An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics
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Abstract
Aging promotes lung function decline and susceptibility to chronic lung diseases, which are the third leading cause of death worldwide. Here, we use single cell transcriptomics and mass spectrometry-based proteomics to quantify changes in cellular activity states across 30 cell types and chart the lung proteome of young and old mice. We show that aging leads to increased transcriptional noise, indicating deregulated epigenetic control. We observe cell type-specific effects of aging, uncovering increased cholesterol biosynthesis in type-2 pneumocytes and lipofibroblasts and altered relative frequency of airway epithelial cells as hallmarks of lung aging. Proteomic profiling reveals extracellular matrix remodeling in old mice, including increased collagen IV and XVI and decreased Fraser syndrome complex proteins and collagen XIV. Computational integration of the aging proteome with the single cell transcriptomes predicts the cellular source of regulated proteins and creates an unbiased reference map of the aging lung.
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An extensive survey of the literature identified a total of eighteen 'gold standard' datasets that met the criteria of matched bulk and scRNA-seq performed on the same population of purified cells, exposed to the same perturbations, and sequenced in the same laboratories.
“An extensive survey of the literature identified a total of eighteen ‘gold standard’ datasets that met these criteria (Fig. 1a ) 12 – 15 .”
From Confronting false discoveries in single-cell differential expression (2021) · cites this paper as [14]
Manual validation of cell type annotation was performed and was consistent with previous studies.
“After classification, we performed a manual validation of cell type annotation consistent with previous studies (Supplemental Methods; Park et al. 2018; The Tabula Muris Consortium 2018; Angelidis et al. 2019).”
From Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging (2019) · cites this paper as Angelidis et al. 2019
Alternative measures of cell-cell heterogeneity using heuristically selected subsets of genes were highly correlated with the primary method.
“We also considered alternative measures of cell–cell heterogeneity using heuristically selected subsets of genes as in previous reports (Enge et al. 2017; Angelidis et al. 2019) and found that results were highly correlated with our primary method (Supplemental Fig. S12; Supplemental Methods).”
From Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging (2019) · cites this paper as Angelidis et al. 2019
Cell identities differentially express unique genes with aging.
“We found that cell identities differentially express unique genes with aging, consistent with previous reports of cell-identity-specific aging phenotypes (Angelidis et al. 2019).”
From Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging (2019) · cites this paper as Angelidis et al. 2019
An extensive literature survey identified eighteen gold standard datasets that met the criteria of matched bulk and scRNA-seq on the same purified cell population, exposed to the same perturbations, and sequenced in the same laboratories.
“An extensive survey of the literature identified a total of eighteen ‘gold standard’ datasets that met these criteria (Fig. 1a)12–15.”
From Confronting false discoveries in single-cell differential expression (2021) · cites this paper as [15]
Within the compendium, fourteen studies had control groups that included six or more samples.
“Within our compendium, we identified a total of fourteen studies with control groups that included six or more samples5,6,15,49–59.”
From Confronting false discoveries in single-cell differential expression (2021) · cites this paper as [15]
Single-cell resolution studies showed elevated cell-to-cell transcriptional variability in the activation program of CD4 T cells and in leukocytes from lungs of old mice.
“Only recently, studies performed at a single-cell resolution showed elevated cell-to-cell transcriptional variability in the activation program of CD4 T cells (16) and in leukocytes from lungs of old mice (17).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [17]
Pragmatic approaches that ignore strongly ambient genes in downstream analysis have been used to tackle ambient RNA.
“Pragmatic approaches that ignore strongly ambient genes in downstream analysis have also been used to tackle this problem (Angelidis et al, 2019).”
From Current best practices in single-cell RNA-seq analysis: a tutorial (2019) · cites this paper as Angelidis et al, 2019
Gene expression analysis has proven inadequate to fully describe the proteome, including the tissue matrix environment.
“However, gene expression analysis has proven inadequate to fully describe the proteome, including the tissue matrix environment”
From Defining the Adult Neural Stem Cell Niche Proteome Identifies Key Regulators of Adult Neurogenesis (2020) · cites this paper as Angelidis et al., 2019
The directionality of change in transcriptional variability was not consistent among cell types, providing evidence that aging is not broadly associated with increased transcriptional variation.
“However, the directionality of change was not consistent among cell types, providing evidence that aging is not broadly associated with increased transcriptional variation 34 .”
From Single-cell transcriptomic profiling of the aging mouse brain (2019) · cites this paper as [34]
The finding on transcriptional variability is in line with Warren et al. but in contrast to other studies that suggested increased transcriptional variability is a common feature of aging.
“This is in line with Warren et al. 51 , but in contrast to other studies that suggested increased transcriptional variability is a common feature of aging 34,52 .”
From Single-cell transcriptomic profiling of the aging mouse brain (2019) · cites this paper as [34]
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The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease
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BackgroundMethodResultInfluentialCOVID-19 revisiting inflammatory pathways of arthritis
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Alveolar Differentiation Drives Resistance to <i>KRAS</i> Inhibition in Lung Adenocarcinoma
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Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages
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- Authors
- Angelidis, I., Simon, L. M., Fernandez, I. E., Strunz, M., Mayr, C. H., Greiffo, F. R., Tsitsiridis, G., Ansari, M., Graf, E., Strom, T.-M., Nagendran, M., Desai, T., Eickelberg, O., Mann, M., Theis, F. J., & Schiller, H. B.
- Affiliations
- Helmholtz Munich (DE)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- University of Colorado Anschutz (US)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Theis, Fabian J.
- Schiller, Herbert B.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-02-27
- Volume
- 10
- Issue
- 1
- Pages
- 963-963
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6393476
- OpenAlex
- W2953064750
- Cited by
- 637
- References
- 71
- Citations by year
- 2026: 51 · 2025: 96 · 2024: 86 · 2023: 114 · 2022: 94 · 2021: 89 · 2020: 76 · 2019: 28 · 2018: 2
- FWCI
- 23.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
- mediaTUM (Technical University of Munich) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- European Commission (753039, HORIZON2020)
- Bundesministerium für Bildung und Forschung
- Deutsches Zentrum für Lungenforschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- lung aging, lung proteome, single-cell transcriptomics, transcriptional noise, epigenetic dysregulation, alveolar type II cells, lipofibroblasts, airway epithelial cells, cholesterol biosynthesis, extracellular matrix remodeling, type IV collagen, chronic lung disease, mouse lung
- MeSH terms
- Aging, Animals, Cholesterol, Collagen, Epithelial Cells, Extracellular Matrix, Lung, Mice, Inbred C57BL, Proteome, Gene Expression Profiling, Proteomics, Mice, Single-Cell Analysis
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