View source for Long non-coding RNAs in aging and aging-associated diseases

'''Long noncoding RNAs (lncRNAs)'''  are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein.<ref>Mattick, J. S., Amaral, P. P., Carninci, P., Carpenter, S., Chang, H. Y., Chen, L. L., ... & Wu, M. (2023). Long non-coding RNAs: definitions, functions, challenges and recommendations. Nature Reviews Molecular Cell Biology, 1-17. PMID: 36596869 DOI: 10.1038/s41580-022-00566-8</ref><ref>Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., ... & Gingeras, T. R. (2012). Landscape of transcription in human cells. Nature, 489(7414), 101-108. PMID: 22955620 PMC3684276 DOI: 10.1038/nature11233</ref> LncRNAs are roughly classified based on their position relative to protein-coding genes: intergenic (between genes), intragenic/intronic (within genes) and antisense.<ref>Mercer, T. R., Dinger, M. E., & Mattick, J. S. (2009). Long non-coding RNAs: insights into functions. Nature reviews genetics, 10(3), 155-159. PMID: 19188922 DOI: 10.1038/nrg2521</ref>  Until recently, these RNAs were disregarded as “junk”, due to their inability to produce functional proteins. But it is now evident that these lncRNAs can assume crucial roles in almost every aspect of biology.<ref>Palazzo, A. F., & Koonin, E. V. (2020). Functional long non-coding RNAs evolve from junk transcripts. Cell, 183(5), 1151-1161. PMID: 33068526 DOI: 10.1016/j.cell.2020.09.047</ref><ref>Lee, H., Zhang, Z., & Krause, H. M. (2019). Long noncoding RNAs and repetitive elements: junk or intimate evolutionary partners?. TRENDS in Genetics, 35(12), 892-902. PMID: 31662190 DOI: 10.1016/j.tig.2019.09.006</ref> Most annotated lncRNAs are RNA polymerase II (Pol II) transcribed; hence, they are similar in structure to mRNA and may have cap structures and poly A tails. Unlike protein-coding mRNAs, lncRNAs exhibit functional uniqueness by participating in and modulating the various cellular processes such as, histone modification, DNA methylation, and cellular transcription.<ref>Wei, J. W., Huang, K., Yang, C., & Kang, C. S. (2017). Non-coding RNAs as regulators in epigenetics. Oncology reports, 37(1), 3-9. PMID: 27841002 DOI: 10.3892/or.2016.5236</ref><ref>Statello, L., Guo, C. J., Chen, L. L., & Huarte, M. (2021). Gene regulation by long non-coding RNAs and its biological functions. Nature reviews Molecular cell biology, 22(2), 96-118. PMID: 33353982 PMCID: PMC7754182 DOI: 10.1038/s41580-020-00315-9</ref>

Studies have indicated that lncRNAs are involved in epigenetic, transcriptional, post-transcriptional, and translation regulation, as well as post-translational modification.<ref>Yao, R. W., Wang, Y., & Chen, L. L. (2019). Cellular functions of long noncoding RNAs. Nature cell biology, 21(5), 542-551. PMID: 31048766 DOI: 10.1038/s41556-019-0311-8</ref><ref>Zhang, X., Wang, W., Zhu, W., Dong, J., Cheng, Y., Yin, Z., & Shen, F. (2019). Mechanisms and functions of long non-coding RNAs at multiple regulatory levels. International journal of molecular sciences, 20(22), 5573. PMID: 31717266 PMCID: PMC6888083 DOI: 10.3390/ijms20225573</ref>

<ref>Sherazi, S. A. M., Abbasi, A., Jamil, A., Uzair, M., Ikram, A., Qamar, S., ... & Bashir, S. (2023). Molecular hallmarks of long non-coding RNAs in aging and its significant effect on aging-associated diseases. Neural Regeneration Research, 18(5), 959-968. PMID: 36254975 PMCID: PMC9827784 DOI: 10.4103/1673-5374.355751</ref>
<ref>Kour, S., & Rath, P. C. (2016). Long noncoding RNAs in aging and age-related diseases. Ageing research reviews, 26, 1-21.  PMID: 26655093 DOI: 10.1016/j.arr.2015.12.001</ref>


