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Age Mosaicism across Multiple Scales in Adult Tissues

Arrojo e Drigo, Rafael and Lev-Ram, Varda and Tyagi, Swati and Ramachandra, Ranjan and Deerinck, Thomas and Bushong, Eric and Phan, Sebastien and Orphan, Victoria and Lechene, Claude and Ellisman, Mark H. and Hetzer, Martin W. (2019) Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism, 30 (2). pp. 343-351. ISSN 1550-4131. doi:10.1016/j.cmet.2019.05.010.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription
Arrojo e Drigo, Rafael0000-0001-7712-013X
Lev-Ram, Varda0000-0001-7649-0550
Bushong, Eric0000-0001-6195-2433
Phan, Sebastien0000-0003-4261-6973
Orphan, Victoria0000-0002-5374-6178
Ellisman, Mark H.0000-0001-8893-8455
Hetzer, Martin W.0000-0002-2111-992X
Additional Information:© 2019 Elsevier Inc. Received 14 June 2018, Revised 18 October 2018, Accepted 11 May 2019, Available online 6 June 2019. This work was supported by grants to M.W.H. from the NIH Transformative Research Award (R01 NS096786), the Keck Foundation, and the NOMIS Foundation. It was also supported by grants to M.H.E. and V.L.-R. from the NIH NINDS (NIH RO1 NS027177-30), which supported the creation of the ^(15)N/^(14)N mice; and the NIH NIGMS (5P41 GM103412-29), which supports the advanced technologies and instrument development activities of the NCMIR, most heavily used, and whose new methods developments were partly driven by this work. V.O. and M.H.E. are also supported to develop and carry out correlated light and electron microscopy with MIMS under an award from the US Department of Energy, Office of Science, Office of Biological and Environmental Research (DE-SC0016469). R.A.eD. is supported by an American Diabetes Association postdoctoral fellowship (1-18-PMF-007) and benefitted from assistance from Daniela Rhodes and the Nanyang Institute of Structural Biology (NISB) (at the Nanyang Technological University, Singapore) from a career development stipend. The authors are also thankful to Yunbin Guan, Ph.D., from the Caltech Microanalysis Center in the Division of Geological and Planetary Sciences, California Institute of Technology for technical support and assistance with MIMS image acquisition; to Dr. Ting-Di Wu and Dr. Jean-Luc Guerquin-Kern from the INSERM, Université Paris-Sud, Paris; and the Cell and Tissue Imaging Facility of the Institut Curie (PICT), a member of the France BioImaging National Infrastructure (ANR-10-INBS-04), for the use of Curie NanoSIMS instrument; Greg McMahon from the National Center of Excellence in Mass Spectrometry Imaging, National Physical Laboratory (NPL), UK; and to David O'Keefe (Salk Institute) for critical inputs on manuscript editing and revision. Author Contributions: R.A.eD. collected and analyzed the data and wrote the article. V.L.-E., S.T., R.R., T.D., E.B., S.P., and C.L. collected the data. V.O., M.H.E., and M.W.H. designed the study and wrote the article. The authors declare no competing interests.
Funding AgencyGrant Number
NIHR01 NS096786
W. M. Keck FoundationUNSPECIFIED
NIHRO1 NS027177-30
NIH5P41 GM103412-29
Department of Energy (DOE)DE-SC0016469
American Diabetes Association1-18-PMF-007
Nanyang Technological UniversityUNSPECIFIED
Subject Keywords:aging; cell longevity; multi-isotope imaging mass spectroscopy; correlated multi-scale multi-modal microscopy; islets of Langerhans; primary cilium
Issue or Number:2
Record Number:CaltechAUTHORS:20190607-131617878
Persistent URL:
Official Citation:Rafael Arrojo e Drigo, Varda Lev-Ram, Swati Tyagi, Ranjan Ramachandra, Thomas Deerinck, Eric Bushong, Sebastien Phan, Victoria Orphan, Claude Lechene, Mark H. Ellisman, Martin W. Hetzer, Age Mosaicism across Multiple Scales in Adult Tissues, Cell Metabolism, Volume 30, Issue 2, 2019, Pages 343-351.e3, ISSN 1550-4131, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96205
Deposited By: Tony Diaz
Deposited On:07 Jun 2019 21:23
Last Modified:16 Nov 2021 17:19

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