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

Interventions targeting conserved aging pathways can markedly extend lifespan in model organisms, yet their efficacy declines with increasing organismal complexity. While this phenomenon is well documented, the underlying constraints remain poorly defined. Here, we integrate comparative experimental data with mechanistic insights to propose a unifying framework explaining the declining ceiling of lifespan extension. We show that in simple organisms, aging is governed by a limited number of high-leverage pathways, whereas in mammals it emerges from distributed, multi-tissue regulatory systems characterized by redundancy, feedback, and competing physiological constraints. By synthesizing findings from Caenorhabditis elegans, Drosophila melanogaster, and rodent models, we identify key determinants of this transition, including metabolic organization, genetic redundancy, endocrine regulation, microbiome interactions, and pharmacokinetic complexity.