=== Long non-coding RNA in aging-related cardiovascular disease ===
Cardiovascular diseases (CVDs) are currently [[Causes of death by rate|the main cause of morbidity and mortality]]. It was found that 145 lncRNAs are differentially expressed in ischemic cardiomyopathy tissues compared with healthy control samples.<ref>Huang, Z. P., Ding, Y., Chen, J., Wu, G., Kataoka, M., Hu, Y., ... & Wang, D. Z. (2016). Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy. Cardiovascular research, 112(2), 543-554. PMID: 27557636 PMCID: PMC5079274 DOI: 10.1093/cvr/cvw201</ref> Thus, overcoming the challenges of determining cardiac-related lncRNAs and their molecular mechanisms may be significantly beneficial to our further investigations in the diagnosis and treatment of CVDs. However, treatment strategies on targeting lncRNA remain difficult to apply to the clinic.            
<ref>Nie, X., Fan, J., & Wang, D. W. (2023). The Function and Therapeutic Potential of lncRNAs in Cardiac Fibrosis. Biology, 12(2), 154.  PMID: 36829433 PMCID: PMC9952806 DOI: 10.3390/biology12020154</ref><ref>Lozano-Vidal, N., Bink, D. I., & Boon, R. A. (2019). Long noncoding RNA in cardiac aging and disease. Journal of molecular cell biology, 11(10), 860-867.  PMID: 31152659 PMCID: PMC6884711 DOI: 10.1093/jmcb/mjz046</ref>
<ref>Bink, D. I., Lozano-Vidal, N., & Boon, R. A. (2019). Long non-coding RNA in vascular disease and aging. Non-coding RNA, 5(1), 26. PMID: 30893946 PMCID: PMC6468806 DOI: 10.3390/ncrna5010026</ref><ref>Chen, C., Tang, Y., Sun, H., Lin, X., & Jiang, B. (2019). The roles of long noncoding RNAs in myocardial pathophysiology. Bioscience reports, 39(11).  PMID: 31694052 PMCID: PMC6851514 DOI: 10.1042/BSR20190966</ref><ref>Bhattacharya, M., Sharma, A. R., & Chakraborty, C. (2022). Challenges of Long Non Coding RNAs in Human Disease Diagnosis and Therapies: Bio-Computational Approaches. In Handbook of Machine Learning Applications for Genomics (pp. 121-131). Singapore: Springer Nature Singapore. https://doi.org/10.1007/978-981-16-9158-4_8</ref>

The endothelial cells that line the vessel walls play an important role in the development of atherosclerosis. Non-coding RNA such as long non-coding RNAs are known to play an important role in endothelial function and are implicated in the disease progression. Of 4465 lncRNAs expressed in the human endothelium, 798 lncRNAs are dysregulated in advanced age.<ref>Bink, D. I., Pauli, J., Maegdefessel, L., & Boon, R. A. (2023). Endothelial microRNAs and long noncoding RNAs in cardiovascular ageing. Atherosclerosis. S0021-9150(23)00136-3 PMID: 37059656 DOI: 10.1016/j.atherosclerosis.2023.03.019</ref> Among these differentially expressed lncRNAs,  prostate-cancer-associated transcript 14 (PCAT14), which is localized in the nucleus of young endothelial cells, but significantly reduced in aged endothelium. By silencing PCAT14, it was demonstrated that endothelial cell migration and sprouting capacity were reduced, without affecting the endothelial proliferative capacity. Furthermore, silencing of PCAT14 resulted in increased expression of inflammatory genes (e.g., ICAM1 and SELE) and genes relevant to endothelial cell stalk formation (e.g., JAG1 and ESM1), suggesting that PCAT14 may be important in maintaining the healthy status of the endothelium.<ref>Drekolia, M. K., Talyan, S., Cordellini Emidia, R., Boon, R. A., Guenther, S., Looso, M., ... & Bibli, S. I. (2022). Unravelling the impact of aging on the human endothelial lncRNA transcriptome. bioRxiv, 2022-09.  PMID: 36338971 PMCID: PMC9634578 DOI: 10.3389/fgene.2022.1035380</ref>

==== Transcribed-Ultra Conserved Regions (T-UCRs) ====
The ultraconserved regions (UCRs) are genomic elements longer than 200 bp (range: 200-779 bp) that are absolutely conserved among orthologous regions of human, mouse, and rat genomes. These regions also exhibit extremely high levels of conservation in other species, such as fish, chicken, and fugu, strongly suggesting an extreme negative selection of these sequences.<ref>Bejerano, G., Pheasant, M., Makunin, I., Stephen, S., Kent, W. J., Mattick, J. S., & Haussler, D. (2004). Ultraconserved elements in the human genome. Science, 304(5675), 1321-1325. PMID: 15131266 DOI: 10.1126/science.1098119</ref> More than 80% of UCRs are intergenic or intronic. The genome-wide profiling reveals that most UCRs are transcriptional active; therefore, these regions are also named transcribed UCRs (T-UCRs).<ref>Calin, G. A., Liu, C. G., Ferracin, M., Hyslop, T., Spizzo, R., Sevignani, C., ... & Croce, C. M. (2007). Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer cell, 12(3), 215-229.</ref>  Most T-UCRs may be lncRNAs (long noncoding RNAs), defined as RNAs larger than 200 bp, mostly without coding potential.  T-UCRs were associated with different hallmarks and showed great potential as biomarkers in many tumor types.<ref>Oliveira, J. C. D. (2023). Transcribed Ultraconserved Regions: New regulators in cancer signaling and potential biomarkers. Genetics and Molecular Biology, 46. PMID: 36622962 PMC9829027 DOI: 10.1590/1678-4685-GMB-2022-0125</ref> 

