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Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16  [PDF]
Christian Büchter,Daniela Ackermann,Susannah Havermann,Sebastian Honnen,Yvonni Chovolou,Gerhard Fritz,Andreas Kampk?tter,Wim W?tjen
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140611895
Abstract: Myricetin is a naturally occurring flavonol found in many plant based food sources. It increases the lifespan of Caenorhabditis elegans, but the molecular mechanisms are not yet fully understood. We have investigated the impact of this flavonoid on the transcription factors DAF-16 ( C. elegans FoxO homologue) and SKN-1 (Nrf2 homologue), which have crucial functions in the regulation of ageing. Myricetin is rapidly assimilated by the nematode, causes a nuclear translocation of DAF-16 but not of SKN-1, and finally prolongs the mean adult lifespan of C. elegans by 32.9%. The lifespan prolongation was associated with a decrease in the accumulation of reactive oxygen species (ROS) detected by DCF. Myricetin also decreases the formation of lipofuscin, a pigment consisting of highly oxidized and cross-linked proteins that is considered as a biomarker of ageing in diverse species. The lifespan extension was completely abolished in a daf-16 loss-of-function mutant strain (CF1038). Consistently with this result, myricetin was also not able to diminish stress-induced ROS accumulation in the mutant. These results strongly indicate that the pro-longevity effect of myricetin is dependent on DAF-16 and not on direct anti-oxidative effects of the flavonoid.
pro-1基因通过DAF-16调控秀丽隐杆线虫的寿命
Pro-1 regulates the lifespan of Caenorhabditis elegans through DAF-16
 [PDF]

毛玉琴, 韩三峰, 王立顺
MAO Yu-qin
, HAN San-feng, WANG Li-shun

- , 2016, DOI: 10.3969/j.issn.1674-8115.2016.10.003
Abstract: 目的·用秀丽隐杆线虫(Caenorhabditis elegans)作为模式生物,观察pro-1基因对寿命的影响,并初步探究其影响寿命的机制。方法·在线虫上以RNAi技术定向干扰pro-1基因的表达,随后对pro-1沉默表达后的线虫进行寿命分析,检测其在生长发育、运动、饮食以及生殖能力等方面的变化。进一步用RNAi方法结合线虫体内荧光定位技术以及RT-PCR技术等探究pro-1影响寿命可能的分子机制。结果·与对照组线虫相比,干扰 pro-1表达后,沉默组线虫平均寿命延长了14.58%(P=0.002);在TJ356线虫中干扰pro-1表达后,DAF-16明显进入细胞核,且DAF-16下游靶基因如old-1、sod-3、hsp-16.1、mtl-1、ctl-2等的mRNA水平被上调。结论·pro-1基因通过促进DAF-16进入细胞核并上调其下游靶基因的mRNA水平,从而延长秀丽隐杆线虫的寿命。
: Objective·To observe the effects of pro-1 gene on the lifespan of Caenorhabditis elegans (C. elegans) and preliminary explore the molecular mechanisms. Methods·RNAi technique was used to intervene the expression of pro-1 gene in C. elegans. The lifespan of C. elegans with silent pro-1 was analyzed and changes in growth, development, motion, diet, and reproduction were detected. The molecular mechanisms of pro-1 to affect the lifespan were explored using RNAi technique, fluorescence localization technology, and RT-PCR. Results·The lifespan of silence group C. elegans was significantly increased by 14.58% after the expression of pro-1 intervented as compared with controls (P=0.002). DAF-16 translocated into nucleus in C. elegans of TJ356 strain after intervening the expression of pro-1 and mRNA expressions of downstream target genes such as old-1, sod-3, hsp-16.1, mtl-1 and ctl-2 were up-regulated. Conclusion·pro-1 prolongs the lifespan of C. elegans via promoting the translocation of DAF-16 into nucleus and up-regulating the mRNA expressions of downstream target genes
Monascus-Fermented Dioscorea Enhances Oxidative Stress Resistance via DAF-16/FOXO in Caenorhabditis elegans  [PDF]
Yeu-Ching Shi, Chan-Wei Yu, Vivian Hsiu-Chuan Liao, Tzu-Ming Pan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039515
Abstract: Background Monascus-fermented products are mentioned in an ancient Chinese pharmacopoeia of medicinal food and herbs. Monascus-fermented products offer valuable therapeutic benefits and have been extensively used in East Asia for several centuries. Several biological activities of Monascus-fermented products were recently described, and the extract of Monascus-fermented products showed strong antioxidant activity of scavenging DPPH radicals. To evaluate whether Monascus-fermented dioscorea products have potential as nutritional supplements, Monascus-fermented dioscorea’s modulation of oxidative-stress resistance and associated regulatory mechanisms in Caenorhabditis elegans were investigated. Principal Findings We examined oxidative stress resistance of the ethanol extract of red mold dioscorea (RMDE) in C. elegans, and found that RMDE-treated wild-type C. elegans showed an increased survival during juglone-induced oxidative stress compared to untreated controls, whereas the antioxidant phenotype was absent from a daf-16 mutant. In addition, the RMDE reduced the level of intracellular reactive oxygen species in C. elegans. Finally, the RMDE affected the subcellular distribution of the FOXO transcription factor, DAF-16, in C. elegans and induced the expression of the sod-3 antioxidative gene. Conclusions These findings suggest that the RMDE acts as an antioxidative stress agent and thus may have potential as a nutritional supplement. Further studies in C. elegans suggest that the antioxidant effect of RMDE is mediated via regulation of the DAF-16/FOXO-dependent pathway.
