Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages
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Abstract
Aging is characterized by gradual immune dysfunction and increased disease risk. Genomic instability is considered central to the aging process, but the underlying mechanisms of DNA damage are insufficiently defined. Cells in confined environments experience forces applied to their nucleus, leading to transient nuclear envelope rupture (NER) and DNA damage. Here, we show that Lamin A/C protects lung alveolar macrophages (AMs) from NER and hallmarks of aging. AMs move within constricted spaces in the lung. Immune-specific ablation of lamin A/C results in selective depletion of AMs and heightened susceptibility to influenza virus-induced pathogenesis and lung cancer growth. Lamin A/C-deficient AMs that persist display constitutive NER marks, DNA damage and p53-dependent senescence. AMs from aged wild-type and from lamin A/C-deficient mice share a lysosomal signature comprising CD63. CD63 is required to limit damaged DNA in macrophages. We propose that NER-induced genomic instability represents a mechanism of aging in AMs.
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Distal lung epithelial progenitor cell function declines with age
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Nuclear deformations, from signaling to perturbation and damage
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- Authors
- De Silva, N. S., Siewiera, J., Alkhoury, C., Nader, G. P. F., Nadalin, F., de Azevedo, K., Couty, M., Izquierdo, H. M., Bhargava, A., Conrad, C., Maurin, M., Antoniadou, K., Fouillade, C., Londono-Vallejo, A., Behrendt, R., Bertotti, K., Serdjebi, C., Lanthiez, F., Gallwitz, L., Saftig, P., Herrero-Fernández, B., Saez, A., González-Granado, J. M., van Niel, G., Boissonnas, A., Piel, M., & Manel, N.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- University Hospital Bonn (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Manel, Nicolas
- ORCID
- Siewiera, Johan
- Alkhoury, Chantal
- Nader, Guilherme P. F.
- Nadalin, Francesca
- Couty, Mickaël
- Izquierdo, Helena M.
- Bhargava, Anvita
- Conrad, Cécile
- Maurin, Mathieu
- Antoniadou, Konstantina
- Fouillade, Charles
- Londono-Vallejo, Arturo
- Behrendt, Rayk
- Serdjebi, Cindy
- Lanthiez, François
- Gallwitz, Lisa
- Boissonnas, Alexandre
- Piel, Matthieu
- Manel, Nicolas
- Venue
- Nature Aging
- Published
- 2023-09-18
- Volume
- 3
- Issue
- 10
- Pages
- 1251-1268
- ISSN
- 2662-8465 (ISSN-L)
- OpenAlex
- W4386826948
- Cited by
- 34
- References
- 98
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 10 · 2022: 1
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Aging (publishedVersion)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- Deposito Digital UFV (Francisco de Vitoria University) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- Funders
- British Heart Foundation
- European Commission (H2020-MSCA-IF-2016, HORIZON2020, H2020, H2020‐MSCA‐IF, H2020-MSCA-IF-2016 DCBIO, H2020-MSCA, PI20/00306)
- Agence Nationale de la Recherche (ANR-19-CE14-0015, ANR‐19, ANR-17-CE15-0025, ANR18, ANR-11-LABX-0043, ANR-19-CE15-0018, ANR-17, ANR-18-CE92-0022)
- Institut National de la Santé et de la Recherche Médicale (19CS007‐00)
- Fondation pour la Recherche Médicale (EQU202103012774)
- Fondation ARC pour la Recherche sur le Cancer (PGA1 RF20190208474)
- Centre National de la Recherche Scientifique
- Institut National Du Cancer (BIO-07-ICR-1)
- Horizon 2020 Framework Programme (MSCA-IF-2016, H2020-MSCA, H2020-MSCA-IF-2016)
- Instituto de Salud Carlos III (PI20/00306, FPU18/00895, PI17/01395, H2020)
- European Regional Development Fund (H2020, PI20/00306, FPU18/00895)
- 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
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- nuclear envelope rupture, lamin A/C, aging, genomic instability, DNA damage, cellular senescence, p53, CD63, lysosomes, lung cancer, immune dysfunction, nuclear confinement
- MeSH terms
- Aging, Animals, Lung, Nuclear Envelope, Macrophages, Alveolar, Lamin Type A, Genomic Instability, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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