Mol. Cells 2019; 42(5): 379~385  https://doi.org/10.14348/molcells.2019.0077
Non-Coding RNAs in Caenorhabditis elegans Aging
Sieun S. Kim1 and Seung-Jae V. Lee2,*
1Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea, 2Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea
Received April 15, 2019; Accepted April 29, 2019.; Published online May 16, 2019.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-sa/3.0/).
ABSTRACT

Non-coding RNAs (ncRNAs) comprise various RNA species, including small ncRNAs and long ncRNAs (lncRNAs). ncRNAs regulate various cellular processes, including transcription and translation of target messenger RNAs. Recent studies also indicate that ncRNAs affect organismal aging and conversely aging influences ncRNA levels. In this review, we discuss our current understanding of the roles of ncRNAs in aging and longevity, focusing on recent advances using the roundworm Caenorhabditis elegans. Expression of various ncRNAs, including microRNA (miRNA), tRNA-derived small RNA (tsRNA), ribosomal RNA (rRNA), PIWI-interacting RNA (piRNA), circular RNA (circRNA), and lncRNA, is altered during aging in C. elegans. Genetic modulation of specific ncRNAs affects longevity and aging rates by modulating established aging-regulating protein factors. Because many aging-regulating mechanisms in C. elegans are evolutionarily conserved, these studies will provide key information regarding how ncRNAs modulate aging and lifespan in complex organisms, including mammals.

Keywords: aging, Caenorhabditis elegans, lifespan, non-coding RNA, small RNA
INTRODUCTION

Caenorhabditis elegans is an excellent model organism for studying aging (Park et al., 2017). Genetic studies using C. elegans have identified many genes that play key roles in organismal aging (Kenyon, 2010; Lee et al., 2015). For example, genetic inhibition of daf-2, which encodes a homolog of insulin/insulin-like growth factor 1 (IGF-1) receptor, dramatically increases lifespan and stress resistance. This is achieved by activating downstream longevity proteins, including the FOXO/DAF-16, heat shock factor 1 (HSF-1), and Nrf/SKN-1 transcription factors (Altintas et al., 2016). Other genetic and environmental factors, including reproductive systems, target of rapamycin, mitochondrial electron transport chain, and dietary restriction (DR), modulate lifespan and alter aging rates. Importantly, many of these pathways that regulate aging are evolutionarily conserved in complex organisms, including mammals.

The term “non-coding RNAs” (ncRNAs) refers to RNA species that do not encode proteins. Various ncRNAs are key regulators of gene expression and chromatin remodeling, by acting through binding to their targets (Cech and Steitz, 2014). MicroRNAs (miRNAs), endogenous small interfering RNAs (siRNAs), and PIWI-interacting RNAs (piRNAs) share certain features for their functions, and are associated with Argonaute proteins to modulate transcriptional or post-translational regulation (Hoogstrate et al., 2014). The exact functions of other small RNAs, such as circular RNAs (circRNAs) and transfer RNA (tRNA)-derived small RNAs (tsRNAs) remain largely unknown. Nevertheless, recent studies have suggested that several circRNAs and tsRNAs regulate gene expression at the transcriptional and translational levels (Li et al., 2018a; 2018b). Long non-coding RNAs (lncRNAs) are over 200 nucleotides in length and regulate transcription in a cis or a trans manner (Ulitsky and Bartel, 2013). Many cellular processes are regulated by ncRNAs and these processes, including small RNA-mediated silencing, are conserved in various species (Qu and Adelson, 2012).

ncRNAs regulate various physiological processes, including development, stress responses, tumorigenesis and immune responses (Fernandes et al., 2019; Oberbauer and Schaefer, 2018; Shin et al., 2018; Szczepanek et al., 2018). Interestingly, recent studies using various organisms, C. elegans in particular, have indicated that ncRNAs influence aging and longevity. Here, we discuss the roles of ncRNAs in the regulation of lifespan and aging in C. elegans. We also describe the findings regarding changes in the expression of these ncRNAs during the aging process. We then discuss how the changes in the expression of ncRNAs over the lifetime play roles in aging or anti-aging processes. Considering the evolutionarily conserved nature of many aging-regulating factors, understanding ncRNA-mediated regulatory roles in C. elegans aging will lead to insights into how mammalian health and age-associated diseases are influenced by ncRNAs.

