Is random mutational damage to nuclear DNA a sizable cause of aging? The consensus in the scientific community on that question is that it is an important cause, with the theory being that this results in sufficient change in protein production and cellular behavior to produce degraded function. That consensus is challenged, however, and at present there is a distinct lack of supporting evidence for either position, even given a few intriguing studies from recent years. It is well known that mutation level correlates with age, and methods of slowing aging also slow the increase of mutational damage. So every aspect of aging does in fact tend to correlate with mutation load, but that doesn't necessarily tell us anything about cause and effect - and that is the case here.
Aging in humans brings increased incidence of nearly all diseases, including neurodegenerative diseases. It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. Markers of DNA damage increase in the brain with age, and genetic progeroid diseases caused by defects in DNA damage repair (DDR) are associated with neurodegeneration and premature aging. While analysis of human bulk brain DNA, comprised of multiple proliferative and non-proliferative cell types, revealed an accumulation of mutations during aging in the human brain, it is not known whether permanent somatic mutations accumulate with age in mature neurons of the human brain. Here, we quantitatively examined whether aging or disorders of defective DDR results in more somatic mutations in single postmitotic human neurons.
Somatic mutations that occur in postmitotic neurons are unique to each cell, and thus can only be comprehensively assayed by comparing the genomes of single cells. Therefore, we analyzed human neurons by single-cell whole-genome sequencing (WGS). Since alterations of the prefrontal cortex (PFC) have been linked to age-related cognitive decline and neurodegenerative disease, we analyzed 93 neurons from PFC of 15 neurologically normal individuals from ages 4 months to 82 years. We further examined 26 neurons from the hippocampal dentate gyrus (DG) of 6 of these individuals because the DG is a focal point for other age-related degenerative conditions such as Alzheimer's disease. Finally, to test whether defective DDR in early-onset neurodegenerative diseases is associated with increased somatic mutations, we analyzed 42 PFC neurons from 9 individuals diagnosed with the progeroid diseases Cockayne syndrome (CS) and Xeroderma pigmentosum (XP).
Our analysis revealed that somatic single-nucleotide variant (sSNVs) accumulated slowly but inexorably with age in the normal human brain, a phenomenon we term genosenium, and more rapidly still in progeroid neurodegeneration. Within one year of birth, postmitotic neurons already have ~300-900 sSNVs. Three signatures were associated with mutational processes in human neurons: a postmitotic, clock-like signature of aging, a possibly developmental signature that varied across brain regions, and a disease- and age-specific signature of oxidation and defective DNA damage repair. The increase of oxidative mutations in aging and in disease presents a potential target for therapeutic intervention. Further, elucidating the mechanistic basis of the clock-like accumulation of mutations across brain regions and other tissues would increase our knowledge of age-related disease and cognitive decline. CS and XP cause neurodegeneration associated with higher rates of sSNVs, and it will be important to define how other, more common causes of neurodegeneration may influence genosenium as well.