Nucleolar expansion and elevated protein translation in premature aging
Open accessAbstract
Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals.
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Ribosomal protein levels and overall translation were elevated in premature aging.
“A previous study also observed that ribosomal protein levels and overall translation were elevated in premature aging (Buchwalter and Hetzer, 2017).”
From Single-Cell Transcriptome Analysis Reveals Six Subpopulations Reflecting Distinct Cellular Fates in Senescent Mouse Embryonic Fibroblasts (2020) · cites this paper as Buchwalter and Hetzer, 2017
Senescent cells generally demonstrate an enlarged and flattened cell morphology, expanded nucleoli, enhanced SA-β-gal activity, telomere shortening, elevation of p16 or p21, macromolecular damage and metabolism dysfunction.
“Senescent cells generally demonstrate an enlarged and flattened cell morphology [27] and expanded nucleoli [28,29], enhanced senescence-associated beta-galactosidase (SA-β-gal) activity [30], telomere shortening, elevation of the cyclin-dependent kinase inhibitor p16 [11,31] or p21 [32], macromolecular damage and metabolism dysfunction [1].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [28]
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- Authors
- Buchwalter, A., & Hetzer, M. W.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Hetzer, Martin W.
- Venue
- Nature Communications
- Published
- 2017-08-30
- Volume
- 8
- Issue
- 1
- Pages
- 328-328
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5577202
- OpenAlex
- W2749445972
- Cited by
- 263
- References
- 74
- Citations by year
- 2026: 24 · 2025: 35 · 2024: 34 · 2023: 25 · 2022: 32 · 2021: 19 · 2020: 27 · 2019: 35 · 2018: 24 · 2017: 8
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- NOMIS Stiftung
- National Institutes of Health (NCI CCSG: P30 014195, P30 014195)
- National Cancer Institute (CCSG:P30 014195, NIH-NCI CCSG: P30 014195, P30014195)
- National Institute of Neurological Disorders and Stroke (R01NS096786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- Hutchinson-Gilford progeria syndrome, premature aging, lamin A, ribosome biogenesis, protein synthesis, protein turnover, aging biomarkers, fibroblasts, lifespan
- MeSH terms
- Aging, Cell Line, Cell Nucleolus, Cells, Cultured, Humans, Mutation, Progeria, Protein Biosynthesis, Microscopy, Confocal, Aging, Premature, RNA Interference, Lamin Type A
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