View source for Small nucleoli as a visible cellular hallmark of longevity and metabolic health

The nucleolus is a nuclear subcompartment where ribosomal RNA is synthesized and assembled into ribosomal subunits. It is a dynamic organelle subject to inputs from growth signalling pathways, nutrients, and stress, whose size correlates with rRNA synthesis.<ref>Guarente, L. (1997). Link between aging and the nucleolus. Genes & development, 11(19), 2449-2455. PMID: 9334311 [https://genesdev.cshlp.org/content/11/19/2449.long DOI: 10.1101/gad.11.19.2449]</ref><ref>Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M., & Lamond, A. I. (2010). The nucleolus under stress. Molecular cell, 40(2), 216-227. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987465/ PMC2987465/] doi: 10.1016/j.molcel.2010.09.024</ref> The nucleolus is also a production site for other ribonucleoprotein particles, including various splicing factors, the signal recognition particle, stress granules and the siRNA machinery.  The expression of nucleolar genes is an excellent predictor of a proliferation index (PRI).<ref>Wang, M., & Lemos, B. (2017). Ribosomal DNA copy number amplification and loss in human cancers is linked to tumor genetic context, nucleolus activity, and proliferation. PLoS genetics, 13(9), e1006994.  PMID: 28880866 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605086/ PMC5605086] DOI: 10.1371/journal.pgen.1006994</ref>

'''Despite not being included as one of the “[[hallmarks of aging]]”, numerous evidences indicate a role for nucleoli in ageing'''.<ref>Kasselimi, E., Pefani, D. E., Taraviras, S., & Lygerou, Z. (2022). Ribosomal DNA and the nucleolus at the heart of aging. Trends in Biochemical Sciences, 47(4), 328-341. PMID: 35063340 [https://doi.org/10.1016/j.tibs.2021.12.007 DOI: 10.1016/j.tibs.2021.12.007]</ref> Studies reveal that multiple longevity pathways strikingly reduce nucleolar size, and diminish expression of the nucleolar protein FIB-1, ribosomal RNA, and ribosomal proteins across different species.<ref>Yi, Y. H., Ma, T. H., Lee, L. W., Chiou, P. T., Chen, P. H., Lee, C. M., ... & Lo, S. J. (2015). A Genetic Cascade of let-7-ncl-1-fib-1 Modulates Nucleolar Size and rRNA Pool in Caenorhabditis elegans. PLoS genetics, 11(10), e1005580. PMID: 26492166 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619655/ PMC4619655] DOI: 10.1371/journal.pgen.1005580</ref><ref name="premature" >Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 328. PMID: 28855503 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577202/ PMC5577202] DOI: 10.1038/s41467-017-00322-z</ref><ref name="hallmark" >Tiku, V., Jain, C., Raz, Y., Nakamura, S., Heestand, B., Liu, W., ... & Antebi, A. (2017). Small nucleoli are a cellular hallmark of longevity. Nature communications, 8(1), 16083. PMID: 28853436 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582349/ PMC5582349] DOI: 10.1038/ncomms16083</ref> A significant correlation between aging and nucleolar size in healthy individuals was also found; specifically, cells derived from individuals with a premature ageing disorder Hutchinson–Gilford progeria syndrome (HGPS) exhibited large nucleoli, which were comparable in size to those of old healthy individuals.<ref name="premature" /><ref>Zlotorynski, E. (2017). Live longer with small nucleoli. Nat Rev Mol Cell Biol 18, 651  https://doi.org/10.1038/nrm.2017.100</ref>

It was assumed that expansion and fragmentation of the nucleolus are the result of the massive accumulation of extrachromosomal ribosomal DNA circles (ERCs) occupying more space and recruiting more ribosome biogenesis factors.<ref>Li, Y., Jiang, Y., Paxman, J., O’Laughlin, R., Klepin, S., Zhu, Y., ... & Hao, N. (2020). A programmable fate decision landscape underlies single-cell aging in yeast. Science, 369(6501), 325-329. PMID: 32675375 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437498/ PMC7437498] DOI: 10.1126/science.aax9552</ref> However, it was discovered that nucleolar expansion occurs independently of ERCs so cannot be taken as evidence of a contribution of ERCs alone to senescence - nucleolar enlargement also occurs in cells lacking ERCs.<ref name="rather" >Zylstra, A., Hadj-Moussa, H., Horkai, D., Whale, A. J., Piguet, B., & Houseley, J. (2023). Senescence in yeast is associated with amplified linear fragments of chromosome XII rather than ribosomal DNA circle accumulation. PLoS Biology, 21(8), e3002250. PMID: 37643194 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464983/ PMC10464983] DOI: 10.1371/journal.pbio.3002250</ref>  

