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Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans

Hannah J. Smith, Anne Lanjuin, Arpit Sharma, Aditi Prabhakar, Emina Tabakovic, Rohan Sehgal, View ORCID ProfileWilliam B. Mair
doi: https://doi.org/10.1101/2021.08.12.456148
Hannah J. Smith
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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Anne Lanjuin
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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Arpit Sharma
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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Aditi Prabhakar
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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Emina Tabakovic
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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Rohan Sehgal
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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William B. Mair
1Dept. Molecular Metabolism, Harvard TH Chan School of Public Health
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  • ORCID record for William B. Mair
  • For correspondence: wmair@hsph.harvard.edu
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ABSTRACT

One of the most robust and reproducible methods to prolong lifespan in a variety of organisms is inhibition of the mTORC1 (mechanistic target of rapamycin complex 1) pathway. mTORC1 is a metabolic sensor that promotes anabolic growth when nutrients are abundant. Inhibition of mTORC1 extends lifespan, but also frequently has other effects such as stunted growth, slowed development, reduced fertility, and disrupted metabolism. It has long been assumed that suppression of anabolism and resulting phenotypes such as impaired growth and reproduction may be causal to mTORC1 longevity, but this hypothesis has not been directly tested. RAGA-1 is an upstream activator of TORC1. Previous work from our lab using a C. elegans model of mTORC1 longevity, the long-lived raga-1 null mutant, found that the presence of raga-1 only in the neurons suppresses longevity of the null mutant. Here, we use the auxin-inducible degradation (AID) system to test whether neuronal mTORC1 inhibition is sufficient for longevity, and whether any changes in lifespan are also linked to stunted growth or fertility. We find that life-long AID of RAGA-1 either in all somatic tissue or only in the neurons of C. elegans is sufficient to extend lifespan. We also find that AID of RAGA-1 or LET-363/mTOR beginning at day 1 of adulthood extends lifespan to a similar extent. Unlike somatic degradation of RAGA-1, neuronal degradation of RAGA-1 doesn’t impair growth, slow development, or decrease the reproductive capacity of the worms. Lastly, while AID of LET-363/mTOR in all somatic cells shortens lifespan, neuronal AID of LET-363/mTOR slows aging. This work demonstrates that targeting mTORC1 specifically in the neurons uncouples longevity from growth and reproductive impairments, challenging previously held ideas about the mechanisms of mTORC1 longevity and elucidating the promise of tissue-specific aging therapeutics.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 12, 2021.
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Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans
Hannah J. Smith, Anne Lanjuin, Arpit Sharma, Aditi Prabhakar, Emina Tabakovic, Rohan Sehgal, William B. Mair
bioRxiv 2021.08.12.456148; doi: https://doi.org/10.1101/2021.08.12.456148
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Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans
Hannah J. Smith, Anne Lanjuin, Arpit Sharma, Aditi Prabhakar, Emina Tabakovic, Rohan Sehgal, William B. Mair
bioRxiv 2021.08.12.456148; doi: https://doi.org/10.1101/2021.08.12.456148

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