End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies
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.
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
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.
- Scott F Leiser, University of Michigan, United States
- Preprint posted: May 31, 2021 (view preprint)
- Received: June 16, 2021
- Accepted: September 8, 2021
- Accepted Manuscript published: September 10, 2021 (version 1)
- Version of Record published: October 5, 2021 (version 2)
© 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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