The studies in the literature about the associations between the presence of SNPs in UCRs and the appearance of different disorders revealed at least 37 polymorphism/phenotype associations covering diseases such as: different types of muscular dystrophies; adolescent idiopathic scoliosis; amyotrophic lateral sclerosis; renal diseases; as well as eye-related diseases; and cancer.<ref>Habic, A., Mattick, J. S., Calin, G. A., Krese, R., Konc, J., & Kunej, T. (2019). Genetic variations of ultraconserved elements in the human genome. OMICS: A Journal of Integrative Biology, 23(11), 549-559. PMID: 31689173 PMC6857462 DOI: 10.1089/omi.2019.0156</ref><ref>Radanova, M. (2023). [https://www.intechopen.com/online-first/88287 Transcribed-Ultra Conserved Regions (T-UCRs) a New Light on a Dark Matter]. DOI: 10.5772/intechopen.113015</ref> 
For example, the T-UCR uc.323 deficiency induced cardiac hypertrophy since uc.323 regulate the expression of cardiac hypertrophy-related genes such as CPT1b (Carnitine Palmitoyl transferase 1b).<ref>Sun, Y., Fan, W., Xue, R., Dong, B., Liang, Z., Chen, C., ... & Liu, C. (2020). Transcribed ultraconserved regions, Uc. 323, ameliorates cardiac hypertrophy by regulating the transcription of CPT1b (carnitine palmitoyl transferase 1b). Hypertension, 75(1), 79-90. PMID: 31735087 DOI: 10.1161/HYPERTENSIONAHA.119.13173</ref>

=== Roles of long non-coding RNAs in the development of aging-related neurodegenerative diseases ===
lncRNA participates in multiple aging-related neurological disorders development. Accumulating evidence has implicated lncRNA dysregulation in neurodegenerative disorders,<ref>Ni, Y. Q., Xu, H., & Liu, Y. S. (2022). Roles of long non-coding RNAs in the development of aging-related neurodegenerative diseases. Frontiers in Molecular Neuroscience, 15.  PMID: 35359573 PMCID: PMC8964039 DOI: 10.3389/fnmol.2022.844193</ref> including Alzheimer’s disease, whereby a group of long non-coding RNAs in blood can serve as a specific biomarker of Alzheimer's disease<ref>Ren, Z., Chu, C., Pang, Y., Cai, H., & Jia, L. (2023). A Group of Long Non-coding RNAs in Blood Acts as a Specific Biomarker of Alzheimer’s Disease. Molecular Neurobiology, 60(2), 566-575. PMID: 36327022 DOI: 10.1007/s12035-022-03105-w</ref><ref>Canseco-Rodriguez, A., Masola, V., Aliperti, V., Meseguer-Beltran, M., Donizetti, A., & Sanchez-Perez, A. M. (2022). Long Non-Coding RNAs, Extracellular Vesicles and Inflammation in Alzheimer’s Disease. International Journal of Molecular Sciences, 23(21), 13171.  PMID: 36361952 PMCID: PMC9654199 DOI: 10.3390/ijms232113171</ref> Parkinson’s disease,<ref>Sivagurunathan, N., Ambatt, A. T., & Calivarathan, L. (2022). Role of Long Non-coding RNAs in the Pathogenesis of Alzheimer’s and Parkinson’s Diseases. Current Aging Science, 15(2), 84-96.  PMID: 35081899 DOI: 10.2174/1874609815666220126095847</ref><ref>Na, C., Wen-Wen, C., Li, W., Ao-Jia, Z., & Ting, W. (2022). Significant Role of Long Non-coding RNAs in Parkinson’s Disease. Current Pharmaceutical Design, 28(37), 3085-3094. PMID: 36154598 DOI: 10.2174/1381612828666220922110551</ref> and Huntington’s disease (Tan et al., 2021)