daf-31 Encodes the Catalytic Subunit of N Alpha-Acetyltransferase that Regulates Caenorhabditis elegans Development, Metabolism and Adult Lifespan  [PDF]
Di Chen equal contributor ,Jiuli Zhang equal contributor,Justin Minnerly,Tiffany Kaul,Donald L. Riddle,Kailiang Jia
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004699
Abstract: The Caenorhabditis elegans dauer larva is a facultative state of diapause. Mutations affecting dauer signal transduction and morphogenesis have been reported. Of these, most that result in constitutive formation of dauer larvae are temperature-sensitive (ts). The daf-31 mutant was isolated in genetic screens looking for novel and underrepresented classes of mutants that form dauer and dauer-like larvae non-conditionally. Dauer-like larvae are arrested in development and have some, but not all, of the normal dauer characteristics. We show here that daf-31 mutants form dauer-like larvae under starvation conditions but are sensitive to SDS treatment. Moreover, metabolism is shifted to fat accumulation in daf-31 mutants. We cloned the daf-31 gene and it encodes an ortholog of the arrest-defective-1 protein (ARD1) that is the catalytic subunit of the major N alpha-acetyltransferase (NatA). A daf-31 promoter::GFP reporter gene indicates daf-31 is expressed in multiple tissues including neurons, pharynx, intestine and hypodermal cells. Interestingly, overexpression of daf-31 enhances the longevity phenotype of daf-2 mutants, which is dependent on the forkhead transcription factor (FOXO) DAF-16. We demonstrate that overexpression of daf-31 stimulates the transcriptional activity of DAF-16 without influencing its subcellular localization. These data reveal an essential role of NatA in controlling C. elegans life history and also a novel interaction between ARD1 and FOXO transcription factors, which may contribute to understanding the function of ARD1 in mammals.
Caffeic Acid Phenethylester Increases Stress Resistance and Enhances Lifespan in Caenorhabditis elegans by Modulation of the Insulin-Like DAF-16 Signalling Pathway  [PDF]
Susannah Havermann, Yvonni Chovolou, Hans-Ulrich Humpf, Wim W?tjen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100256
Abstract: CAPE is an active constituent of propolis which is widely used in traditional medicine. This hydroxycinnamic acid derivate is a known activator of the redox-active Nrf2 signalling pathway in mammalian cells. We used C. elegans to investigate the effects of this compound on accumulation of reactive oxygen species and the modulation of the pivotal redox-active pathways SKN-1 and DAF-16 (homologues of Nrf2 and FoxO, respectively) in this model organism; these results were compared to the effects in Hct116 human colon carcinoma cells. CAPE exerts a strong antioxidative effect in C. elegans: The increase of reactive oxygen species induced by thermal stress was diminished by about 50%. CAPE caused a nuclear translocation of DAF-16, but not SKN-1. CAPE increased stress resistance of the nematode against thermal stress and finally a prolongation of the median and maximum lifespan by 9 and 17%, respectively. This increase in stress resistance and lifespan was dependent on DAF-16 as shown in experiments using a DAF-16 loss of function mutant strain. Life prolongation was retained under SKN-1 RNAi conditions showing that the effect is SKN-1 independent. The results of CAPE obtained in C. elegans differed from the results obtained in Hct116 colon carcinoma cells: CAPE also caused strong antioxidative effects in the mammalian cells, but no activation of the FoxO4 signalling pathway was detectable. Instead, an activation of the Nrf2 signalling pathway was shown by luciferase assay and western blots. CONCLUSION: CAPE activates the insulin-like DAF-16, but not the SKN-1 signalling pathway in C. elegans and therefore enhances the stress resistance and lifespan of this organism. Since modulation of the DAF-16 pathway was found to be a pivotal effect of CAPE in C. elegans, this has to be taken into account for the investigation of the molecular mechanisms of the traditional use of propolis.