The senescence entry point (SEP) represents an abrupt transition in ageing at which yeast cells cease to divide rapidly and the cell cycle becomes slow and heterogeneous.<ref>Fehrmann, S., Paoletti, C., Goulev, Y., Ungureanu, A., Aguilaniu, H., & Charvin, G. (2013). Aging yeast cells undergo a sharp entry into senescence unrelated to the loss of mitochondrial membrane potential. Cell reports, 5(6), 1589-1599.</ref> Cells passed the SEP irrespective of ERCs, while at least in yeast, the SEP across a wide range of conditions and mutants is obviously tightly associated with copy number amplification of a region of chromosome XII between the rDNA and the telomere (ChrXIIr) forming linear fragments up to approximately 1.8 Mb size, which arises in aged cells through a different mechanism to ERCs.<ref name="rather" /> 

<ref>Sharifi, S., Chaudhari, P., Martirosyan, A., Eberhardt, A. O., Witt, F., Gollowitzer, A., ... & Ermolaeva, M. (2024). Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans. Nature Communications, 15(1), 1702.  PMID: 38402241 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10894287/ PMC10894287] DOI: 10.1038/s41467-024-46037-w</ref>

Nucleolar stress induced by arginine-rich peptides leads to a generalized accumulation of orphan ribosomal proteins, which is toxic in cells and drives accelerated aging in mice. The toxicity of arginine-rich peptides is alleviated by targeting ribosome biogenesis pathways such as mTOR or MYC.<ref>Sirozh, O., Jung, B., Sanchez-Burgos, L., Ventoso, I., Lafarga, V., & Fernandez-Capetillo, O. (2024). Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice. bioRxiv, 2023-08. Molecular Cell  https://doi.org/10.1016/j.molcel.2024.02.031
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<ref>Cockrell, A. J., & Gerton, J. L. (2022). Nucleolar organizer regions as transcription-based scaffolds of nucleolar structure and function. In Nuclear, Chromosomal, and Genomic Architecture in Biology and Medicine (pp. 551-580). Cham: Springer International Publishing.   PMID: 36348121 DOI: 10.1007/978-3-031-06573-6_19</ref>

<ref name="hallmark" />

== Ribosome biogenesis ==
Eukaryotes partition many of the complex, essential process of ribosome biogenesis (RB) steps into the nucleolus, a phase-separated membraneless organelle within the enveloped nucleus. In human cells, three of the four mature ribosomal RNAs (rRNAs), the 18S, 5.8S and 28S rRNAs, are synthesized in the nucleolus as components of the polycistronic 47S primary pre-rRNA precursor transcript from tandem ribosomal DNA (rDNA) repeats by RNA Polymerase 1 (RNAP1). The 5S rRNA is separately transcribed in the nucleus by RNA Polymerase 3 (RNAP3). A myriad of ribosome assembly factors (AFs) execute endo- and exonucleolytic pre-rRNA processing and modification events to liberate the mature rRNAs from the 47S transcript, forming the small 40S and large 60S ribosomal subunits. AFs also facilitate the binding of structurally-constitutive ribosomal proteins (RPs) and the folding of the maturing subunits at the macromolecular scale. Defects in RB can trigger the nucleolar stress response during which labile members of the 5S RNP including RPL5 (uL18) or RPL11 (uL5) bind and sequester the TP53-specific E3 ligase MDM2, effectively stabilizing TP53 levels and leading to CDKN1A (p21) induction, cell cycle arrest, and apoptosis. In aging, there is a decrease in the cellular rate of ribosome synthesis, which includes reduced expression of both rRNA and r-proteins, and an associated decrease in nucleolar size.<ref>Correll, C. C., Bartek, J., & Dundr, M. (2019). The nucleolus: a multiphase condensate balancing ribosome synthesis and translational capacity in health, aging and ribosomopathies. Cells, 8(8), 869. PMID: 31405125 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721831/ PMC6721831] DOI: 10.3390/cells8080869</ref> <ref name="repressors" >Bryant, C. J., McCool, M. A., Rosado González, G. T., Abriola, L., Surovtseva, Y. V., & Baserga, S. J. (2024). Discovery of novel microRNA mimic repressors of ribosome biogenesis. Nucleic Acids Research, 52(4), 1988-2011.  PMID: 38197221 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10899765/ PMC10899765] DOI: 10.1093/nar/gkad1235</ref><ref>Ganley, A. R., & Kobayashi, T. (2014). Ribosomal DNA and cellular senescence: new evidence supporting the connection between rDNA and aging. FEMS yeast research, 14(1), 49-59. PMID: 24373458 DOI: 10.1111/1567-1364.12133</ref><ref>Wang, M., & Lemos, B. (2019). Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome research, 29(3), 325-333. PMID: 30765617 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396418/ PMC6396418] DOI: 10.1101/gr.241745.118</ref>

