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Ageing hallmarks exhibit organ-specific temporal signatures

Authors
Nicholas Schaum,Benoit Lehallier
Oliver Hahn,Róbert Pálovics,Shayan Hosseinzadeh,Song Lee,Rene Sit,Davis Lee,Patricia Losada,Macy Zardeneta,Tobias Fehlmann,James Webber,Aaron McGeever,Kruti Calcuttawala,Hui Zhang,Daniela Berdnik,Vidhu Mathur,Weilun Tan,Alexander Zee,Michelle Tan,Nicole Almanzar,Jane Antony,Ankit Baghel,Isaac Bakerman,Ishita Bansal,Ben Barres,Philip Beachy,Biter Bilen,Douglas Brownfield,Corey Cain,Charles Chan,Michelle Chen,Michael Clarke,Stephanie Conley,Spyros Darmanis,Aaron Demers,Kubilay Demir,Antoine Morrée,Tessa Divita,Haley Bois,Hamid Ebadi,F. Espinoza,Matt Fish,Qiang Gan,Benson George,Astrid Gillich,Rafael Gómez-Sjöberg,Foad Green,Geraldine Genetiano,Xueying Gu,Gunsagar Gulati,Michael Haney,Yan Hang,Lincoln Harris,Mu He,Albin Huang,Kerwyn Huang,Tal Iram,Taichi Isobe,Feather Ives,Robert Jones,Kevin Kao,Jim Karkanias,Guruswamy Karnam,Andreas Keller,Aaron Kershner,Nathalie Khoury,Seung Kim,Bernhard Kiss,William Kong,Mark Krasnow,Maya Kumar,Christin Kuo,Jonathan Lam,Olivia Leventhal,Guang Li,Qingyun Li,Ling Liu,Annie Lo,Wan-Jin Lu,Maria Lugo-Fagundo,Anoop Manjunath,Andrew May,Ashley Maynard,Marina McKay,M. McNerney,Bryan Merrill,Ross Metzger,Marco Mignardi,Dullei Min,Ahmad Nabhan,Norma Neff,Katharine Ng,Patricia Nguyen,Joseph Noh,Roel Nusse,Rasika Patkar,Weng Peng,Lolita Penland,Angela Pisco,Katherine Pollard,Robert Puccinelli,Zhen Qi,Stephen Quake,Thomas Rando,Eric Rulifson,Joe Segal,Shaheen Sikandar,Rahul Sinha,Justin Sonnenburg,Daniel Staehli,Krzysztof Szade,Cristina Tato,Krissie Tellez,Laughing Dulgeroff,Kyle Travaglini,Carolina Tropini,Margaret Tsui,Lucas Waldburger,Bruce Wang,Linda Weele,Kenneth Weinberg,Irving Weissman,Michael Wosczyna,Sean Wu,Tony Wyss‐Coray,Jinyi Xiang,Soso Xue,Kevin Yamauchi,Andrew Yang,Lakshmi Yerra,Justin Youngyunpipatkul,Brian Yu,Fabio Zanini,Chunyu Zhao,Fan Zhang,Martin Zhang,Lu Zhou,James Zou
+137 authors
,Francisco Espinoza
Journal
Published
Jul 15, 2020
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Abstract

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1—these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2—or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

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