Cited by 267Nuclear Structure and FunctionGenetics, Aging, and Longevity in Model OrganismsRNA and protein synthesis mechanisms

Nucleolar expansion and elevated protein translation in premature aging

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Buchwalter, Abigail, Hetzer, Martin W.·2017·Nature Communications

Abstract

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).”
  • 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].”

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Research works printed but not linked: 2

  1. [41]Gesson K A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha Genome Res. 2016 26 462 473 10.1101/gr.196220.115 26798136 PMC4817770 · DOI
  2. [47]Scaffidi P Misteli T Lamin A-dependent nuclear defects in human aging Science 2006 312 1059 1063 10.1126/science.1127168 16645051 PMC1855250 · DOI

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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)
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
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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