Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila
What this study shows
Identifies Lsp2, a Drosophila fat-body storage protein, as an amino-acid-induced feedback activator of mTORC1 that specifically boosts translation of TOP-motif mRNAs (mostly ribosomal proteins) via 4E-BP — a rapamycin-resistant arm of mTORC1 output. Genetic loss of Lsp2 reduces TOP mRNA translation and robustly extends lifespan without cost to reproduction, revealing a rapamycin-independent route from mTORC1 activity to organismal longevity.
Abstract
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Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes that are crucial for physiological homeostasis and ageing. mTORC1 preferentially regulates the translation of 5'-terminal oligopyrimidine (TOP) motif-containing mRNAs (which encode mainly ribosomal proteins) through the 4E-BP translational repressor; however, this function of mTORC1 is resistant to rapamycin inhibition.
Read the full abstract on PubMed →At a glance
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| Evidence type | A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Drosophila melanogaster — Lsp2 genetic ablation, lifespan assay, translatomic (ribosome profiling) analysis); the code names the system studied -- animal work can be rigorous and still not be human data. |
| Study type | 4 - Animal Study |
| Model system | Drosophila melanogaster — Lsp2 genetic ablation, lifespan assay, translatomic (ribosome profiling) analysis |
| Journal | Nature |
| Year | 2026 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41586-026-11029-x · PMID 42778591 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Pathway relations
Supports
mTORC1 inhibits LongevityStrongest evidence: A (Animal model) · settled in the literature · Status: Proposed
not tested in people
No human hard-endpoint evidence. This is the Atlas's flagged 'human endpoint desert'.
Supports
mTORC1 activates 5'TOP mRNAStrongest evidence: A (Animal model) · settled in the literature · Status: Proposed
plausible in people, not shown directly
The selectivity is from ribosome profiling in cancer cell lines (HSI2012); the lifespan link is Drosophila only (WAN2026); PLEDGER2026 shows the same arm being repressed in chronically activated human CD8+ T cells. No human in vivo…
Open question
Contradiction / tension · H2
Does mTORC1-selective dosing extend lifespan, and is rapamycin's glucose intolerance a cost at all?Cited there as evidence. Evidence stands at: Clinical outcome in humans (oncology); no ageing endpoint.
People in the Atlas
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Senior author of a 2026 Nature study identifying Lsp2 as a rapamycin-resistant mTORC1 effector that extends lifespan in Drosophila when removed
Related studies
- M mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency
FAN2026 · 2026 · Shares: 5'TOP mRNA, mTORC1, Protein synthesis
- M The translational landscape of mTOR signalling steers cancer initiation and metastasis
HSI2012 · 2012 · Shares: mTORC1, Protein synthesis, 4E-BP1
- R Translational control of long-lasting synaptic plasticity and memory
COS2009 · 2009 · Shares: mTORC1, Protein synthesis, 4E-BP1
- A 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila
ZID2009 · 2009 · Shares: Longevity, mTORC1, 4E-BP1
- A Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis
RUV2005 · 2005 · Shares: 5'TOP mRNA, Protein synthesis
More related studies
- M Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k
JEF1997 · 1997 · Shares: 5'TOP mRNA, mTORC1
- M Translational repression of 5' TOP mRNAs in chronically activated CD8+ T cells in vitro.
PLEDGER2026 · 2026 · Shares: 5'TOP mRNA
- A Autism-related deficits via dysregulated eIF4E-dependent translational control
GKO2013 · 2013 · Shares: Protein synthesis, 4E-BP1
- A Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans
HAN2007 · 2007 · Shares: Longevity, Protein synthesis
- M IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells
DEM2026 · 2026 · Shares: mTORC1, Protein synthesis
- A Feeding-Induced Muscle mTORC1 Signaling Regulates Postprandial Protein Synthesis and Endurance but Not Muscle Size
LAP2026 · 2026 · Shares: mTORC1, Protein synthesis
- A D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia.
SHIM2026 · 2026 · Shares: mTORC1, Protein synthesis
- M Firefox, a protein encoded by circular PVT1, is essential for MYC-driven oncogenesis.
TIW2026 · 2026 · Shares: mTORC1, Protein synthesis
Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | genetic ablation of Lsp2 in Drosophila; essential amino acid feeding; rapamycin comparison |
| Target | mTORC1 output to TOP-motif mRNA translation via 4E-BP |
| Model | Drosophila melanogaster |
| Effect | Loss of Lsp2 selectively reduced TOP mRNA translation in a 4E-BP-dependent way and robustly extended lifespan without impairing reproduction. |
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