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Updated: Jun 16, 2025
Using Caenorhabditis elegans as a Model System to Study Protein Homeostasis in a Multicellular Organism
Published on: December 18, 2013
Characterization of Effects of mTOR Inhibitors on Aging in Caenorhabditis elegans
Aihan Zhang1, Gadea Meecham-Garcia1, Chiminh Nguyen Hong1
1Institute of Healthy Ageing, and Research Department of Genetics, Evolution and Environment, University College London, London, UK.
Abstract:
Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from Day 16 (or ~70 years in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.
Insights
Rapamycin extends lifespan in C. elegans, especially when given later in life. Optimal dosing and timing are key to maximizing benefits and avoiding toxicity in aging research.
Area of Science:
- Gerontology
- Molecular Biology
- Biochemistry
Background:
- The mechanistic target of rapamycin (mTOR) pathway is crucial for aging.
- Rapamycin extends lifespan in various organisms, but its effects in C. elegans are inconsistent.
- Optimizing rapamycin's use in C. elegans requires understanding dosage and timing.
Purpose of the Study:
- To determine the optimal dosage and delivery timing of rapamycin for lifespan extension in C. elegans.
- To investigate the impact of rapamycin on age-related pathologies and mortality in C. elegans.
- To compare the efficacy of rapamycin with its analogs, temsirolimus and everolimus.
Main Methods:
- Liposome-mediated rapamycin administration to adult C. elegans.
- Varying rapamycin dosages and treatment initiation times.
- Assessment of lifespan, development, fertility, and age-related pathologies.
Main Results:
- Maximal 21.9% lifespan extension with optimal rapamycin dosage; toxicity observed at highest doses.
- Later-life rapamycin treatment robustly extended lifespan, equivalent to ~70 human years.
- Rapamycin inhibited uterine tumor growth but not other pathologies, indicating a segmental anti-aging effect.
Conclusions:
- Rapamycin's lifespan-extending effects in C. elegans are dose- and timing-dependent.
- Later-life administration is a potent strategy for rapamycin-mediated lifespan extension in C. elegans.
- Rapamycin exhibits a segmental anti-aging effect, impacting specific pathologies.
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