and behavioral disorders. Ginseng (Panax ginseng C.A. Meyer) is widely used in China to treat various kinds of nervous system disorders. The study aimed to explore the therapeutic effect of ginseng protein (GP) on Alzheimer's disease and its correlation with the PI3K/Akt signaling pathway to understand the mechanism underlying the neuroprotective effect of ginseng. MATERIAL AND METHODS:The AD rat model was established by intraperitoneally injecting D-galactose [60mg/(kgd)] followed by intragastrically administering AlCl3 [40mg/(kgd)] for 90 days. From day 60, the GP groups were intragastrically administered with GP 0.05 or 0.1g/kg twice daily for 30 days. The ethology of rats was tested by Morris water maze test. The content of Aβ1-42 and p-tau in the hippocampus of rats was detected by enzyme-linked immunosorbent assay. The expression of mRNAs and proteins of PI3K, Akt, phosphorylated Akt (p-Akt), Bcl-2, and Bax in the hippocampus was detected by real-time quantitative reverse transcription polymerase chain reaction and Western blot assay. RESULTS:GP was found to significantly improve the memory ability of AD rats and prolong the times of crossing the platform and the percentage of residence time in the original platform quadrant of spatial probe test. GP also reduced the content of Aβ1-42 and p-tau and improved the mRNA and protein expression of PI3K, p-Akt/Akt, and Bcl-2/Bax in the hippocampus. CONCLUSIONS:GP could improve the memory ability and reduce the content of Aβ1-42 and p-tau in AD rats. The anti-AD effects of GP were in part mediated by PI3K/Akt signaling pathway activation.
10.1016/j.jep.2015.12.020
Wnt/β-catenin signaling and disease.
Clevers Hans,Nusse Roel
Cell
The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future.
10.1016/j.cell.2012.05.012
Salidroside Protection Against Oxidative Stress Injury Through the Wnt/β-Catenin Signaling Pathway in Rats with Parkinson's Disease.
Wu Dong-Mei,Han Xin-Rui,Wen Xin,Wang Shan,Fan Shao-Hua,Zhuang Juan,Wang Yong-Jian,Zhang Zi-Feng,Li Meng-Qiu,Hu Bin,Shan Qun,Sun Chun-Hui,Lu Jun,Zheng Yuan-Lin
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND/AIMS:Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and recent studies suggested that oxidative stress (OS) contributes to the cascade that leads to dopamine cell degeneration in PD. In this study, we hypothesized that salidroside (SDS) offers protection against OS injury in 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats as well as the underlying mechanism. METHODS:SDS and LiCl (activators of the Wnt/β-catenin signaling pathway) administration alone and in combination with 6-OHDA injection in rats was performed 3 days before modeling for 17 consecutive days to verify the regulatory mechanism by which SDS affects the Wnt/β-catenin signaling pathway as well as to evaluate the protective effect of SDS on PD in relation to OS in vivo. In addition, pheochromocytoma 12 (PC12) cells were incubated with 10 µmol/L SDS or LiCl alone or with both in combination for 1 h followed by a 24-h incubation with 100 µmol/L 6-OHDA to obtain in vitro data. RESULTS:In vivo the administration of LiCl was found to ameliorate behavioral deficits and dopaminergic neuron loss; increase superoxide dismutase (SOA) activity, glutathione peroxidase (GSH-Px) levels, and glycogen synthase kinase 3β phosphorylation (GSK-3β-Ser9); reduce malondialdehyde (MDA) accumulation in the striatum and the GSK-3β mRNA level; as well as elevate β-catenin and cyclinD1 mRNA and protein levels in 6-OHDA-injected rats. This SDS treatment regimen was found to strengthen the beneficial effect of LiCl on 6-OHDA-injected rats. In vitro LiCl treatment decreased the toxicity of 6-OHDA on PC12 cells and prevented apoptosis. Additionally, LiCl treatment increased SOA activity, GSH-Px levels, and GSK-3β-Ser9 phosphorylation; decreased MDA accumulation in the striatum and GSK-3β mRNA levels; as well as increased β-catenin and cyclinD1 mRNA and protein levels in 6-OHDA-treated PC12 cells. Additionally, SDS treatment increased the protective effect of LiCl on 6-OHDA-treated PC12 cells. CONCLUSION:Evidence from experimental models suggested that SDS may confer neuroprotection against the neurotoxicity of 6-OHDA in response to OS injury and showed that these beneficial effects may be related to regulation of the Wnt/β-catenin signaling pathway. Therefore, SDS might be a potential therapeutic agent for treating PD.