miRNAs

Biogenesis of miRNAs

miRNAs are short ncRNAs that regulate various cellular processes, including transcription, translation, and gene silencing, which affect cellular growth, proliferation, and senescence (Ha and Kim, 2014; Szczepanek et al., 2018; Treiber et al., 2019). In particular, miRNAs mediate translational repression or messenger RNA (mRNA) silencing by binding to complementary mRNAs. miRNAs are first transcribed as pri-miRNAs by RNA polymerase II (Pol II) (Fig. 1A). Nuclear Drosha (C. elegans DRSH-1)-DGCR8 (C. elegans PASH-1) complex then cleaves pri-miRNAs for conversion to pre-miRNAs. Next, the exportin proteins translocate pre-miRNAs from the nucleus to the cytosol, which are then cleaved by Dicer (C. elegans DCR-1), a type III ribonuclease that generates short double-stranded RNAs. One of the strands then forms an miRNA-induced silencing complex (miRISC) with Argonaute proteins that unwind the RNA duplex. Recent studies using model organisms including C. elegans have indicated that the levels of many miRNAs are altered during aging and in turn affect organismal aging rates and lifespan. Several outstanding review papers discuss the relationship between miRNAs and C. elegans aging in detail (Garg and Cohen, 2014; Inukai and Slack, 2013; Kato and Slack, 2013). Here, we briefly summarize important findings and provide an update of the recent literature in the field.

The expression of several miRNAs changes during aging

Various miRNAs whose primary role is the down-regulation of target mRNA expression display age-dependent changes in their levels. Total miRNA levels decline during aging, but individual miRNAs display variable age-dependent changes in their expression (Kato et al., 2011) (Fig. 2). miR-71 generally decreases age-dependent miRNA expression by down-regulating alg-1 (C. elegans Argonaute) expression (Inukai et al., 2018). Therefore, mir-71 mutation increases the overall abundance of miRNAs during aging. Many individual miRNAs display age-dependent decreases in their expression shown in at least two out of three transcriptomic studies (de Lencastre et al., 2010; Kato et al., 2011; Lucanic et al., 2013). These include let-7 miRNA, miR-70, miR-252, miR-81, miR-65, miR-237, miR-248, miR-1 and miR-235. In particular, all these three papers reported that let-7 miRNA and miR-70 display age-dependent decreases in expression (de Lencastre et al., 2010; Kato et al., 2011; Lucanic et al., 2013). In contrast, the levels of miR-71, miR-239a, miR-34, miR-35, miR-37, miR-36, miR-39, and several members of the miR-35 family increase with age, shown in two out of the four reports (de Lencastre et al., 2010; Kato et al., 2011; Lucanic et al., 2013; Yang et al., 2013). These studies indicate that aging affects the levels of miRNAs in different ways and that miRNAs may influence mRNA expression during aging.

miRNAs that influence lifespan

One of the first breakthrough discoveries that demonstrated the roles of miRNAs in organismal longevity was reported by Frank Slack’s group in 2005. They showed that loss-of-function mutations in an miRNA gene, lin-4, significantly shorten C. elegans lifespan by down-regulating FOXO/DAF-16 via up-regulating lin-14 (Boehm and Slack, 2005). Since this seminal publication, many other lifespan-modulating miRNAs have been identified. Here, we focus on recent papers describing lifespan-changing miRNAs after the publication of previous review papers regarding miRNAs and C. elegans aging (Garg and Cohen, 2014; Inukai and Slack, 2013; Kato et al., 2011). Mutations in mir-71, mir-238, mir-246, mir-81/82, or mir-58 shorten lifespan, whereas overexpression of mir-71 or mir-246 promotes longevity (de Lencastre et al., 2010; Zhang et al., 2018). Among these, miR-71 and miR-246 levels are also increased with age (de Lencastre et al., 2010; Kato et al., 2011), implying that the age-dependent increase in miRNAs plays a protective role against a short lifespan. In contrast, mutations in mir-80, mir-83, mir-239a/b, or mir-228 extend lifespan (de Lencastre et al., 2010; Dzakah et al., 2018; Lucanic et al., 2013; Vora et al., 2013). An early study showed that two loss-of-function mir-34 mutant alleles do not alter lifespan (de Lencastre et al., 2010), whereas another study reported that the same mir-34 mutations significantly extend lifespan by enhancing autophagy (Yang et al., 2013). mir-80 deletion mediates longevity conferred by DR via acting with FOXO/DAF-16 and HSF-1 transcription factors (Vora et al., 2013). As miR-80 down-regulates cbp-1, which encodes cAMP-response element (CREB)-binding protein 1, FOXO/DAF-16 and HSF-1 that are associated with CBP-1 fail to induce the expression of genes required for DR-induced longevity. mir-83 loss-of-function mutation also increases lifespan through FOXO/DAF-16 (Dzakah et al., 2018). mir-228 loss-of-function mutation extends lifespan via a DR pathway that requires FOXA/PHA-4 and Nrf/SKN-1 (Smith-Vikos et al., 2014). Thus, specific miRNAs play distinct roles in lifespan by modulating several aging-regulating factors, including FOXO/DAF-16, HSF-1, FOXA/PHA-4, and Nrf/SKN-1. Currently, the mechanisms by which gene expression changes caused by specific miRNAs affect lifespan remain poorly understood. Additionally, understanding how aging influences the expression of various miRNAs will be a key task for future research.

miRNA machinery regulates longevity in C. elegans

In addition to miRNAs, several miRNA machinery protein components influence longevity (Kogure et al., 2017). A recent study has shown that the mRNA levels of miRNA machinery component genes, alg-1 and drsh-1, are up-regulated by fasting and that knockdown of these components suppresses longevity conferred by intermittent fasting, a paradigm for DR. Thus, miRNA machinery appears to mediate the effect of DR on long lifespan.

