mTOR/TOR pathway interventions achieve large lifespan extensions in simple organisms but face declining efficacy in mammals due to distributed multi-tissue buffering, redundancy, and pharmacokinetic complexity - proposing a unifying framework for the translational challenge of aging pathway targeting.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | Narrative Review |
| Model system | Multi-species (C. elegans, Drosophila, rodents) |
| Journal | Mechanisms of Ageing and Development |
| Year | 2026 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.mad.2026.112231 · PMID 42437600 |
Interventions targeting conserved aging pathways (including TOR/mTOR signaling) markedly extend lifespan in model organisms, yet efficacy declines with organismal complexity. Synthesizing data from C. elegans, Drosophila, and rodent models, the authors propose that simple organisms are governed by high-leverage pathways, while in mammals aging emerges from distributed, multi-tissue regulatory systems with redundancy, feedback, and competing physiological constraints. Key determinants include metabolic organization, genetic redundancy, endocrine regulation, microbiome interactions, and pharmacokinetic complexity.
| Intervention | TOR/mTOR pathway interventions (rapamycin and analogues) |
| Target | TOR/mTOR signaling; conserved aging pathways |
| Model | Multi-species |
| Effect | Lifespan extension via mTOR inhibition declines with organismal complexity; mammals show system-level buffering that limits single-pathway leverage |