Ageing hallmarks exhibit organ-specific temporal signatures

Nicholas Schaum, Benoit Lehallier, Oliver Hahn, Róbert Pálovics, Shayan Hosseinzadeh, Song E. Lee, Rene Sit, Davis P. Lee, Patricia Morán Losada, Macy E. Zardeneta, Tobias Fehlmann, James T. Webber, Aaron McGeever, Kruti Calcuttawala, Hui Zhang, Daniela Berdnik, Vidhu Mathur, Weilun Tan, Alexander Zee, Michelle Tan, Angela Oliveira Pisco, Jim Karkanias, Norma F. Neff, Andreas Keller, Spyros Darmanis, Stephen R. Quake () and Tony Wyss-Coray ()
Additional contact information
Nicholas Schaum: Stanford University School of Medicine
Benoit Lehallier: Stanford University School of Medicine
Oliver Hahn: Stanford University School of Medicine
Róbert Pálovics: Stanford University School of Medicine
Shayan Hosseinzadeh: Chan Zuckerberg Biohub
Song E. Lee: Stanford University School of Medicine
Rene Sit: Chan Zuckerberg Biohub
Davis P. Lee: Stanford University School of Medicine
Patricia Morán Losada: Stanford University School of Medicine
Macy E. Zardeneta: Stanford University School of Medicine
Tobias Fehlmann: Saarland University
James T. Webber: Chan Zuckerberg Biohub
Aaron McGeever: Chan Zuckerberg Biohub
Kruti Calcuttawala: Stanford University School of Medicine
Hui Zhang: Stanford University School of Medicine
Daniela Berdnik: Stanford University School of Medicine
Vidhu Mathur: Stanford University School of Medicine
Weilun Tan: Chan Zuckerberg Biohub
Alexander Zee: Chan Zuckerberg Biohub
Michelle Tan: Chan Zuckerberg Biohub
Angela Oliveira Pisco: Chan Zuckerberg Biohub
Jim Karkanias: Chan Zuckerberg Biohub
Norma F. Neff: Chan Zuckerberg Biohub
Andreas Keller: Stanford University School of Medicine
Spyros Darmanis: Chan Zuckerberg Biohub
Stephen R. Quake: Chan Zuckerberg Biohub
Tony Wyss-Coray: Stanford University School of Medicine

Nature, 2020, vol. 583, issue 7817, 596-602

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2499-y

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