In contrast, another study has shown that the two C. elegans Argonaute proteins, ALG-1 and ALG-2, have distinct expression patterns and exert differential effects on lifespan; a loss-of-function mutation in alg-1 decreases lifespan, whereas a loss-of-function mutation in alg-2 extends lifespan (Aalto et al., 2018). These seemingly contradictory results may have originated from substantial sequence homology between alg-1 and alg-2. Therefore, RNAi knockdown of either alg-1 or alg-2 appears to decrease the expression of both alg-1 and alg-2, whereas DNA mutations are specific to individual alg-1 and alg-2 genes. Overall, miRNA biogenesis mediated by the miRNA machinery complexes appears to affect aging and lifespan in C. elegans by modulating the expression of genes that encode factors in various aging-regulating pathways, including insulin/IGF-1 signaling and DR effectors.

tsRNAs

Definition of tsRNAs

tsRNAs (also known as tRNA-derived fragments [tRFs]) are fragments derived from tRNAs (Kumar et al., 2016). tsRNA can be categorized based on the position of cleavage in tRNA transcripts. tRNAs are transcribed by RNA polymerase III (Pol III) (Fig. 1B). Precursor tRNA (pre-tRNA) transcripts exist as cloverleaf shapes and have 5′-leader and 3′-trailer sequences. The 5′-leader sequence is cleaved by endoribonuclease P (RNase P) and the 3′-trailer sequence is removed by endonuclease Z (RNase Z). Nucleotidyltransferases then mediate the addition of a 3′-CCA tail. Dicer may cleave these mature tRNAs to tsRNAs that are loaded onto Argonautes. In mammals, various stresses appear to induce a mammalian ribonuclease A angiogenin (ANG) that cleaves tRNAs and generates tRNA half-types of tsRNAs, also known as tRNA-derived stress-induced RNAs (tiRNAs). tsRNAs regulate various biological processes, including gene expression, interference of translation, intergenerational inheritance, apoptosis, and viral infection (Oberbauer and Schaefer, 2018).

The levels of tsRNAs increase during aging

While the total levels of miRNAs gradually decrease during aging, the levels of tsRNAs generally increase during C. elegans aging (Kato et al., 2011), perhaps in response to stresses induced by aging (Fig. 2). Interestingly, the levels of 3′-tiRNAs generally increase in aged rat brain (Karaiskos and Grigoriev, 2016). Therefore, age-dependent increases in tsRNA levels appear to have common features between C. elegans and mammals. A recent study has also shown that the inhibition of Pol III extends lifespan by reducing protein synthesis and decreasing pre-tRNA levels (Filer et al., 2017). Because pre-tRNAs can be processed to tsRNAs, this study raises the possibility that changes in tsRNA levels contribute to longevity and healthspan.

rRNAs

Ribosomal RNAs (rRNAs) are the RNA components of the large and small subunits of the ribosome, which is essential for protein synthesis (Lambert et al., 2019). In eukaryotes, the large subunit contains 5S, 5.8S, and 28S rRNAs, and the small subunit contains 18S rRNAs. Among them, 18S, 5.8S, and 28S rRNAs are transcribed by RNA polymerase I (Pol I) in the nucleolus, whereas 5S rRNA is transcribed by Pol III in the nucleus (Fig. 1C). In C. elegans, the levels of 28S and 18S rRNAs do not show any substantial differences between young and old animals in a temperature-sensitive sterile mutant [spe-9(hc88); fer-15(b26)] background, or by longevity-promoting phosphoinositide 3-kinase (PI3K)/age-1 mutations (Fabian and Johnson, 1995). However, a recent study reported that the total levels of rRNAs gradually increase during aging in another sterile mutant [spe-9(hc88)] background (Kato et al., 2011) (Fig. 2). Therefore, whether rRNA levels influence aging and longevity requires further investigation.

