Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster

By I. Bjedov, J. Toivonen, F. Kerr, Cathy Slack, J. Jacobson, A. Foley, Linda Partridge. Cell Metabolism, 2010

1,042 citations recorded by the source corpus.

Summary The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.

Subfields: Aging, Endocrine and Autonomic Systems, Immunology

View Paper: https://www.semanticscholar.org/paper/5fd6afd3e258f253ec7b7bd9f071df0e69af618d

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “Consistent with this, the mTOR inhibitor rapamycin is currently the only pharmacological treatment proven to extend life span in all of these model organisms (Bjedov et al., 2010; Harrison et al., 2009; Powers et al., 2006; Robida-Stubbs et al., 2012).”
The hallmarks of aging. (2013, background): “The lifespan-extending effect of rapamycin is strictly dependent on the induction of autophagy in yeast, nematodes, and flies (Bjedov et al., 2010; Rubinsztein et al., 2011).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Consistent with this, the mTOR inhibitor rapamycin is currently the only pharmacological treatment proven to extend lifespan in all of these model organisms (Bjedov et al., 2010; Harrison et al., 2009; Powers et al., 2006; Robida-Stubbs et al., 2012).”
Autophagy: Renovation of Cells and Tissues (2011, background): “Autophagosome Formation and Atg Proteins in Mammalian Cells mTOR complex 1 (mTORC1) suppresses the ULK1 (Atg1 homolog) complex under nutrient-rich conditions.”
Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity (2012, background): “Yeast that lack the mTOR homolog TOR1 have an extended replicative lifespan that is not further enhanced by CR, suggesting a common mechanism (4), but in flies, rapamycin increases lifespan beyond the maximum achieved by CR, and thus may act through additional mechanisms (11).”
Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control (2011, background): “TOR is indeed dedicated to controlling cell growth, but what is this target and how does it control cell growth?”
TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO (2012, background): “TOR inhibition, rapamycin, and DR seem to promote longevity at least in part by reducingmRNA translation (Bjedov et al., 2010; Kapahi et al., 2010; Kenyon, 2010; Stanfel et al., 2009; Zid et al., 2009).”
Ageing as a risk factor for disease. (2012, background): “Autophagy is regulated both by AMPK and TOR, and is required for lifespan-extension by rapamycin in flies, worms and yeast [24,25].”
mTOR signaling in growth control and disease (2012, neutral): “the lifespan of flies subject to DR (Bjedov et al., 2010).”