=== Long non-coding RNAs and rheumatoid arthritis ===
Various lncRNAs have proven potential as biomarkers and targets for diagnosing, prognosis and treating rheumatoid arthritis.<ref>Elazazy, O., Midan, H. M., Shahin, R. K., Elesawy, A. E., Elballal, M. S., Sallam, A. A. M., ... & Doghish, A. S. (2023). Long non-coding RNAs and rheumatoid arthritis: Pathogenesis and clinical implications. Pathology-Research and Practice, 154512. PMID: 37172525 DOI: 10.1016/j.prp.2023.154512</ref>
 Accumulating evidence revealed that the regulatory network that includes long non-coding RNAs (lncRNAs)/circular RNAs (circRNAs), micro RNAs (miRNAs), and messenger RNAs (mRNA) plays important roles in regulating the pathological and physiological processes in rheumatoid arthritis. lncRNAs/circRNAs act as the miRNA sponge and competitively bind to miRNA to regulate the expression mRNA in synovial tissue, fibroblast-like synoviocytes (FLS), and peripheral blood mononuclear cells (PBMCs), participate in the regulation of proliferation, apoptosis, invasion, and inflammatory response.<ref>Han, J. J., Wang, X. Q., & Zhang, X. A. (2022). Functional interactions between lncRNAs/circRNAs and miRNAs: Insights into rheumatoid arthritis. Frontiers in Immunology, 13, 810317.  PMID: 35197980 PMCID: PMC8858953 DOI: 10.3389/fimmu.2022.810317</ref>

=== Role of the lncRNA–miRNA–mRNA Axis in Chronic Inflammatory Airway Diseases ===
<ref>Qiao, X., Hou, G., He, Y. L., Song, D. F., An, Y., Altawil, A., ... & Yin, Y. (2022). The Novel Regulatory Role of the lncRNA–miRNA–mRNA Axis in Chronic Inflammatory Airway Diseases. Frontiers in Molecular Biosciences, 605.  PMID: 35769905 PMCID: PMC9234692 DOI: 10.3389/fmolb.2022.927549</ref>
Emerging evidence suggests that lncRNAs account for the regulation of macrophage polarization and subsequent effects on respiratory diseases.<ref>Qiao, X., Ding, Y., Wu, D., Zhang, A., Yin, Y., Wang, Q., ... & Kang, J. (2022). The roles of long noncoding RNA-mediated macrophage polarization in respiratory diseases. Frontiers in Immunology, 13.  PMID: 36685535 PMCID: PMC9849253 DOI: 10.3389/fimmu.2022.1110774</ref>

=== The aging-induced lncRNA MIRIAL ===
Mirial (MicroRNA-cluster 23a~27a~24-2-associated and Induced by Aging Long non-coding RNA) (transcript ID: Gm26532, ENSMUSG00000097296)  is a stable, single-exonic lncRNA with a half-life of 3 hours. MIRIAL is an aging-induced lncRNA which acts as a key regulator of endothelial metabolic and cellular function. MIRIAL promotes cell proliferation, migration and basal angiogenic sprouting while decreasing mitochondrial function. It is polyadenylated, strictly localized to the nucleus and associated with chromatin.
In endothelial cells, where it exerts regulatory control over metabolism and [[Mitochondrial Dysfunction|mitochondrial]] copy number by activating the [[FOXO longevity genes|FOXO1 signaling pathway]]. Forkhead Box O1 (FOXO1) plays a pivotal role in repressing MYC signaling and promoting endothelial quiescence. It is assumed that an '''Alu element'''<ref>Liang, L., Cao, C., Ji, L., Cai, Z., Wang, D., Ye, R., ... & Xue, Y. (2023). Complementary Alu sequences mediate enhancer–promoter selectivity. Nature, 619(7971), 868-875. PMID: 37438529 [https://doi.org/10.1038/s41586-023-06323-x DOI: 10.1038/s41586-023-06323-x] </ref> within the MIRIAL transcript forms an RNA∙DNA:DNA triplex with a regulatory region of the FOXO1 gene, resulting in its increased expression. Experiments show that loss of Mirial in vivo has an adverse effect on cardiac outcome after acute myocardial infarction. Moreover, Mirial is an important regulator of vascular endothelial growth factor (VEGF)-A-response.   
Silencing MIRIAL in pro-angiogenic conditions improves angiogenesis by affecting [[P53 protein involvement in Longevity|the p53 pathway]] and mitochondrial respiration through FOXO1 signaling. Transcriptional modulation of MIRIAL, particularly in the elderly, might be a good strategy to improve therapeutic angiogenesis.<ref>Kohnle, C., Koziarek, S., Warwick, T., Theodorou, K., Fischer, A., Juni, R. P., ... & Boon, R. A. (2024). The aging-induced long non-coding RNA MIRIAL controls endothelial cell and mitochondrial function. bioRxiv, 2024-02. https://doi.org/10.1101/2024.02.28.582649</ref>

== References ==
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