piRNAs

piRNAs are small ncRNAs that form an RNA–protein complex through binding to the PIWI Argonaute (Ozata et al., 2019). The piRNA–PIWI Argonaute complex maintains the genome stability of the germline, and suppresses transposition in many animals, including C. elegans (Weick and Miska, 2014). The PRG-1 (a C. elegans PIWI Argonaute)–piRNA complex interacts with target mRNAs that are partially complementary to the piRNAs, and is important for gene silencing in germ cells. This is evidenced by many findings, including one showing that mutations in prg-1 result in decreased fertility because of defects in germline integrity (Batista et al., 2008). Importantly, this fertility defect is suppressed by increasing the activity of longevity transcription factor FOXO/DAF-16 in insulin/IGF-1 receptor/daf-2 mutants (Simon et al., 2014). In addition, the total levels of piRNAs decline during aging in C. elegans (Kato et al., 2011) (Fig. 2). In Drosophila, PIWI is necessary and sufficient for reducing age-related intestinal stem cell dysfunction and apoptosis (Sousa-Victor et al., 2017). In addition, transposable element expression and transposition are increased during aging in Drosophila. All of these findings are consistent with the possibility that PIWI and piRNAs play anti-aging roles at least in these two invertebrate models. However, the direct relationship between piRNAs and lifespan remains unknown and should be tested experimentally in future work.

circRNAs

circRNAs are mostly ncRNAs produced by the back-splicing of precursor mRNAs of diverse genes in eukaryotes (Li et al., 2018b) (Fig. 1D). Another type of non-coding circRNA can be produced during metazoan tRNA splicing, which is called tRNA intronic circular RNAs (tricRNAs) (Lu et al., 2015). circRNAs are highly stable because the lack of free 5′- and 3′-ends confers resistance to exonucleases. circRNAs were discovered over two decades ago (Cocquerelle et al., 1993). Dramatic advances in RNA sequencing (RNA-seq) technology that has enabled a global analysis of non-polyadenylated transcriptomes have recently boosted interest in circRNAs. Although circRNAs were once thought to be by-products of mis-splicing and their exact role remains poorly understood, emerging evidence indicates that circRNAs affect various biological pathways. For example, specific circRNAs regulate gene expression by titrating miRNAs (Hansen et al., 2013) or by interacting with RNA Pol II (Li et al., 2015). A circRNA participates in cell cycle regulation by binding to p21 and CDK2 (Du et al., 2016). RNA-seq results indicate that circRNA isoforms are much more diverse than linear RNAs from the same loci, suggesting that circRNAs have various functional roles (Salzman et al., 2013; Zhang et al., 2016).

Interestingly, circRNAs accumulate during aging in Drosophila brain (Westholm et al., 2014) and in C. elegans (Cortes-Lopez et al., 2018) (Fig. 2). In C. elegans, circRNAs are also differentially expressed during development (Memczak et al., 2013). These results raise the possibility that circRNAs participate in modulating development and aging. In addition, circRNAs play important roles in the senescence of mammalian cells (Du et al., 2017; Wang et al., 2015). Mammalian Foxo3 circRNA promotes cardiac senescence by inhibiting the translocation of several transcription factors that regulate heart aging (Du et al., 2017). Moreover, circRNA 100783 may play a role in the immunosenescence of CD28-related CD8(+) T cells (Wang et al., 2015). Therefore, specific and general circRNAs may act as biomarkers of aging and/or may serve as anti-aging therapeutic tools.

lncRNAs

lncRNAs are ncRNAs that are longer than 200 nucleotides (Quinn and Chang, 2016). Most lncRNAs are derived from loci that do not overlap with protein-coding exons or are from opposite strands of protein-coding genes (Grammatikakis et al., 2014). While the functions of most lncRNAs remain poorly understood, some lncRNAs’ roles in gene regulation have been extensively investigated, as exemplified by mammalian Xist (X-inactive specific transcript), an effector of X-chromosome inactivation (Sahakyan et al., 2018). In C. elegans, 170 potential lncRNAs were initially identified (Nam and Bartel, 2012), and a recent study extended the potential number of lncRNAs in this species to 3,397 (Akay et al., 2019). lncRNAs affect various cellular processes such as senescence, proliferation, differentiation, and age-associated diseases (Kour and Rath, 2016). For example, MIAT and TUG1 lncRNAs are essential for brain development and neurogenesis (Briggs et al., 2015; Kour and Rath, 2016). Because declines in neurogenesis in aged brain are potential causes of brain aging, these lncRNAs may contribute to the age-dependent declines in brain function. Several studies have also shown that lncRNAs can influence organismal aging and lifespan (Grammatikakis et al., 2014). For example, lncRNA tts-1 in C. elegans is required for longevity conferred by mutations in the insulin/IGF-1 receptor gene, daf-2 (Essers et al., 2015). Therefore, it is likely that other lncRNAs also modulate lifespan by affecting known or novel longevity signaling pathways.

