Project description:One of the most important issues in the study of aging is to discover compounds with longevity-promoting activity and to unravel their underlying mechanisms. Queen honey bees are continuously fed royal jelly (RJ), and they live more than 10 times longer than hive workers, derived from the same diploid genome, which are fed it only for a short period of time during their larval stages. Therefore, RJ is likely to contain longevity-promoting agents for queens. RJ has been reported to possess diverse pharmacological properties. Furthermore, protease-treated RJ (pRJ) has additional beneficial activities. How RJ and pRJ exert these effects and which components in them play a critical role is largely unknown. The evolutionally conserved mechanisms that control lifespan have been indicated. The nematode Caenorhabditis elegans has been widely used for study of aging and longevity, due to its relatively short lifespan and well-established genetic pathways. The purpose of the present study was to elucidate whether RJ and its related substances contain the life span-extending activity in C. elegans and to obtain some insight into the active agents and their mechanisms. We found that both RJ and pRJ extended the lifespan of C. elegans. The life span-extending activity of pRJ was enriched by ODS column chromatography (pRJ-Fraction 5). pRJ-Fr. 5 extended the life span partly by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr. 5 induced changes in the expression of 3 genes encoding insulin-like peptides. Moreover, pRJ-Fr. 5 and reduced IIS shared some common features in terms of their effect on gene expression, such as up-regulation of dod-3 and down-regulation of dod-19, dao-4 and fkb-4. The dod-19 is a previously identified life span determinant in C. elegans, and the fkb-4 encodes a homologue of the mammalian FK506-binding protein. 10-Hydroxy-2-decenoic acid (10-HDA), which was present in high concentration in pRJ-Fr. 5, increased the lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extended the life span in C. elegans, suggesting that RJ may contain longevity-promoting factors common to diverse species across phyla. pRJ-Fr. 5 had higher life span-extending activity than either RJ or pRJ and extended the life span in part through the IIS-DAF-16 pathway. We provide the first evidence that 10-HDA, a defined natural product in RJ, extended organismal lifespan. It is noteworthy that 10-HDA performed its lifespan-extending function through a mechanism totally different from the IIS-DAF-16 pathway. Further search and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network of longevity regulation in diverse species and provide the possibility for nutraceutical interventions in the aging process. C. elegans N2 hermaphrodites were untreated or treated with pRJ-Fr. 5 (25mg/ml) for 24 h starting at the larval 4 (L4) stage.

Project description:The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family1, 2, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals3. Regulators of histone methylation have been associated with ageing in worms4, 5, 6, 7 and flies8, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex9, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms. Deficiencies in members of the ASH-2 complex—ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2—extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation—a mark associated with active chromatin—is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results indicate that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline. There are 23 samples in total. ASH-2 knock-down increases lifespan in a germline dependent manner. We examined ASH-2 regulated genes that are dependent on the presence of an intact germline using WT or glp-1(e2141ts) mutant worms which develop only 5-15 meiotic germ cells treated with either empty vector (EV) or ash-2 RNAi. We examined gene expression at the L3 stage (when we observe changes in H3K4me3) and at a mid life stage (day 8). The majority of ASH-2 controlled genes were regulated in a germline dependent manner. Samples were collected in triplicate for each condition (but Day 8 N2 (WT) E.V. #3 was excluded from all analysis due to quality issues).

