Researchers from Skoltech (part of the VEB.RF Group) and their co‑authors from AIRI have for the first time quantitatively assessed how somatic mutations — random DNA changes that accumulate in cells with age — limit the maximum human lifespan. The work was published in the journal npj Aging (Nature Portfolio) and was supported by a grant from the Russian Science Foundation.

Somatic mutations are random changes in DNA that occur in the body’s cells throughout life. Unlike germline mutations, they are not inherited, but they gradually accumulate with age and can damage cells, impair their function, and contribute to the development of age‑related diseases.

The researchers developed a multi‑stage mathematical model that allowed them to sequentially “switch on” various aging mechanisms and assess how long a person could live if all reversible aging processes were eliminated except somatic mutations.

“The key finding of the study is the discovery of substantial differences between tissue types. Neurons and cardiomyocytes, which lack the ability to divide, turned out to be the main limiting factor: when all other causes of aging are eliminated, somatic mutations alone reduce the theoretical median lifespan from 1,759 years (for a hypothetical non‑aging human organism) to 156 years. At the same time, tissues with high regenerative capacity — such as the liver — can maintain their function for thousands of years through continuous cell renewal, effectively neutralizing the negative impact of mutations,” shared the results Evgeny Efimov, one of the key authors of the study, a research intern at the Skoltech Biomed Technologies Center and a researcher at AIRI.

Integration of models of all critical organs allowed the researchers to calculate that even when all other reversible signs of aging are completely eliminated, somatic mutations still limit the median human lifespan to a range of 146–194 years — roughly twice the current average life expectancy in developed countries.

“Our study shows that somatic mutations contribute significantly to aging, but they cannot by themselves explain the observed mortality,” noted co‑author Dmitrii Kriukov, a research scientist at the Skoltech Biomed Technologies Center and a senior research scientist at AIRI. “This means that other aging mechanisms — such as loss of proteostasis, mitochondrial dysfunction, or epigenetic changes — contribute comparably to limiting lifespan.”

The study offers a new quantitative approach to studying aging, allowing individual mechanisms to be ranked by their contribution to limiting lifespan and priorities to be determined for the development of therapeutic strategies.

“We can now not just say that mutations are harmful, but quantify exactly how much they shorten life and compare their contribution with other aging processes,” added the study’s principal investigator Ekaterina Khrameeva, an associate professor at the Skoltech Biomed Technologies Center. “This work is important for understanding which aging mechanisms deserve the most attention and resources.”

In the future, the proposed approach can be extended to other tissues and organs, as well as to other species, enabling cross‑species testing of hypotheses about aging mechanisms. The authors also plan to incorporate other hallmarks of aging into the model — mitochondrial dysfunction, loss of proteostasis, telomere shortening, and epigenetic changes — to build a comprehensive quantitative theory of human aging.