CONCLUSIONS

A large fraction of mammalian genomes consist of non-protein-coding sequences, as exemplified by the finding that only 1.5% of the human genome is transcribed to protein-coding mRNAs. Thanks to newly developed RNA-seq technologies and bioinformatics approaches, RNA fragments that were once regarded as by-products of RNA degradation have now become focal points as interesting bio-molecules that have important and specific roles. For example, tsRNAs play inhibitory roles in translation in response to stress, and circRNAs appear to act as regulatory factors that interact with miRNAs or Pol II. Other ncRNAs, including miRNAs, rRNAs, piRNAs, and lncRNAs regulate gene expression. In this review paper, we have discussed the roles of various ncRNAs in aging and lifespan, focusing on the findings obtained using C. elegans. However, the mechanisms and functions of most ncRNAs in aging and lifespan remain elusive. For example, it is unclear how specific ncRNAs play different roles in lifespan, either as pro- or anti-longevity factors. As many ncRNAs modulate target gene expression, it will be crucial to identify and characterize target genes that influence aging and lifespan. C. elegans is a genetically amenable metazoan with a short lifespan; it is, therefore, suitable as a key model for unraveling the mechanisms and functions of ncRNAs in aging regulation.

Mutations in several miRNAs and miRNA machinery factors affect the lifespan of C. elegans. In addition, the expression levels of many miRNAs, tsRNAs, piRNAs, and circRNAs change during aging. Interestingly, it has been shown that many ncRNA levels are altered in patients with age-associated diseases (Chalbatani et al., 2019; Dimmeler and Nicotera, 2013; Kour and Rath, 2016; Yang et al., 2018). Therefore, these ncRNAs have potential as biomarkers of aging and aging-related diseases. In addition, several ncRNAs have the potential for use as therapeutic targets for aging-associated diseases. Further studies of aging and RNA biology in C. elegans will eventually enhance our understanding of human aging and age-related diseases.

ACKNOWLEDGMENTS

We thank all Lee laboratory members for help and discussion. This work was supported by the Korean Government (MSIP) through the National Research Foundation of Korea (NRF) (NRF-2016R1E1A1A01941152) to S.-J.V.L.

