The Aging Brain
Unglued
Rudolph Virchow (18—190-) is often referred to as “The Pope of Medicine”, for his multifarious groundbreaking discoveries that remain relevant to this day. He also mentored eminent biologists of various sorts, including two who are protagonists in the study of the rare cancer for which I have skin in the game, both literally and metaphorically (https://richardcfrancis.substack.com/p/this-strange-cancer-of-mine)
It was Virchow who also discovered (1856) the cells in the brain we call glia. We call them Glia, because that’s what Virchow christened them. He used the term neuroglia, which means nerve glue. The epithet, “glia”, is not one to excite interest in the study of these cells, and their brain functions were long neglected. Virchow himself viewed them as scaffolding or structural support for neurons. Yet Virchow also observed that his neuroglia were more subject to age-related deterioration than the neurons themselves. You might say that for Virchow the brain becomes progressively unglued with age.
We now know, as a result of an explosion in glia research, a glial revolution of sorts, that glial cells are a whole lot more than glue. Glia are in fact a sine qua none of proper brain functions. That message has even penetrated the artificial intelligence community, where there are efforts underway to make artificial intelligence more brain-like. (https://doi.org/10.1155/2012/476324). But Virchow’s initial discovery that glia are more age sensitive than neurons remains valid. The best way to determine age-related changes in a cell is through what is called the transcriptome, by way of analogy to the genome.
Transcriptome refers to transcripts (AKA messenger RNAs), products of the process called transcription, the first stage of gene expression. Messenger RNA is far less stable than DNA, which makes them harder to work with. But the genome (DNA sequences) tells us nothing, in and of itself, as to which particular genes are active at any given point in time, how the ensemble of activated genes vary by cell type (neuron, glia, skin cell etc.), cell state (just chillin or working hard) and cell age (newly born, mature, senescent).
When I was studying mRNAs, the state-of-the-art procedure was to remove tissue (thousands to millions of cells) from a particular area of interest, in my case the hypothalamus of the brain, centrifuge the cells into oblivion, cell-identity-wise, separate the mRNA transcript from every other cellular element, including DNA. Then, with radioactively labeled probes, measure the amount of one single kind of mRNA transcript, in my case, the mRNA transcript for gonadotropin releasing hormone (GnRH mRNA). In other words, the transcriptome could only be studied one transcript at a time. Soon thereafter, a technological advance made it possible to measure mRNA transcripts from thousands of different genes at the same time. That was the firs step in transcriptomics.
This technology can be used to measure age related changes in cells of a particular cell type, say neurons, by comparing the transcriptomes neurons from young and old brains. The relative rate at which neurons and glia age can also be measured in this way. That was the goal of a recent study of postmortem brains from individuals spanning 16—102 years of age, using neuron-specific and glia-specific transcriptome probes (28076797). The brain tissue came from 10 distinct regions of the forebrain (cerebral cortex plus subcortical areas including the limbic system.) Overall, the transcriptomes of neurons changed far less with age than did the transcriptomes of glial cells. As such, glial cell transcriptomes are better indicators of brain age than neurons. Put another way, glial cells are the first cells in the brain to senesce. As such, to ameliorate brain aging, we should start with the glial cells, figure out how to delay their senescence.
Of the several types of glial cells the one that is most sensitive to aging is a type of glia we have not yet met. That will be the subject of the next post in this series.