Activates transcription and protein synthesis related to growth Inhibits

Activates transcription and protein synthesis related

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Activates transcription and protein synthesis related to growth Inhibits catabolism (via inhibiting autophagy) Activates maintenance of cellular cytoskeleton Activated by nutrient signals Inhibited by RAP STUDY ( C. elegans ) RNAi on TOR Inhibiting TOR expression increases lifespan in nematodes Therefore expect downregulating TOR activity in other organisms to extend lifespan Background: Rapamycin inhibits TOR activity and extends the lifespan. Diet restriction, via mutating eat-2 in C. elegans, also extends the lifespan. Question: Is there a mechanistic overlap between the TOR and the eat-2 pathways in their effect on the lifespan? How does TOR prevent aging? STUDY ( C. elegans ) Additive effect with TOR inhibition?: eat-2 with no RNAi tx worms and eat-2 with RNAi tx worms (remember, eat-2 mutants eat less) Found no significant difference: eat-2 and eat-2/ RNAi- TOR worms had equally extended life spans compared to the wild type Therefore, there is a mechanistic overlap in TOR and eat-2 STUDY ( C. elegans ) autophagy in DR worms DR increases autophagy Reporter line made where GFP attached to LGG-1 (important in autophagy) reveals autophagy expression Increased GFP presence in DR ( eat-2 ) worms vs. control Therefore, increased autophagy expression in the mutant worms Furthermore, increased autophagy is key in lifespan extension in DR worms Recall: bec-1 is key to initiate autophagosome formation RNAi on bec-1 limits the lifespan extension in eat-2 mutant worms (poses no effect on WT worms) TOR also increases autophagy And, increased autophagy is key in lifespan extension in TOR mutant worms TOR mutation increased GFP-LGG-1 signals (increased autophagy expression) RNAi on bec-1 shortened the lifespan extension in TOR mutants What about in other species… like Drosophila ? STUDY ( Drosophila ) rapamycin on flies
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Similar, supporting results Also increases lifespan Microscopy tracked protein synthesis and lysosome synthesis Decreased protein synthesis Increases lysosome synthesis (implied increased autophagy) If apply RNAi against Atg5 (signaling protein to induce autophagy), suppresses lifespan extension Lifespan extension in eat-2 mutants and TOR down-regulation is autophagy-dependent … But it is still unclear how a nutrient signal affects TOR. AMPK (AMP-activated protein kinase) Background: involved in increasing energy availability during times of insufficient nutrient intake; promotes catabolism (e.g. glycolysis, lipolysis) and inhibits anabolism (e.g. protein synthesis, other biosynthesis pathways). Inhibits TOR in order to inhibit protein synthesis and growth. Part of AMPK’s function is also to promote autophagy expression (directly, and indirectly via inhibiting TOR) to breakdown proteins and damaged organelles.
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  • Spring '18
  • David Walker

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