MicroRNAs Both Promote and Antagonize Longevity in C. elegans

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511 USA.
Current biology: CB (Impact Factor: 9.57). 12/2010; 20(24):2159-68. DOI: 10.1016/j.cub.2010.11.015
Source: PubMed


aging is under genetic control in C. elegans, but the mechanisms of life-span regulation are not completely known. MicroRNAs (miRNAs) regulate various aspects of development and metabolism, and one miRNA has been previously implicated in life span.
here we show that multiple miRNAs change expression in C. elegans aging, including novel miRNAs, and that mutations in several of the most upregulated miRNAs lead to life-span defects. Some act to promote normal life span and stress resistance, whereas others inhibit these phenomena. We find that these miRNAs genetically interact with genes in the DNA damage checkpoint response pathway and in the insulin signaling pathway.
our findings reveal that miRNAs both positively and negatively influence life span. Because several miRNAs upregulated during aging regulate genes in conserved pathways of aging and thereby influence life span in C. elegans, we propose that miRNAs may play important roles in stress response and aging of more complex organisms.

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Available from: Alexandre de Lencastre
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    • "Little is yet known about the functions of these miRNAs. Members of the miR-100 family, as well as miR-34, let-7 and lin-4, are involved in developmental events or longevity in C. elegans [1] [15] [16]. Poole and colleagues predicted six putative filarial-specific miR- NAs based on B. malayi and B. pahangi published miRNAs and on genome data of O. volvulus, Wuchereria bancrofti and L. loa that were not found in the present study [6]. "
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    ABSTRACT: A combination of deep-sequencing and bioinformatics analysis enabled identification of twenty-two microRNA candidates of potential nematode origin in plasma from Loa loa-infected baboons and a further ten from the plasma of an Onchocerca ochengi-infected cow. The obtained data were compared to results from previous work on miRNA candidates from Dirofilaria immitis and O. volvulus found in host circulating blood, to examine the species specificity of the released miRNA. None of the miRNA candidates was found to be present in all four host-parasite scenarios and most of them were specific to only one of them. Eight candidate miRNAs were found to be identical in the full sequence in at least two different infections, while nine candidate miRNAs were found to be similar but not identical in at least four filarial species.
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    • "This strong consistency between RNA-seq results and qPCR analysis suggests that the stable miRNAs found by RNA-seq could all be potentially used as reference genes in qPCR analysis. In fact, a previous sequencing study has shown that two of the miRNAs identified in our study, mir-46-3p and mir-47-3p, are remarkably stable when expression levels are compared between young adults and aged animals [11]. However, we strongly advise the prospective user to perform qPCR validation in each experimental setup and test the stability of chosen miRNAs using geNorm or other similar analysis tool (e.g. "
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    ABSTRACT: Quantitative real-time PCR (qPCR) has become the "gold standard" for measuring expression levels of individual miRNAs. However, little is known about the validity of reference miRNAs, the improper use of which can result in misleading interpretation of data. Here we undertook a systematic approach to identify highly stable miRNAs in different stress conditions such as low oxygen (hypoxia), UV-stress and high temperature (heat-stress) in the nematode Caenorhabditis elegans. We conducted genome-wide RNA-seq for small RNAs and selected abundant miRNAs with minimal variation of expression between the different conditions. We further validated the stable expression of a selection of those constitutively expressed candidates in the different stress conditions by SYBR Green qPCR. The selected miRNA candidates were analyzed for stability by applying the widely used geNorm logarithm. With this approach, we were able to successfully identify suitable reference miRNAs for each stress condition. Interestingly, we also found that 3 miRNAs, namely mir-2-5p, mir-46-3p and mir-47-3p, are stable in all the above-mentioned conditions suggesting that they might have general functions independent of stress. Our analysis offers a comprehensive list of stably expressed miRNAs in different stress conditions that can be confidently used as reference miRNAs for qPCR analysis in C. elegans.
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    • "The serine threonine kinase CHK-1 is required for the DNA damage and S-M checkpoints and is necessary for germline development (Kalogeropoulos et al., 2004). chk-1 knockdown by RNAi confers increased thermotolerance and lifespan as does knockdown of the downstream phosphatase cdc-25 (Olsen et al., 2006; de Lencastre et al., 2010). To further test a possible involvement of checkpoint proteins in the longevity of the ndg-4 mutants, we examined the effect of inactivating chk-1. "
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    ABSTRACT: NDG-4 is a predicted transmembrane acyltransferase protein that acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long-chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here, we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin/IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold. Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling. The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan.
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