FIGURES
Fig. 1. (A) miRNAs are first transcribed to pri-miRNAs by RNA polymerase II (Pol II). Nuclear Drosha (C. elegans DRSH-1)-DGCR8 (C. elegans PASH-1) complex then cleaves pri-miRNAs for conversion to pre-miRNAs. Next, pre-miRNAs are translocated from the nucleus to the cytosol, for cleavage by Dicer (C. elegans DCR-1). One of the strands then forms miRNA-induced silencing complex (miRISC) with Argonaute proteins that unwind the RNA duplex. (B) tRNAs are transcribed by RNA polymerase III (Pol III) to precursor tRNA (pre-tRNA) transcripts, which have 5′-leader and 3′-trailer sequences. The 5′-leader sequence is cleaved by endoribonuclease P (RNase P) and the 3′-trailer sequence is removed by endonuclease Z (RNase Z) for generating mature tRNAs. Dicer may cleave the mature tRNAs to tRNA-derived fragments (tRFs). In mammals, angiogenin (ANG, ribonuclease A) cleaves tRNAs and generates tRNA-derived stress-induced RNAs (tiRNAs), also known as tRNA halves, tRNA halftypes of tRNA-derived small RNAs (tsRNAs). (C) RNA polymerase I (Pol I) transcribes 18S, 5.8S, and 28S rRNAs in the nucleolus, whereas 5S rRNA is transcribed by Pol III in the nucleus. (D) Circular RNAs (circRNAs) are produced by back-splicing of precursor mRNAs that are transcribed by Pol II.
Fig. 2. Total microRNA (miRNA) and PIWI-interacting RNA (piRNA) levels are gradually decreased during C. elegans aging. In contrast, tRNA-derived small RNA (tsRNA), ribosomal RNA (rRNA) and circular RNA (circRNA) levels generally display age-dependent increases.
REFERENCES
  1. Aalto, A.P., Nicastro, I.A., Broughton, J.P., Chipman, L.B., Schreiner, W.P., Chen, J.S., and Pasquinelli, A.E. (2018). Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging. PLoS Genet. 14, e1007379.
    Pubmed KoreaMed CrossRef
  2. Akay, A., Jordan, D., Navarro, I.C., Wrzesinski, T., Ponting, C.P., Miska, E.A., and Haerty, W. (2019). Identification of functional long non-coding RNAs in C. elegans. BMC Biol. 17, 14.
    Pubmed KoreaMed CrossRef
  3. Altintas, O., Park, S., and Lee, S.J.V. (2016). The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster. BMB Rep. 49, 81-92.
    Pubmed KoreaMed CrossRef
  4. Batista, P.J., Ruby, J.G., Claycomb, J.M., Chiang, R., Fahlgren, N., Kasschau, K.D., Chaves, D.A., Gu, W., Vasale, J.J., and Duan, S. (2008). PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans. Mol Cell. 31, 67-78.
    Pubmed KoreaMed CrossRef
  5. Boehm, M. and Slack, F. (2005). A developmental timing microRNA and its target regulate life span in C. elegans. Science. 310, 1954-1957.
    Pubmed CrossRef
  6. Briggs, J.A., Wolvetang, E.J., Mattick, J.S., Rinn, J.L., and Barry, G. (2015). Mechanisms of long non-coding RNAs in mammalian nervous system development, plasticity, disease, and evolution. Neuron. 88, 861-877.
    Pubmed CrossRef
  7. Cech, T.R. and Steitz, J.A. (2014). The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 157, 77-94.
    Pubmed CrossRef
  8. Chalbatani, G.M., Dana, H., Memari, F., Gharagozlou, E., Ashjaei, S., Kheirandish, P., Marmari, V., Mahmoudzadeh, H., Mozayani, F., and Maleki, A.R. (2019). Biological function and molecular mechanism of piRNA in cancer. Pract Lab Med. 13, e00113.
    Pubmed KoreaMed CrossRef
  9. Cocquerelle, C., Mascrez, B., Hetuin, D., and Bailleul, B. (1993). Mis-splicing yields circular RNA molecules. FASEB J. 7, 155-160.
    Pubmed CrossRef
  10. Cortes-Lopez, M., Gruner, M.R., Cooper, D.A., Gruner, H.N., Voda, A.I., van der Linden, A.M., and Miura, P. (2018). Global accumulation of circRNAs during aging in Caenorhabditis elegans. BMC Genomics. 19, 8.
    Pubmed KoreaMed CrossRef
  11. de Lencastre, A., Pincus, Z., Zhou, K., Kato, M., Lee, S.S., and Slack, F.J. (2010). MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol. 20, 2159-2168.
    Pubmed KoreaMed CrossRef
  12. Dimmeler, S. and Nicotera, P. (2013). MicroRNAs in age-related diseases. EMBO Mol Med. 5, 180-190.
    Pubmed KoreaMed CrossRef
  13. Du, W.W., Yang, W., Chen, Y., Wu, Z.K., Foster, F.S., Yang, Z., Li, X., and Yang, B.B. (2017). Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses. Eur Heart J. 38, 1402-1412.
    Pubmed CrossRef
  14. Du, W.W., Yang, W., Liu, E., Yang, Z., Dhaliwal, P., and Yang, B.B. (2016). Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 44, 2846-2858.
    Pubmed KoreaMed CrossRef
  15. Dzakah, E.E., Waqas, A., Wei, S., Yu, B., Wang, X., Fu, T., Liu, L., and Shan, G. (2018). Loss of miR-83 extends lifespan and affects target gene expression in an age-dependent manner in Caenorhabditis elegans. J Genet Genomics. 45, 651-662.
    Pubmed CrossRef
