End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies

  1. Richard Venz
  2. Tina Pekec
  3. Iskra Katic
  4. Rafal Ciosk
  5. Collin Yvès Ewald  Is a corresponding author
  1. Swiss Federal Institute of Technology in Zurich, Switzerland
  2. Friedrich Miescher Institute, Switzerland
  3. University of Oslo, Norway

Abstract

Preferably, lifespan-extending therapies should work when applied late in life without causing undesired pathologies. Reducing Insulin/IGF-1 signaling (IIS) increases lifespan across species, but the effects of reduced IIS interventions in extreme geriatric ages remains unknown. Using the nematode C. elegans, we engineered the conditional depletion of the DAF-2/insulin/IGF-1 transmembrane receptor using an auxin-inducible degradation (AID) system. This allowed for the temporal and spatial reduction in DAF-2 protein levels at time points after which interventions such as RNAi become ineffective. Using this system, we found that AID-mediated depletion of DAF-2 protein surpasses the longevity of daf-2 mutants. Depletion of DAF-2 during early adulthood resulted in multiple adverse phenotypes, including growth retardation, germline shrinkage, egg retention, and reduced brood size. By contrast, AID-mediated depletion of DAF-2 post reproduction, or specifically in the intestine in early adulthood, resulted in an extension of lifespan without these deleterious effects. Strikingly, at geriatric ages, when 75% of the population had died, AID-mediated depletion of DAF-2 protein resulted in a doubling in lifespan. Thus, we provide a proof-of-concept that even close to the end of an individual's lifespan, it is possible to slow aging and promote longevity.

Data availability

Source Data 1 for all figuresSource Data 2 showing all full western blotsSource Data 3 raw data for all arsenite stress asssays

Article and author information

Author details

  1. Richard Venz

    Swiss Federal Institute of Technology in Zurich, Schwerzenbach, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Tina Pekec

    Friedrich Miescher Institute, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Iskra Katic

    Friedrich Miescher Institute, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Rafal Ciosk

    University of Oslo, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2234-6216
  5. Collin Yvès Ewald

    Swiss Federal Institute of Technology in Zurich, Schwerzenbach, Switzerland
    For correspondence
    collin-ewald@ethz.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1166-4171

Funding

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PP00P3_163898)

  • Collin Yvès Ewald

Research Council of Norway (FRIMEDBIO-286499)

  • Rafal Ciosk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Scott F Leiser, University of Michigan, United States

Publication history

  1. Preprint posted: May 31, 2021 (view preprint)
  2. Received: June 16, 2021
  3. Accepted: September 8, 2021
  4. Accepted Manuscript published: September 10, 2021 (version 1)
  5. Version of Record published: October 5, 2021 (version 2)

Copyright

© 2021, Venz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Richard Venz
  2. Tina Pekec
  3. Iskra Katic
  4. Rafal Ciosk
  5. Collin Yvès Ewald
(2021)
End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies
eLife 10:e71335.
https://doi.org/10.7554/eLife.71335

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