Cell-Nonautonomous Signaling of FOXO/DAF-16 to the Stem Cells of Caenorhabditis elegans  [PDF]
Wenjing Qi,Xu Huang,Elke Neumann-Haefelin,Ekkehard Schulze,Ralf Baumeister
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002836
Abstract: In Caenorhabditis elegans (C. elegans), the promotion of longevity by the transcription factor DAF-16 requires reduced insulin/IGF receptor (IIR) signaling or the ablation of the germline, although the reason for the negative impact of germ cells is unknown. FOXO/DAF-16 activity inhibits germline proliferation in both daf-2 mutants and gld-1 tumors. In contrast to its function as a germline tumor suppressor, we now provide evidence that somatic DAF-16 in the presence of IIR signaling can also result in tumorigenic activity, which counteracts robust lifespan extension. In contrast to the cell-autonomous IIR signaling, which is required for larval germline proliferation, activation of DAF-16 in the hypodermis results in hyperplasia of the germline and disruption of the surrounding basement membrane. SHC-1 adaptor protein and AKT-1 kinase antagonize, whereas AKT-2 and SGK-1 kinases promote, this cell-nonautonomous DAF-16 function. Our data suggest that a functional balance of DAF-16 activities in different tissues determines longevity and reveals a novel, cell-nonautonomous role of FOXO/DAF-16 to affect stem cells.
A Novel Role for the SMG-1 Kinase in Lifespan and Oxidative Stress Resistance in Caenorhabditis elegans  [PDF]
Ingrid Masse, Laurent Molin, Laurent Mouchiroud, Philippe Vanhems, Francesca Palladino, Marc Billaud, Florence Solari
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003354
Abstract: The PTEN tumour suppressor encodes a phosphatase, and its daf-18 orthologue in Caenorhabditis elegans negatively regulates the insulin/IGF-1 DAF-2 receptor pathway that influences lifespan in worms and other species. In order to identify new DAF-18 regulated pathways involved in aging, we initiated a candidate RNAi feeding screen for clones that lengthen lifespan. Here, we report that smg-1 inactivation increases average lifespan in a daf-18 dependent manner. Genetic analysis is consistent with SMG-1 acting at least in part in parallel to the canonical DAF-2 receptor pathway, but converging on the transcription factor DAF-16/FOXO. SMG-1 is a serine-threonine kinase which plays a conserved role in nonsense-mediated mRNA decay (NMD) in worms and mammals. In addition, human SMG-1 has also been implicated in the p53-mediated response to genotoxic stress. The effect of smg-1 inactivation on lifespan appears to be unrelated to its NMD function, but requires the p53 tumour suppressor orthologue cep-1. Furthermore, smg-1 inactivation confers a resistance to oxidative stress in a daf-18-, daf-16- and cep-1-dependent manner. We propose that the role of SMG-1 in lifespan regulation is at least partly dependent on its function in oxidative stress resistance. Taken together, our results unveil a novel role for SMG-1 in lifespan regulation.
A Transcription Elongation Factor That Links Signals from the Reproductive System to Lifespan Extension in Caenorhabditis elegans  [PDF]
Arjumand Ghazi,Sivan Henis-Korenblit,Cynthia Kenyon
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000639
Abstract: In Caenorhabditis elegans and Drosophila melanogaster, the aging of the soma is influenced by the germline. When germline-stem cells are removed, aging slows and lifespan is increased. The mechanism by which somatic tissues respond to loss of the germline is not well-understood. Surprisingly, we have found that a predicted transcription elongation factor, TCER-1, plays a key role in this process. TCER-1 is required for loss of the germ cells to increase C. elegans' lifespan, and it acts as a regulatory switch in the pathway. When the germ cells are removed, the levels of TCER-1 rise in somatic tissues. This increase is sufficient to trigger key downstream events, as overexpression of tcer-1 extends the lifespan of normal animals that have an intact reproductive system. Our findings suggest that TCER-1 extends lifespan by promoting the expression of a set of genes regulated by the conserved, life-extending transcription factor DAF-16/FOXO. Interestingly, TCER-1 is not required for DAF-16/FOXO to extend lifespan in animals with reduced insulin/IGF-1 signaling. Thus, TCER-1 specifically links the activity of a broadly deployed transcription factor, DAF-16/FOXO, to longevity signals from reproductive tissues.
Caenorhabditis elegans HCF-1 Functions in Longevity Maintenance as a DAF-16 Regulator  [PDF]
Ji Li,Atsushi Ebata,Yuqing Dong,Gizem Rizki,Terri Iwata,Siu Sylvia Lee
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060233
Abstract: The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.
Caenorhabditis elegans HCF-1 Functions in Longevity Maintenance as a DAF-16 Regulator  [PDF]
Ji Li,Atsushi Ebata,Yuqing Dong,Gizem Rizki,Terri Iwata,Siu Sylvia Lee
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060233
Abstract: The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.
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