  16. Essers, P.B., Nonnekens, J., Goos, Y.J., Betist, M.C., Viester, M.D., Mossink, B., Lansu, N., Korswagen, H.C., Jelier, R., and Brenkman, A.B. (2015). A long noncoding RNA on the ribosome is required for lifespan extension. Cell Rep. 10, 339-345.
    Pubmed CrossRef
  17. Fabian, T.J. and Johnson, T.E. (1995). Total RNA, rRNA and poly(A)+RNA abundances during aging in Caenorhabditis elegans. Mech Ageing Dev. 83, 155-170.
    Pubmed CrossRef
  18. Fernandes, J.C.R., Acuna, S.M., Aoki, J.I., Floeter-Winter, L.M., and Muxel, S.M. (2019). Long non-coding RNAs in the regulation of gene expression: physiology and disease. Noncoding RNA. 5, 17.
    Pubmed KoreaMed CrossRef
  19. Filer, D., Thompson, M.A., Takhaveev, V., Dobson, A.J., Kotronaki, I., Green, J.W.M., Heinemann, M., Tullet, J.M.A., and Alic, N. (2017). RNA polymerase III limits longevity downstream of TORC1. Nature. 552, 263-267.
    Pubmed KoreaMed CrossRef
  20. Garg, D. and Cohen, S.M. (2014). miRNAs and aging: a genetic perspective. Ageing Res Rev. 17, 3-8.
    Pubmed CrossRef
  21. Grammatikakis, I., Panda, A.C., Abdelmohsen, K., and Gorospe, M. (2014). Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging. Aging. 6, 992-1009.
    Pubmed KoreaMed CrossRef
  22. Ha, M. and Kim, V.N. (2014). Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol. 15, 509-524.
    Pubmed CrossRef
  23. Hansen, T.B., Jensen, T.I., Clausen, B.H., Bramsen, J.B., Finsen, B., Damgaard, C.K., and Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature. 495, 384-388.
    Pubmed CrossRef
  24. Hoogstrate, S.W., Volkers, R.J., Sterken, M.G., Kammenga, J.E., and Snoek, L.B. (2014). Nematode endogenous small RNA pathways. Worm. 3, e28234.
    Pubmed KoreaMed CrossRef
  25. Inukai, S., Pincus, Z., de Lencastre, A., and Slack, F.J. (2018). A microRNA feedback loop regulates global microRNA abundance during aging. RNA. 24, 159-172.
    Pubmed KoreaMed CrossRef
  26. Inukai, S. and Slack, F. (2013). MicroRNAs and the genetic network in aging. J Mol Biol. 425, 3601-3608.
    Pubmed KoreaMed CrossRef
  27. Karaiskos, S. and Grigoriev, A. (2016). Dynamics of tRNA fragments and their targets in aging mammalian brain. F1000Res. 5, 2758.
    Pubmed KoreaMed CrossRef
  28. Kato, M., Chen, X., Inukai, S., Zhao, H., and Slack, F.J. (2011). Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans. RNA. 17, 1804-1820.
    Pubmed KoreaMed CrossRef
  29. Kato, M. and Slack, F.J. (2013). Ageing and the small, non-coding RNA world. Ageing Res Rev. 12, 429-435.
    Pubmed KoreaMed CrossRef
  30. Kenyon, C.J. (2010). The genetics of ageing. Nature. 464, 504-512.
    Pubmed CrossRef
  31. Kogure, A., Uno, M., Ikeda, T., and Nishida, E. (2017). The microRNA machinery regulates fasting-induced changes in gene expression and longevity in Caenorhabditis elegans. J Biol Chem. 292, 11300-11309.
    Pubmed KoreaMed CrossRef
  32. Kour, S. and Rath, P.C. (2016). Long noncoding RNAs in aging and age-related diseases. Ageing Res Rev. 26, 1-21.
    Pubmed CrossRef
  33. Kumar, P., Kuscu, C., and Dutta, A. (2016). Biogenesis and function of transfer RNA-related fragments (tRFs). Trends Biochem Sci. 41, 679-689.
    Pubmed KoreaMed CrossRef
  34. Lambert, M., Benmoussa, A., and Provost, P. (2019). Small non-coding RNAs derived from Eukaryotic ribosomal RNA. Noncoding RNA. 5, 16.
    Pubmed KoreaMed CrossRef
  35. Lee, Y., An, S.W.A., Artan, M., Seo, M., Hwang, A.B., Jeong, D.E., Son, H.G., Hwang, W., Lee, D., and Seo, K. (2015). Genes and pathways that influence longevity in Caenorhabditis elegans. Aging Mechanisms, Mori, N. and Mook-Jung, I., ed. Tokyo, Japan: Springer Japan, pp. 123-169
    CrossRef
  36. Li, S., Xu, Z., and Sheng, J. (2018a). tRNA-derived small RNA: a novel regulatory small non-coding RNA. Genes (Basel). 9, 246.
    Pubmed KoreaMed CrossRef
  37. Li, X., Yang, L., and Chen, L.L. (2018b). The biogenesis, functions, and challenges of circular RNAs. Mol Cell. 71, 428-442.
    Pubmed CrossRef
  38. Li, Z., Huang, C., Bao, C., Chen, L., Lin, M., Wang, X., Zhong, G., Yu, B., Hu, W., and Dai, L. (2015). Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 22, 256-264.
    Pubmed CrossRef
  39. Lu, Z., Filonov, G.S., Noto, J.J., Schmidt, C.A., Hatkevich, T.L., Wen, Y., Jaffrey, S.R., and Matera, A.G. (2015). Metazoan tRNA introns generate stable circular RNAs in vivo. RNA. 21, 1554-1565.
    Pubmed KoreaMed CrossRef
  40. Lucanic, M., Graham, J., Scott, G., Bhaumik, D., Benz, C.C., Hubbard, A., Lithgow, G.J., and Melov, S. (2013). Age-related micro-RNA abundance in individual C. elegans. Aging. 5, 394-411.
    Pubmed KoreaMed CrossRef
  41. Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L., Mackowiak, S.D., Gregersen, L.H., and Munschauer, M. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495, 333-338.
