Somatic mutations impose an entropic upper bound on human lifespan | npj Aging

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Somatic mutations impose an entropic upper bound on human lifespan

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Cardiology<br>Cell biology

Abstract<br>Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations. Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 1759 years to 156 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline. Multi-organ integration predicts median lifespans of 146–194 years—approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

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Acknowledgements<br>This study was funded by the Russian Science Foundation [25-71-20017 to E.K.]. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript. The authors thank Alexander Fedintsev and Alexey A. Alekseev for insightful comments and discussions on a preprint version of this manuscript.

Author information<br>Author notesThese authors contributed equally: Evgeniy Efimov, Vlad Fedotov, Leonid Malaev.

Authors and Affiliations<br>Skolkovo Institute of Science and Technology, Moscow, Russia<br>Evgeniy Efimov, Vlad Fedotov, Leonid Malaev, Ekaterina E. Khrameeva & Dmitrii Kriukov

Artificial Intelligence Research Institute, Moscow, Russia<br>Evgeniy Efimov, Vlad Fedotov & Dmitrii Kriukov

AuthorsEvgeniy EfimovView author publications<br>Search author on:PubMed Google Scholar

Vlad FedotovView author publications<br>Search author on:PubMed Google Scholar

Leonid MalaevView author publications<br>Search author on:PubMed Google Scholar

Ekaterina E. KhrameevaView author publications<br>Search author on:PubMed Google Scholar

Dmitrii KriukovView author publications<br>Search author on:PubMed Google Scholar

Corresponding author<br>Correspondence to<br>Dmitrii Kriukov.

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Cite this article<br>Efimov, E., Fedotov, V., Malaev, L. et al. Somatic mutations impose an entropic upper bound on human lifespan.<br>npj Aging (2026). https://doi.org/10.1038/s41514-026-00421-6<br>Download citation<br>Received: 17 December 2025

Accepted: 19 May 2026

Published: 25 June 2026

DOI: https://doi.org/10.1038/s41514-026-00421-6

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