Connected the dots between diet, mTOR, and lifespan. Dietary restriction lowers mTOR activity, which frees up 4E-BP - and here 4E-BP was shown to be REQUIRED for the lifespan boost, working by selectively boosting translation of mitochondrial genes. A rare case pinning a specific mTOR effector to the longevity benefit of eating less.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Drosophila (fruit fly) |
| Journal | Cell |
| Year | 2009 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.cell.2009.07.034 · PMID 19804760 · Free full text (PMC2759400) |
Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5'UTRs, which were important for their enhanced mRNA translation. The translational repressor 4E-BP, the eukaryotic translation initiation factor 4E binding protein, was upregulated upon DR and mediated DR dependent changes in mitochondrial activity and lifespan extension. Inhibition of individual mitochondrial subunits from Complex I and IV diminished the lifespan extension obtained upon DR, reflecting the importance of enhanced mitochondrial function during DR. Our results imply that translational regulation of nuclear-encoded mitochondrial gene expression by 4E-BP plays an important role in lifespan extension upon DR. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.
| Intervention | Genetic (4E-BP) |
| Target | 4E-BP / mitochondria |
| Model | Drosophila |
| Effect | 4E-BP extends lifespan under dietary restriction by enhancing mitochondrial activity |