    Pubmed CrossRef
  42. Nam, J.W. and Bartel, D.P. (2012). Long noncoding RNAs in C. elegans. Genome Res. 22, 2529-2540.
    Pubmed KoreaMed CrossRef
  43. Oberbauer, V. and Schaefer, M.R. (2018). tRNA-derived small RNAs: biogenesis, modification, function and potential impact on human disease development. Genes (Basel). 9, 607.
    Pubmed KoreaMed CrossRef
  44. Ozata, D.M., Gainetdinov, I., Zoch, A., O’Carroll, D., and Zamore, P.D. (2019). PIWI-interacting RNAs: small RNAs with big functions. Nat Rev Genet. 20, 89-108.
    Pubmed CrossRef
  45. Park, H.H., Jung, Y., and Lee, S.V. (2017). Survival assays using Caenorhabditis elegans. Mol Cells. 40, 90-99.
    Pubmed KoreaMed CrossRef
  46. Qu, Z. and Adelson, D.L. (2012). Evolutionary conservation and functional roles of ncRNA. Front Genet. 3, 205.
    Pubmed KoreaMed CrossRef
  47. Quinn, J.J. and Chang, H.Y. (2016). Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 17, 47-62.
    Pubmed CrossRef
  48. Sahakyan, A., Yang, Y., and Plath, K. (2018). The role of Xist in X-chromosome dosage compensation. Trends Cell Biol. 28, 999-1013.
    Pubmed KoreaMed CrossRef
  49. Salzman, J., Chen, R.E., Olsen, M.N., Wang, P.L., and Brown, P.O. (2013). Cell-type specific features of circular RNA expression. PLoS Genet. 9, e1003777.
    Pubmed KoreaMed CrossRef
  50. Shin, H., Kim, Y., Kim, M., and Lee, Y. (2018). BC200 RNA: an emerging therapeutic target and diagnostic marker for human cancer. Mol Cells. 41, 993-999.
    Pubmed KoreaMed CrossRef
  51. Simon, M., Sarkies, P., Ikegami, K., Doebley, A.L., Goldstein, L.D., Mitchell, J., Sakaguchi, A., Miska, E.A., and Ahmed, S. (2014). Reduced insulin/IGF-1 signaling restores germ cell immortality to Caenorhabditis elegans Piwi mutants. Cell Rep. 7, 762-773.
    Pubmed KoreaMed CrossRef
  52. Smith-Vikos, T., de Lencastre, A., Inukai, S., Shlomchik, M., Holtrup, B., and Slack, F.J. (2014). MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Curr Biol. 24, 2238-2246.
    Pubmed KoreaMed CrossRef
  53. Sousa-Victor, P., Ayyaz, A., Hayashi, R., Qi, Y., Madden, D.T., Lunyak, V.V., and Jasper, H. (2017). Piwi is required to limit exhaustion of aging somatic stem cells. Cell Rep. 20, 2527-2537.
    Pubmed KoreaMed CrossRef
  54. Szczepanek, J., Pareek, C.S., and Tretyn, A. (2018). The role of microRNAs in animal physiology and pathology. Transl Res Vet Sci. 1, 13-33.
    CrossRef
  55. Treiber, T., Treiber, N., and Meister, G. (2019). Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat Rev Mol Cell Biol. 20, 5-20.
    Pubmed CrossRef
  56. Ulitsky, I. and Bartel, D.P. (2013). lincRNAs: genomics, evolution, and mechanisms. Cell. 154, 26-46.
    Pubmed KoreaMed CrossRef
  57. Vora, M., Shah, M., Ostafi, S., Onken, B., Xue, J., Ni, J.Z., Gu, S., and Driscoll, M. (2013). Deletion of microRNA-80 activates dietary restriction to extend C. elegans healthspan and lifespan. PLoS Genet. 9, e1003737.
    Pubmed KoreaMed CrossRef
  58. Wang, Y.H., Yu, X.H., Luo, S.S., and Han, H. (2015). Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing. Immun Ageing. 12, 17.
    Pubmed KoreaMed CrossRef
  59. Weick, E.M. and Miska, E.A. (2014). piRNAs: from biogenesis to function. Development. 141, 3458-3471.
    Pubmed CrossRef
  60. Westholm, J.O., Miura, P., Olson, S., Shenker, S., Joseph, B., Sanfilippo, P., Celniker, S.E., Graveley, B.R., and Lai, E.C. (2014). Genome-wide analysis of drosophila circular RNAs reveals their structural and sequence properties and age-dependent neural accumulation. Cell Rep. 9, 1966-1980.
    Pubmed KoreaMed CrossRef
  61. Yang, D., Yang, K., and Yang, M. (2018). Circular RNA in aging and age-related diseases. Adv Exp Med Biol. 1086, 17-35.
    Pubmed CrossRef
  62. Yang, J., Chen, D., He, Y., Melendez, A., Feng, Z., Hong, Q., Bai, X., Li, Q., Cai, G., and Wang, J. (2013). MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9. Age (Dordr). 35, 11-22.
    Pubmed KoreaMed CrossRef
  63. Zhang, X.O., Dong, R., Zhang, Y., Zhang, J.L., Luo, Z., Zhang, J., Chen, L.L., and Yang, L. (2016). Diverse alternative back-splicing and alternative splicing landscape of circular RNAs. Genome Res. 26, 1277-1287.
    Pubmed KoreaMed CrossRef
  64. Zhang, Y., Zhang, W., and Dong, M. (2018). The miR-58 microRNA family is regulated by insulin signaling and contributes to lifespan regulation in Caenorhabditis elegans. Sci China Life Sci. 61, 1060-1070.
    Pubmed CrossRef


Current Issue

30 September 2019 Volume 42,
Number 9, pp. 617~685

This Article


Cited By Articles
  • CrossRef (0)

Social Network Service
Services

Indexed in

  • Science Central
  • CrossMark