Somatic mutations and genome mosaicism in aging and disease

Abstract

Age-related genome mosaicism is an inherent feature of multicellularity and genomic instability. It occurs because of DNA mutations, the accumulation of which leads to diverse genomic landscapes across different tissues. DNA mutations in the genome are consequences of DNA damage, changes in the chemical structure of DNA, such as strand breaks or loss of bases. DNA damage is very frequent and normally repaired quickly. However, errors intrinsic to DNA repair or replication can give rise to permanent changes in genome sequence information. Such DNA mutations are diverse and include single-nucleotide variants, small insertions and deletions, and larger genome structural variants. Since the 1950s, somatic mutations have been proposed to be a major cause of aging. Indeed, somatic mutations are the cause of cancer, the risk of which increases exponentially with age, and possibly other age-related diseases, such as neurodegenerative diseases and cardiomyopathies. Somatic mutations vary from cell to cell owing to the innate stochasticity of their occurrence, from error-prone processing of randomly inflicted DNA damage. With the emergence of single-cell and single-molecule sequencing, it has become possible to quantitatively analyze somatic mutations in human cells and tissues. Here, we discuss a possible causal relationship between mutation-driven mosaicism of the somatic genome and aging-related functional decline and disease by exploring several predictions of the somatic mutation theory of aging. The inherent instability of genome increases with age, leading to the accumulation of mutations and resulting in genome mosaicism, in which genetic diversity exists within an individual’s cells. This Review explores the role of somatic mutations in aging and age-related diseases, examining their origins and potential impacts. The authors discuss methods for studying mutations, including next-generation sequencing, and highlight findings from studies on human progeroid syndromes and long-lived species. Results indicate that somatic mutations accumulate with age, contributing to functional decline and increased disease risk. For example, somatic mutations in liver cells rise significantly with age, potentially due to the detoxification role of the liver. These findings suggest that understanding somatic mutations could provide insights into aging mechanisms and inform future research directions, such as improving DNA repair to mitigate mutation accumulation and its effects. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.