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Network analyses unveil ageing-associated pathways evolutionarily conserved from fungi to animals

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Abstract

The genetic roots of the diverse paces and shapes of ageing and of the large variations in longevity observed across the tree of life are poorly understood. Indeed, pathways associated with ageing/longevity are incompletely known, both in terms of their constitutive genes/proteins and of their molecular interactions. Moreover, there is limited overlap between the genes constituting these pathways across mammals. Yet, dedicated comparative analyses might still unravel evolutionarily conserved, important pathways associated with longevity or ageing. Here, we used an original strategy with a double evolutionary and systemic focus to analyse protein interactions associated with ageing or longevity during the evolution of five species of Opisthokonta. We ranked these proteins and interactions based on their evolutionary conservation and centrality in past and present protein–protein interaction (PPI) networks, providing a big systemic picture of the evolution of ageing and longevity pathways that identified which pathways emerged in which Opisthokonta lineages, were conserved, and/or central. We confirmed that longevity/ageing-associated proteins (LAPs), be they pro- or anti-longevity, are highly central in extant PPI, consistently with the antagonistic pleiotropy theory of ageing, and identified key antagonistic regulators of ageing/longevity, 52 of which with homologues in humans. While some highly central LAPs were evolutionarily conserved for over a billion years, we report a clear transition in the functionally important components of ageing/longevity within bilaterians. We also predicted 487 novel evolutionarily conserved LAPs in humans, 54% of which are more central than mTOR, and 138 of which are druggable, defining new potential targets for anti-ageing treatments in humans.

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Acknowledgements

We thank Duncan Sussfeld, Cameron Osborne, and three anonymous reviewers for critical reading of the manuscript.

Funding

This work was supported by an Emergence grant from Sorbonne Université (S21JR31001—IP/S/V2 EMERG-ESPA) to EB and JM and by a grant from the Ministère de la Recherche to CB.

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Authors and Affiliations

  1. Institut de Systématique, Evolution, Biodiversité (ISYEB), Sorbonne Université, CNRS, Museum National d’Histoire Naturelle, EPHE, Université Des Antilles, Paris, France

    Jérôme Teulière, Charles Bernard, Eduardo Corel, Philippe Lopez & Eric Bapteste

  2. Département de Sciences Biologiques, Complexe Des Sciences, Université de Montréal, Montréal, QC, Canada

    François-Joseph Lapointe

  3. Sciences, Normes, Démocratie (SND), Sorbonne Université, CNRS, 75005, Paris, France

    Johannes Martens

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  1. Jérôme Teulière
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Correspondence to Eric Bapteste.

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Teulière, J., Bernard, C., Corel, E. et al. Network analyses unveil ageing-associated pathways evolutionarily conserved from fungi to animals. GeroScience 45, 1059–1080 (2023). https://doi.org/10.1007/s11357-022-00704-2

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