In Cell, researchers have published a paper outlining the different ways in which brain cells slowly mutate with aging.
The genomic damage of aging
Cells accumulate mutations with aging, including brain cells [1]. However, as these researchers note, most previous research into these mutations has been on neurons rather than the glia, the helper cells that make up more than half of the brain’s mass and perform helpful and regulatory roles.
This study focuses on oligodendrocytes, which make up a large part of the white matter [2], are responsible for creating protective myelin sheaths around neuronal axons, and whose proper functioning is necessary for brain health over the human lifespan [3]. Problems with these cells have been associated with mental disorders [4], age-related brain diseases [5], brain tumors [6], and even the autoimmune disease of multiple sclerosis [7].
Unlike neurons, whose natural replenishment is limited, oligodendrocytes are regularly replenished through stem cells. Like many other processes, this replenishment diminishes with aging [8], and mutations in these cells can be responsible for some forms of brain cancer [9].
This study took a look at the mutational differences between neurons and oligodendrocytes, and it found significant, fundamental differences between them, even though these cells share the same microenvironment.
Indels and SNVs
A single-nucleotide variant (SNV) is the classically known form of mutation: one of the nucleotides in DNA changes into another one. An insertion or deletion (indel), on the other hand, refers to a section of DNA that is added to or deleted from the middle of an existing sequence.
The human brain donors in this study were from a very wide variety of ages, from babies to 83-year-olds. Using cells derived from these donors, the researchers found mutational signatures in both kinds of cells. While the technical procedures used to detect these signatures is not quite perfect, cross-checking through multiple methods determined that while oligodendrocytes accumulate 28% fewer indels than neurons, they accumulate 81% more SNVs. The gene-altering effects of the indels was found to be twice as powerful in neurons as in oligodendrocytes.
While there did not seem to be any individual genes that were significantly affected by this difference in mutation, the kinds of mutations that oligodendrocytes accumulate with age are the same ones associated with cancer, even if the cells themselves do not become cancerous.
A reason for the mutational differences
The researchers examined the cells’ origin and behavior more closely, and found that these mutational differences were, as expected, related to the natural reproduction of these cells. Olidogendrocytes and other glial cells, even from birth, can accumulate SNVs in the natural process of division. The majority of these changes were found to be present in non-coding regions rather than functional regions of DNA. Mature neurons, however, do not divide, and their indel mutations are associated with the process of transcription rather than replication, suggesting that their activity is primarily responsible for their mutations.
The cancerous mutations found in oligodendrocytes are hypothesized to be related to internal competition. Over time, the natural process of growth and development favors mutations that encourage more rapid growth, and these pro-replication mutations, unsurprisingly, are related to cancer. Because mature neurons do not divide, this process does not happen in them, and neural stem cells divide much more slowly.
The researchers also hypothesize that the DNA repair process is less efficient in SNVs than in neurons. However, this study did not include any direct measurements of DNA repair, and they hope that future studies will address this question.
This study also focuses on causes rather than any potential solution. It is likely that any solutions to this fundamental aspect of biology must involve stem cell replenishment or gene editing of a kind that is not yet feasible in human beings. In the short term, it appears that avoiding mutation-inducing toxins or other exposures is the best way to hope to stave off age-related brain cancer.
Literature
[1] Lodato, M. A., Rodin, R. E., Bohrson, C. L., Coulter, M. E., Barton, A. R., Kwon, M., … & Walsh, C. A. (2018). Aging and neurodegeneration are associated with increased mutations in single human neurons. Science, 359(6375), 555-559.
[2] Von Bartheld, C. S., Bahney, J., & Herculano‐Houzel, S. (2016). The search for true numbers of neurons and glial cells in the human brain: A review of 150 years of cell counting. Journal of Comparative Neurology, 524(18), 3865-3895.
[3] Bennett, I. J., & Madden, D. J. (2014). Disconnected aging: cerebral white matter integrity and age-related differences in cognition. Neuroscience, 276, 187-205.
[4] Nagy, C., Maitra, M., Tanti, A., Suderman, M., Théroux, J. F., Davoli, M. A., … & Turecki, G. (2020). Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons. Nature neuroscience, 23(6), 771-781.
[5] Kang, S. H., Li, Y., Fukaya, M., Lorenzini, I., Cleveland, D. W., Ostrow, L. W., … & Bergles, D. E. (2013). Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nature neuroscience, 16(5), 571-579.
[6] Liu, C., Sage, J. C., Miller, M. R., Verhaak, R. G., Hippenmeyer, S., Vogel, H., … & Zong, H. (2011). Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell, 146(2), 209-221.
[7] Chang, A., Tourtellotte, W. W., Rudick, R., & Trapp, B. D. (2002). Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. New England Journal of Medicine, 346(3), 165-173.
[8] Sim, F. J., Zhao, C., Penderis, J., & Franklin, R. J. (2002). The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. Journal of Neuroscience, 22(7), 2451-2459.
[9] Ganz, J., Maury, E. A., Becerra, B., Bizzotto, S., Doan, R. N., Kenny, C. J., … & Walsh, C. A. (2022). Rates and patterns of clonal oncogenic mutations in the normal human brain. Cancer discovery, 12(1), 172-185.
