Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species

Denisa Fv Pirscoveanu, Mihai-Cristian Papa, Britta Kaltwasser, Dirk M Hermann, Ulf Brockmeier, Andrea Cercel, Anthony Oliver, Johannes Gruillari, Marius Viorel Ionica, Aurel Popa-Wagner · 2026 · Mechanisms of Ageing and Development · Atlas ID PIR2026

What this study shows

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.

Abstract

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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.

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At a glance

Evidence type	R Review — secondary literature, not a new result Marked R because it is a review or synthesis of existing evidence rather than a new primary result; that is a different form of writing, not a weaker one.
Study type	Narrative Review
Model system	Multi-species (C. elegans, Drosophila, rodents)
Journal	Mechanisms of Ageing and Development
Year	2026
Peer reviewed	Yes
Record last updated	2026-08-22
Source	DOI 10.1016/j.mad.2026.112231 · PMID 42437600

Extracted findings

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

In the Atlas

Cite this paper

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Denisa Fv Pirscoveanu, Mihai-Cristian Papa, Britta Kaltwasser, Dirk M Hermann, Ulf Brockmeier, Andrea Cercel, Anthony Oliver, Johannes Gruillari, Marius Viorel Ionica, & Aurel Popa-Wagner (2026). Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species. Mechanisms of Ageing and Development. https://doi.org/10.1016/j.mad.2026.112231

@article{PIR2026,
  author       = {Denisa Fv Pirscoveanu and Mihai-Cristian Papa and Britta Kaltwasser and Dirk M Hermann and Ulf Brockmeier and Andrea Cercel and Anthony Oliver and Johannes Gruillari and Marius Viorel Ionica and Aurel Popa-Wagner},
  title        = {{Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species}},
  journal      = {Mechanisms of Ageing and Development},
  year         = {2026},
  doi          = {10.1016/j.mad.2026.112231},
  note         = {PMID: 42437600},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record PIR2026) [Data set]. https://mtor-atlas.org/study/PIR2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_PIR2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record PIR2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/PIR2026/},
  doi          = {10.5281/zenodo.22059963}
}