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Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.

Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L - Cell Metab. (2010)

Bottom Line: We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, UK.

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Effect of Rapamycin Treatment on Long-Lived IIS Mutants(A) Rapamycin extends the life span of long-lived chico1 heterozygotes, (p = 0.0005) but decreases the life span of chico1/chico1 homozygotes (p < 0.0001). On control food, chico1 heterozygotes (p = 0.039) and chico1/chico1 s (p < 0.0001) have increased median life span compared to control wDah flies. Log-rank test is used for analyses.(B) Rapamycin does not extend the life span of mNSC-ablated flies. mNSCs were partially ablated by driving expression of the proapoptotic factor reaper (UAS-rpr) in the mNSCs using the dilp2-GAL4 driver (d2GAL4). On control food, mNSC-ablated flies are long lived (p < 0.0001, log-rank test compared to control). Log-rank test p values for rapamycin-treated versus nontreated flies of the same genotype are p < 0.0001 for wDah and p = 0.97 for d2GAL4 > UAS-rpr.(C) Flies pretreated with 200 μM rapamycin survived longer under starvation conditions compared to untreated flies. Log-rank statistics for nontreated versus rapamycin-pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, both chico1 heterozygotes and mNSC-ablated flies were more resistant to starvation without rapamycin pretreatment (p = 0.006 and p = 0.001, respectively, log-rank tests).(D) Flies pretreated with 200 μM rapamycin survive longer when fed 20 mM paraquat. Log-rank statistics for nontreated versus rapamycin pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, mNSC-ablated flies were more resistant to paraquat ingestion without rapamycin pretreatment (p < 0.0001, log-rank test).
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fig6: Effect of Rapamycin Treatment on Long-Lived IIS Mutants(A) Rapamycin extends the life span of long-lived chico1 heterozygotes, (p = 0.0005) but decreases the life span of chico1/chico1 homozygotes (p < 0.0001). On control food, chico1 heterozygotes (p = 0.039) and chico1/chico1 s (p < 0.0001) have increased median life span compared to control wDah flies. Log-rank test is used for analyses.(B) Rapamycin does not extend the life span of mNSC-ablated flies. mNSCs were partially ablated by driving expression of the proapoptotic factor reaper (UAS-rpr) in the mNSCs using the dilp2-GAL4 driver (d2GAL4). On control food, mNSC-ablated flies are long lived (p < 0.0001, log-rank test compared to control). Log-rank test p values for rapamycin-treated versus nontreated flies of the same genotype are p < 0.0001 for wDah and p = 0.97 for d2GAL4 > UAS-rpr.(C) Flies pretreated with 200 μM rapamycin survived longer under starvation conditions compared to untreated flies. Log-rank statistics for nontreated versus rapamycin-pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, both chico1 heterozygotes and mNSC-ablated flies were more resistant to starvation without rapamycin pretreatment (p = 0.006 and p = 0.001, respectively, log-rank tests).(D) Flies pretreated with 200 μM rapamycin survive longer when fed 20 mM paraquat. Log-rank statistics for nontreated versus rapamycin pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, mNSC-ablated flies were more resistant to paraquat ingestion without rapamycin pretreatment (p < 0.0001, log-rank test).

Mentions: Downregulation of IIS can extend life span in diverse organisms (Piper et al., 2008). Because of the many potential interactions between the TOR pathway and IIS, we investigated whether rapamycin treatment could further increase the life span of long-lived IIS mutants. Rapamycin treatment of flies heterozygous for chico1, a mutation in the gene encoding the single Drosophila IRS homolog, extended life span beyond that induced by rapamycin treatment of controls (Figure 6A). However, rapamycin treatment of chico1 homozygotes, which have more strongly reduced IIS and longer life span than heterozygotes (Figure 6A), shortened life span to levels comparable with non-rapamycin-treated controls (Figure 6A). Rapamycin treatment was biochemically effective in chico1 homozygotes, because phosphorylation of S6K was similarly downregulated by rapamycin (Figure S4). Rapamycin treatment of flies with reduced levels of Drosophila insulin-like peptides (DILPs) due to the partial ablation of the DILP-producing median neurosecretory cells (mNSC) (Broughton et al., 2005) did not further increase life span in these long-lived flies (Figure 6B). Taken together, these data suggest that, when life span by rapamycin treatment is maximized, weak downregulation of IIS, as in chico1 heterozygotes, can further extend life span, showing that IIS extends life span by mechanisms additional to those affected by rapamycin. However, stronger downregulation of IIS, which alone extends life span, can be deleterious in the presence of rapamycin, through as-yet-unidentified mechanisms.


Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.

Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L - Cell Metab. (2010)

Effect of Rapamycin Treatment on Long-Lived IIS Mutants(A) Rapamycin extends the life span of long-lived chico1 heterozygotes, (p = 0.0005) but decreases the life span of chico1/chico1 homozygotes (p < 0.0001). On control food, chico1 heterozygotes (p = 0.039) and chico1/chico1 s (p < 0.0001) have increased median life span compared to control wDah flies. Log-rank test is used for analyses.(B) Rapamycin does not extend the life span of mNSC-ablated flies. mNSCs were partially ablated by driving expression of the proapoptotic factor reaper (UAS-rpr) in the mNSCs using the dilp2-GAL4 driver (d2GAL4). On control food, mNSC-ablated flies are long lived (p < 0.0001, log-rank test compared to control). Log-rank test p values for rapamycin-treated versus nontreated flies of the same genotype are p < 0.0001 for wDah and p = 0.97 for d2GAL4 > UAS-rpr.(C) Flies pretreated with 200 μM rapamycin survived longer under starvation conditions compared to untreated flies. Log-rank statistics for nontreated versus rapamycin-pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, both chico1 heterozygotes and mNSC-ablated flies were more resistant to starvation without rapamycin pretreatment (p = 0.006 and p = 0.001, respectively, log-rank tests).(D) Flies pretreated with 200 μM rapamycin survive longer when fed 20 mM paraquat. Log-rank statistics for nontreated versus rapamycin pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, mNSC-ablated flies were more resistant to paraquat ingestion without rapamycin pretreatment (p < 0.0001, log-rank test).
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fig6: Effect of Rapamycin Treatment on Long-Lived IIS Mutants(A) Rapamycin extends the life span of long-lived chico1 heterozygotes, (p = 0.0005) but decreases the life span of chico1/chico1 homozygotes (p < 0.0001). On control food, chico1 heterozygotes (p = 0.039) and chico1/chico1 s (p < 0.0001) have increased median life span compared to control wDah flies. Log-rank test is used for analyses.(B) Rapamycin does not extend the life span of mNSC-ablated flies. mNSCs were partially ablated by driving expression of the proapoptotic factor reaper (UAS-rpr) in the mNSCs using the dilp2-GAL4 driver (d2GAL4). On control food, mNSC-ablated flies are long lived (p < 0.0001, log-rank test compared to control). Log-rank test p values for rapamycin-treated versus nontreated flies of the same genotype are p < 0.0001 for wDah and p = 0.97 for d2GAL4 > UAS-rpr.(C) Flies pretreated with 200 μM rapamycin survived longer under starvation conditions compared to untreated flies. Log-rank statistics for nontreated versus rapamycin-pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, both chico1 heterozygotes and mNSC-ablated flies were more resistant to starvation without rapamycin pretreatment (p = 0.006 and p = 0.001, respectively, log-rank tests).(D) Flies pretreated with 200 μM rapamycin survive longer when fed 20 mM paraquat. Log-rank statistics for nontreated versus rapamycin pretreated flies for all genotypes are p < 0.0001. Compared to wild-type controls, mNSC-ablated flies were more resistant to paraquat ingestion without rapamycin pretreatment (p < 0.0001, log-rank test).
Mentions: Downregulation of IIS can extend life span in diverse organisms (Piper et al., 2008). Because of the many potential interactions between the TOR pathway and IIS, we investigated whether rapamycin treatment could further increase the life span of long-lived IIS mutants. Rapamycin treatment of flies heterozygous for chico1, a mutation in the gene encoding the single Drosophila IRS homolog, extended life span beyond that induced by rapamycin treatment of controls (Figure 6A). However, rapamycin treatment of chico1 homozygotes, which have more strongly reduced IIS and longer life span than heterozygotes (Figure 6A), shortened life span to levels comparable with non-rapamycin-treated controls (Figure 6A). Rapamycin treatment was biochemically effective in chico1 homozygotes, because phosphorylation of S6K was similarly downregulated by rapamycin (Figure S4). Rapamycin treatment of flies with reduced levels of Drosophila insulin-like peptides (DILPs) due to the partial ablation of the DILP-producing median neurosecretory cells (mNSC) (Broughton et al., 2005) did not further increase life span in these long-lived flies (Figure 6B). Taken together, these data suggest that, when life span by rapamycin treatment is maximized, weak downregulation of IIS, as in chico1 heterozygotes, can further extend life span, showing that IIS extends life span by mechanisms additional to those affected by rapamycin. However, stronger downregulation of IIS, which alone extends life span, can be deleterious in the presence of rapamycin, through as-yet-unidentified mechanisms.

Bottom Line: We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, UK.

Show MeSH
Related in: MedlinePlus