Project description:One of the most important issues in the study of aging is to discover compounds with longevity-promoting activity and to unravel their underlying mechanisms. Queen honey bees are continuously fed royal jelly (RJ), and they live more than 10 times longer than hive workers, derived from the same diploid genome, which are fed it only for a short period of time during their larval stages. Therefore, RJ is likely to contain longevity-promoting agents for queens. RJ has been reported to possess diverse pharmacological properties. Furthermore, protease-treated RJ (pRJ) has additional beneficial activities. How RJ and pRJ exert these effects and which components in them play a critical role is largely unknown. The evolutionally conserved mechanisms that control lifespan have been indicated. The nematode Caenorhabditis elegans has been widely used for study of aging and longevity, due to its relatively short lifespan and well-established genetic pathways. The purpose of the present study was to elucidate whether RJ and its related substances contain the life span-extending activity in C. elegans and to obtain some insight into the active agents and their mechanisms. We found that both RJ and pRJ extended the lifespan of C. elegans. The life span-extending activity of pRJ was enriched by ODS column chromatography (pRJ-Fraction 5). pRJ-Fr. 5 extended the life span partly by acting through the FOXO transcription factor DAF-16, the activation of which is known to promote longevity in C. elegans by reducing insulin/IGF-1 signaling (IIS). pRJ-Fr. 5 induced changes in the expression of 3 genes encoding insulin-like peptides. Moreover, pRJ-Fr. 5 and reduced IIS shared some common features in terms of their effect on gene expression, such as up-regulation of dod-3 and down-regulation of dod-19, dao-4 and fkb-4. The dod-19 is a previously identified life span determinant in C. elegans, and the fkb-4 encodes a homologue of the mammalian FK506-binding protein. 10-Hydroxy-2-decenoic acid (10-HDA), which was present in high concentration in pRJ-Fr. 5, increased the lifespan independently of DAF-16 activity.These results demonstrate that RJ and its related substances extended the life span in C. elegans, suggesting that RJ may contain longevity-promoting factors common to diverse species across phyla. pRJ-Fr. 5 had higher life span-extending activity than either RJ or pRJ and extended the life span in part through the IIS-DAF-16 pathway. We provide the first evidence that 10-HDA, a defined natural product in RJ, extended organismal lifespan. It is noteworthy that 10-HDA performed its lifespan-extending function through a mechanism totally different from the IIS-DAF-16 pathway. Further search and characterization of the lifespan-extending agents in RJ and pRJ may broaden our understanding of the gene network of longevity regulation in diverse species and provide the possibility for nutraceutical interventions in the aging process.

Project description:Inflammation is highly associated with colon carcinogenesis. Epigenetic mechanisms play an important role in the initiation and progression of colon cancer. Curcumin is a dietary cancer preventive phytochemical with promising effect in suppressing colitis-associated colon cancer (CAC) in azoxymethane (AOM) and dextran sulfate sodium (DSS) mouse model. In the present study, we confirmed the effect of curcumin in suppressing colon cancer. Using Agilent SureSelect Methyl-seq and RNA-seq, we obtained single-base methylation profile and transcriptome analyses of epithelial cells from control group, AOM and DSS induced group (AOM+DSS), and AOM and DSS induced plus curcumin treated group (AOM+DSS+Curcumin) in a 18 weeks long-term colon cancer mouse model. We observed differentially expressed genes in pair-wise comparison and identified several pathways of small set of genes involved in the potential preventive effect of curcumin. These pathways include LPS/IL-1 mediated inhibition of RXR function, NRF2-mediated oxidative stress response, aldosterone signaling in epithelial cells, production of NO and ROS in macrophages, and IL-6 signaling. The average DNA methylation levels of the three groups are significantly different also. Based on differential methylation patterns of three groups, several pathways of genes were identified including IL-8 signaling, LPS-stimulated MAPK signaling and colorectal cancer metastasis signaling. Among these methylated pathways and genes, Tnf, an inflammatory gene stood out with decreased DNA CpG methylation in the AOM-DSS as compared to the control group and interestingly curcumin reversed the CpG methylation (validated by pyrosequencing). These observations correlated with decreased, and increased with curcumin, Tnf expression in RNA-seq (validated by qPCR), respectively. The functional role of DNA methylation of Tnf was confirmed by in vitro luciferase transcriptional activity assay. In addition, we found that a group of genes associated with the inflammatory responses and their methylation level was decreased in AOM+DSS group but restored in the curcumin treated group. Taken together, in this study, aberrant DNA CpG methylation of the inflammatory response was found in colitis-associated colon cancer and curcumin restored their CpG methlyation, which could potentially explain the inflammatory and cancer protective effects of curcumin. (Note this GEO/dataset is the RNA-seq part of the study.)

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Screening bioactive food compounds in honey bees suggests curcumin blocks alcohol-induced damage to longevity and DNA methylation

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