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

From Longevity Wiki

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.[1][2] 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).[3]

Despite not being included as one of the “hallmarks of aging”, numerous evidences indicate a role for nucleoli in ageing.[4] 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.[5][6][7] 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.[6][8]

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.[9] 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.[10]

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.[11] 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.[10]

[12]

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.[13] [14]

[7]

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.[15] [16][17][18]

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.[19][20] Small nucleolar RNAs (snoRNAs) regulate cardiac-relevant signaling pathways, oxidative and metabolic cellular stress, gene expression, and intercellular communication.[21] An association between levels of circulating snoRNAs and myocardial infarction and heart failure has been found, indicating the potential of these snoRNAs as biomarkers.[21]

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.[16] [22]

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.[23]

References

  1. ↑ Guarente, L. (1997). Link between aging and the nucleolus. Genes & development, 11(19), 2449-2455. PMID: 9334311 DOI: 10.1101/gad.11.19.2449
  2. ↑ Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M., & Lamond, A. I. (2010). The nucleolus under stress. Molecular cell, 40(2), 216-227. PMC2987465/ doi: 10.1016/j.molcel.2010.09.024
  3. ↑ 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 PMC5605086 DOI: 10.1371/journal.pgen.1006994
  4. ↑ 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 DOI: 10.1016/j.tibs.2021.12.007
  5. ↑ 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 PMC4619655 DOI: 10.1371/journal.pgen.1005580
  6. ↑ 6.0 6.1 Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 328. PMID: 28855503 PMC5577202 DOI: 10.1038/s41467-017-00322-z
  7. ↑ 7.0 7.1 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 PMC5582349 DOI: 10.1038/ncomms16083
  8. ↑ Zlotorynski, E. (2017). Live longer with small nucleoli. Nat Rev Mol Cell Biol 18, 651 https://doi.org/10.1038/nrm.2017.100
  9. ↑ 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 PMC7437498 DOI: 10.1126/science.aax9552
  10. ↑ 10.0 10.1 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 PMC10464983 DOI: 10.1371/journal.pbio.3002250
  11. ↑ 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.
  12. ↑ 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 PMC10894287 DOI: 10.1038/s41467-024-46037-w
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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 PMC6721831 DOI: 10.3390/cells8080869
  16. ↑ 16.0 16.1 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 PMC10899765 DOI: 10.1093/nar/gkad1235
  17. ↑ 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
  18. ↑ Wang, M., & Lemos, B. (2019). Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome research, 29(3), 325-333. PMID: 30765617 PMC6396418 DOI: 10.1101/gr.241745.118
  19. ↑ 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
  20. ↑ 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
  21. ↑ 21.0 21.1 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
  22. ↑ 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
  23. ↑ 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 DOI: 10.1016/j.cell.2024.06.019
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