Age mosaicism across multiple scales in adult tissues
Open accessAbstract
Most neurons are not replaced during an animal's lifetime. This nondividing state is characterized by extreme longevity and age-dependent decline of key regulatory proteins. To study the lifespans of cells and proteins in adult tissues, we combined isotope labeling of mice with a hybrid imaging method (MIMS-EM). Using 15 N mapping, we show that liver and pancreas are composed of cells with vastly different ages, many as old as the animal. Strikingly, we also found that a subset of fibroblasts and endothelial cells, both known for their replicative potential, are characterized by the absence of cell division during adulthood. In addition, we show that the primary cilia of beta cells and neurons contains different structural regions with vastly different lifespans. Based on these results, we propose that age mosaicism across multiple scales is a fundamental principle of adult tissue, cell, and protein complex organization.
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Proteins with diverse lifespans coexist within the basal body and axoneme of neuronal primary cilia, suggesting dynamic turnover.
“Furthermore, proteins with diverse lifespans coexist within the basal body and axoneme of neuronal primary cilia, suggesting dynamic turnover (Arrojo et al., 2019).”
From Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis (2025) · cites this paper as Arrojo et al., 2019
Ultrastructural studies of human tissues have shown similar results, and different human brain regions exhibit different gene expression trajectories with age.
“Ultrastructural studies of human tissues157 have shown similar results, and even different human brain regions exhibit different gene expression trajectories with age158.”
From Measuring biological age using omics data (2022) · cites this paper as [157]
Cells of the same type have vastly different ages based on DNA dating (including postmitotic cells), some as old as the animal, and subcellular structures within individual neurons or pancreatic beta cells have different ages based on protein dating.
“Cells of the same type have vastly different ages based on DNA dating (including postmitotic cells), some as old as the animal, and subcellular structures within individual neurons or pancreatic beta cells have different ages based on protein dating.”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [46]
Isotope-based dating of DNA and protein at the ultrastructural level in various tissues in mice revealed extensive cellular mosaicism within aging tissues.
“Isotope-based dating of DNA and protein at the ultrastructural level in various tissues in mice revealed extensive cellular mosaicism within aging tissues.46”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [46]
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- Authors
- Arrojo e Drigo, R., Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., Phan, S., Orphan, V., Lechene, C., Ellisman, M. H., & Hetzer, M. W.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- California Institute of Technology (US)
- Corresponding author
- Hetzer, Martin W.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 30
- Issue
- 2
- Pages
- 343-351.e3
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7289515
- OpenAlex
- W2948247960
- Cited by
- 137
- References
- 46
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 19 · 2023: 14 · 2022: 18 · 2021: 33 · 2020: 19 · 2019: 8
- FWCI
- 7.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- NIH (R01 NS096786, RO1 NS027177-30, 5P41 GM103412-29)
- Keck Foundation
- NOMIS Foundation
- US Department of Energy
- Office of Science
- Office of Biological and Environmental Research (DE-SC0016469)
- American Diabetes Association (1-18-PMF-007)
- Nanyang Technological University
- Division of Geological and Planetary Sciences
- California Institute of Technology
- INSERM
- Université Paris-Sud
- Cell and Tissue Imaging Facility of the Institut Curie (ANR-10-INBS-04)
- Salk Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- cellular aging, cell lifespan, protein turnover, 15N labeling, liver, pancreas, fibroblasts, endothelial cells, pancreatic beta cells, primary cilia, neurons, replicative potential, tissue organization
- MeSH terms
- Aging, Animals, Cilia, Female, Fibroblasts, Liver, Mice, Inbred Strains, Mosaicism, Neurons, Organ Specificity, Pancreas, Cellular Senescence, Endothelial Cells, Insulin-Secreting Cells, Mice
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