10.1159/000489365
Novel target for treating Alzheimer's Diseases: Crosstalk between the Nrf2 pathway and autophagy.
Zhang Weiwei,Feng Cong,Jiang Hong
Ageing research reviews
In mammals, the Keap1-Nrf2-ARE pathway (henceforth, "the Nrf2 pathway") and autophagy are major intracellular defence systems that combat oxidative damage and maintain homeostasis. p62/SQSTM1, a ubiquitin-binding autophagy receptor protein, links the Nrf2 pathway and autophagy. Phosphorylation of p62 dramatically enhances its affinity for Keap1, which induces Keap1 to release Nrf2, and the p62-Keap1 heterodimer recruits LC3 and mediates the permanent degradation of Keap1 in the selective autophagy pathway. Eventually, Nrf2 accumulates in the cytoplasm and then translocates into the nucleus to activate the transcription of downstream genes that encode antioxidant enzymes, which protect cells from oxidative damage. Since Nrf2 also upregulates the expression of the p62 gene, a p62-Keap1-Nrf2 positive feedback loop is created that further enhances the protective effect on cells. Studies have shown that the p62-activated noncanonical Nrf2 pathway is an important marker of neurodegenerative diseases. The p62-Keap1-Nrf2 positive feedback loop and the Nrf2 pathway are involved in eliminating the ROS and protein aggregates induced by AD. Therefore, maintaining the homeostasis of the p62-Keap1-Nrf2 positive feedback loop, which is a bridge between the Nrf2 pathway and autophagy, may be a potential target for the treatment of AD.
10.1016/j.arr.2020.101207
The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update.
Lu Meng-Chen,Ji Jian-Ai,Jiang Zheng-Yu,You Qi-Dong
Medicinal research reviews
The Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway is one of the most important defense mechanisms against oxidative and/or electrophilic stresses, and it is closely associated with inflammatory diseases, including cancer, neurodegenerative diseases, cardiovascular diseases, and aging. In recent years, progress has been made in strategies aimed at modulating the Keap1-Nrf2-ARE pathway. The Nrf2 activator DMF (Dimethylfumarates) has been approved by the FDA as a new first-line oral drug to treat patients with relapsing forms of multiple sclerosis, while a phase 3 study of another promising candidate, CDDO-Me, was terminated for safety reasons. Directly inhibiting Keap1-Nrf2 protein-protein interactions as a novel Nrf2-modulating strategy has many advantages over using electrophilic Nrf2 activators. The development of Keap1-Nrf2 protein-protein interaction inhibitors has become a topic of intense research, and potent inhibitors of this target have been identified. In addition, inhibiting Nrf2 activity has attracted an increasing amount of attention because it may provide an alternative cancer therapy. This review summarizes the molecular mechanisms and biological functions of the Keap1-Nrf2-ARE system. The main focus of this review is on recent progress in studies of agents that target the Keap1-Nrf2-ARE pathway and the therapeutic applications of such agents.
10.1002/med.21396
Ginsenoside Rg1 protects H9c2 cells against nutritional stress-induced injury via aldolase /AMPK/PINK1 signalling.
Xu ZhiMeng,Li ChengBin,Liu QingLing,Yang Hua,Li Ping
Journal of cellular biochemistry
Insufficient nutrients supply will greatly affect the function of cardiac myocytes. The adaptive responses of cardiac myocytes to nutritional stress are not fully known. Ginsenoside Rg1 is one of the most pharmacologically active components in Panax Ginseng and possesses protective effects on cardiomyocyte. Here, we investigate the effects of ginsenoside Rg1 on H9c2 cells which were subjected to nutritional stress. Nutritional stress-induced by glucose deprivation strongly induced cell death and this response was inhibited by ginsenoside Rg1. Importantly, glucose deprivation decreased intracellular ATP levels and mitochondrial membrane potential. Ginsenoside Rg1 rescued ATP levels and mitochondrial membrane potential in nutrient-starved cells. For molecular mechanisms, ginsenoside Rg1 increased the expressions of PTEN-induced kinase 1 (PINK1) and p-AMPK in glucose deprivation treated H9c2 cells. Reducing the expression of aldolase in H9c2 cells inhibited ginsenoside Rg1's actions on PINK1 and p-AMPK. Further, the nutritional stress mice were used to verify the mechanisms obtained in vitro. Ginsenoside Rg1 increased the expressions of aldolase, p-AMPK, and PINK1 in starved mice heart. Taken together, our results reveal that ginsenoside Rg1 limits nutritional stress-induced H9c2 cells injury by regulating the aldolase /AMP-activated protein kinase/PINK1 pathway.
10.1002/jcb.29150