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Published August 6, 2019 | Supplemental Material
Journal Article Open

Age Mosaicism across Multiple Scales in Adult Tissues

Abstract

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.

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.

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