== Small nucleolar RNAs ==
Small nucleolar RNAs (snoRNAs) are a large class of small noncoding RNAs present in all eukaryotes. They have been characterized as playing a central role in ribosome biogenesis, guiding either the sequence-specific chemical modification of pre-rRNA (ribosomal RNA) or its processing.<ref>Dupuis-Sandoval, F., Poirier, M., & Scott, M. S. (2015). The emerging landscape of small nucleolar RNAs in cell biology. Wiley Interdisciplinary Reviews: RNA, 6(4), 381-397. https://doi.org/10.1002/wrna.1284</ref><ref>Piñeiro Ugalde, A., Roiz del Valle, D., Moledo Nodar, L., Menéndez Caravia, X., Pérez Freije, J. M., & López Otín, C. (2024). Non-coding RNA contribution to aging and lifespan. The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 79(4), glae058, https://doi.org/10.1093/gerona/glae058</ref> 
Small nucleolar RNAs (snoRNAs) regulate cardiac-relevant signaling pathways, oxidative and metabolic cellular stress, gene expression, and intercellular communication.<ref name="snoRNAs" >Chabronova, A., Holmes, T. L., Hoang, D. M., Denning, C., James, V., Smith, J. G., & Peffers, M. J. (2024). SnoRNAs in cardiovascular development, function, and disease. Trends in Molecular Medicine. https://doi.org/10.1016/j.molmed.2024.03.004</ref>  An association between levels of circulating snoRNAs and myocardial infarction and heart failure has been found, indicating the potential of these snoRNAs as biomarkers.<ref name="snoRNAs" />   

The MIR-28 family members, '''hsa-miR-28-5p''' and '''hsa-miR-708-5p''', are strong inhibitors of pre-18S pre-rRNA processing (a key step in ribosome biogenesis) by way of potent downregulation of the levels of the mRNA of the ribosomal protein S28 (RPS28, a ribosomal protein component of the 40S ribosomal subunit.<ref name="repressors" /> <ref>Gawade, K., & Raczynska, K. D. (2024). Imprinted small nucleolar RNAs: Missing link in development and disease?. Wiley Interdisciplinary Reviews: RNA, 15(1), e1818. PMID: 37722601 DOI: 10.1002/wrna.1818</ref>

=== SNORA13 ===
SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13, a highly conserved H/ACA box snoRNA, is essential for multiple forms of senescence in human cells and in mice.<ref>Cheng, Y., Wang, S., Zhang, H., Lee, J. S., Ni, C., Guo, J., ... & Mendell, J. T. (2024). A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence. Cell. 187(17), 4770-4789.e23 PMID: 38981482 [https://doi.org/10.1016/j.cell.2024.06.019 DOI: 10.1016/j.cell.2024.06.019]</ref>

== References ==
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[[Category:Aging pathways and hallmarks]]
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