Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing1. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor2; however, this function of mTORC1 is resistant to rapamycin inhibition3. TOP mRNAs are exceptionally abundant, and thus impose a major translational burden on cells, but how their translation is physiologically tuned and linked with lifespan remains unclear. Here we show that Lsp2, which was previously known to be a storage protein4, is also an adipose effector and feedback activator of mTORC1 that modulates lifespan in Drosophila. Expression of Lsp2 is induced by essential amino acids through mTORC1 and is gated by additional signals of nutrient sufficiency. Genetic ablation of Lsp2 robustly extends lifespan without impairing key life history traits such as reproduction. Translatomic profiling shows that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan through a mechanism distinct from the effects of rapamycin. Evolutionarily, TOP motifs co-emerged with 4E-BP and are present in nearly all Drosophila ribosomal protein mRNAs. Moreover, we show that the role of TOP motifs in translational control extends to Drosophila. Collectively, our findings reveal a nutrient-induced physiological factor that amplifies mTORC1 output in TOP mRNA translation and regulates organismal longevity.
Longevity & Aging