Fight Aging!

Beyond the risk of cancer, does random mutational damage to nuclear DNA provide a significant contribution to degenerative aging? Mutation counts rise with age, but if it was a case of every cell becoming a little mutated over the course of its duties before it is replaced, than it would be fairly clear that nuclear DNA damage isn't all that important. The vast majority of single mutations have little significant effect within the cell in which they occur, and that cell is just one of countless others. Cells divide, however, and thus mutations spread. Mutations in stem cells and other prolific cell populations can lead to large numbers of cells carrying the same mutation, and even in youth our bodies are a patchwork of such mutant populations.

Is this process of clonal expansion of mutations throughout tissues important in aging, beyond cancer? Does it cause sufficient metabolic disarray over the present human life span to be counted alongside the other contributions to aging? Or would it only cause issues once we have removed those other contributions, and thus live far longer? The consensus is yes, nuclear DNA damage is significant over the present human life span, but definitive proof of that position is elusive. There is plenty of evidence for either side of the debate. In the article here, the focus is on populations of clonally expanded mutant cells specifically in the brain, and whether they might contribute to neurodegeneration.

The results are suggestive, supporting a role for clonally expanded mutant populations in neurodegenerative disease. This is true of other work as well. It remains the case that the next step in any of this research is to figure out how to do better than suggestive results, to produce a compelling proof or disproof of the hypothesis. This will likely require gene therapy technologies that are somewhat more advanced than the present state of the art, but precision approaches with good cell coverage and tissue specificity will arrive in the next decade or two. That may be enough to enable proof of principle animal studies in which localized mutations can be created or removed to a some degree.

Islands of Mutated Neurons Dot the Brain. Are They Bad for Us?

Researchers have long suspected that the brain contains a genomic patchwork of cells harboring mutations that arose at different stages of development. These variants have even been tied to a handful of sporadic cases of neurodegenerative disease. However, due to the localized nature of these mutations throughout the brain, tracking them down, let alone investigating their involvement in disease, requires cutting-edge sequencing, cell isolation, and computational techniques. Using single-cell sequencing, a recent study estimated that each cell in the brain harbors 200-400 somatic mutations that arose during brain development, while another study reported around 1,500 per post-mitotic neuron. The mutation rate of human neurons also reportedly ramps up with age. Yet the cumulative impact of these mutations, and how many cells harbor each one, remains uncertain.

To address these questions, researchers employed ultra-deep sequencing of 56 genes linked to neurodegenerative disease in different regions from postmortem brain samples. The scientists resequenced each sample more than 1,000 times, allowing them to detect variants with high specificity and sensitivity, even for genes that are typically extremely difficult to sequence. Then, using a computational model of brain development, they used their findings to estimate the burden of somatic variation in the entire brain. In all, the researchers found 39 somatic variants among 44 of the 173 brain samples that were taken from from 54 post-mortem brains. Eight variants were in neurodegenerative disease-related genes.

The researchers next sought to extrapolate their findings to estimate the burden of variants in neurodegenerative disease-related genes across the entire brain. Using a cellular barcoding technique, they estimated they had sequenced DNA from around 611,000 cells. They were also able to estimate the proportion of cells in any given region that carried a somatic mutation in a neurodegenerative disease-related gene.

They fed this data into a statistical algorithm that simulated brain development to predict the total number and distribution of mutated cells among the estimated 86 billion in each brain. The answer: 100,000 to 1 million cells carry a somatic mutation in a disease-related gene. Incorporating information about how cells divide, differentiate, and mutate during development, the algorithm also foretold that each person likely had one large island of 10,000 to 100,000 cells that grew from one original mutation in a disease gene, while 10 percent of people had at least one island of more than 200,000 such cells. In addition, each brain contained 75 to 481 smaller islands, each consisting of just more than 100 descendants of a cell carrying a pathological variant. The researchers speculated that these islands of somatic variants trigger sporadic neurodegenerative disease, which reportedly affects roughly 10 percent of the human population.