Challenges of proving a causal role of somatic mutations in the aging process

Aging is accompanied by the progressive accumulation of permanent changes to the genomic sequence, termed somatic mutations. Small mutations, including single-base substitutions and insertions/deletions, are key determinants of the malignant transformations leading to cancer, but their role as initiators of other age-related phenotypes is controversial. Here, we present recent advances in the study of somatic mutagenesis in aging tissues and posit that the current uncertainty about its causal effects in the aging process is due to technological and methodological weaknesses. We highlight classical and novel experimental systems, including premature aging syndromes, that could be used to model the increase of somatic mutation burden and understand its functional role. It is important that studies are designed to take into account the biological context and peculiarities of each tissue and that the downstream impact of somatic mutation accumulation is measured by methods able to resolve subtle cellular changes.