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Biological limits of lifespan extension: Evidence for a shift from pathway leverage to system-level buffering across species
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DOI：10.1016/j.mad.2026.112231.png)
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Abstract
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• Lifespan-extending interventions show progressively smaller effects with increasing organismal complexity. • Systems-level factors outweigh single molecular pathways in limiting maximal lifespan extension. • Increasing network buffering and inter-organ communication reduce pathway leverage in mammals. • Caloric restriction and mTOR inhibition retain efficacy but face intrinsic biological constraints in complex organisms. • A conceptual framework linking pathway leverage and system buffering explains declining translational impact across species.
Keywords:
Lifespan extension
Geroscience
Systems biology of aging
MTOR signaling
Biological complexity
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