Mutational Damage in Long-Lived Brain Cells Correlates with Age

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.



"Additionally, the researchers found that the portions of the genome that neurons used the most accumulated mutations at the highest rate, with help from collaborators at WuXi NextCODE."

This is a good target for current gene therapy vectors. Even though they can only carry small fractions of DNA and if we're talking about a handful of regions it should be quite possible to develop a therapy.

It's interesting though what could be a cause of mutation in post somatic cells beyond oxidative damage. Transposons maybe?

Posted by: Anonymoose at December 11th, 2017 7:58 AM

This clock-like accumulation of mutation called genosenium sounds a lot like epigenetic aging that different tissues undergo. Can someone explain the difference between these two types of aging?

Posted by: Biotechy at December 11th, 2017 2:47 PM

@Biotechy: Epigenetic changes occur in the decorations to DNA that control the pace of gene expression. They do not change protein structure.

Mutational damage is in the DNA structure that encodes for proteins, so the proteins produced are structurally different, or missing entirely as a result of deletion mutations.

It is more complicated than that simple division into two parts, though.

Posted by: Reason at December 11th, 2017 2:58 PM

Thanks, Reason. That makes it very clear to me. So a lot genosenium aging has to do with single and double-stranded mutations, which several genes act to repair such as SIRT1, SIRT6, PARP1, FOXO3A to name a few.

Posted by: Biotechy at December 11th, 2017 3:58 PM

@anonymoose these are post-mitotic mutations. Each neuron has a different set of mutations. You can't do anything about this with current gene therapy

Posted by: ale at December 11th, 2017 8:50 PM

Well actually the problem with fixing mutations in post mitotic cells with CRISPR was the fact post mitotic cells don't do homology directed repair. But that problem has been solved recently. The variety of the mutations are irrelevant when you use CRISPR as long as the guiding RNA can find it's target.

Really the aim of a therapy like that would be to deactivate or delete a sizable chunk of DNA with only general specificity and introduce a new one in it's place - CRISPR can do that.

The researchers didn't say how big of a region and how many of them we're talking about here, but it shouldn't be impossible in theory. George Church inserted 60 genes into a pig couple of years back.

This isn't all that different from what Aubrey is proposing with mitochondrial genes actually.

Posted by: Anonymoose at December 11th, 2017 11:27 PM

@anonymoose they didn't specify a region because they aren't specific regions. They are semi-random mutations all over the genome. You would need to substitute in the whole genome piece by piece.

Figure 2 on the paper seems to indicate a couple of thousand per neuron, but again, these are post-mitotic SNVs so each one will have a different set.

Posted by: ale at December 12th, 2017 5:45 AM

You seem to be misunderstanding what I mean on purpose.
First of all - why the hell repair the whole genome?
The whole genome isn't operational. A completely random mutation sans cancer doesn't do anything.
Secondly, why repair genes not critical to neuron operation? It would be a waste of time.

Repair the regions of coding DNA getting hit the hardest and be done with it.
Some regulatory regions might be important as well but, this is a question of efficiency.

I'll post the quote again:
"Additionally, the researchers found that the portions of the genome that neurons used the most accumulated mutations at the highest rate, with help from collaborators at WuXi NextCODE."

Unfortunately I can't read the paper currently but going from mainstream knowledge, it's not like brain cells would accumulate most of the random mutations in adulthood. Most of the random load would happen during development - while neurons are still dividing. And significantly slower later on, mostly from ROS.

Most brains operate perfectly fine with the initial accumulation of mutations, so it's safe to assume there is a specificity in regions hit in the case of disease. And there is a high chance the predisposition to neurodegeneration is determined early on in development when mutations can take over large areas of the brain.

That being said, I expect most problems in the brain come from loss of neurons in general, and from mitotic neurons, rather than non dividing ones. I was just musing over a possible therapy in the off chance causation to disease is proven at some point rather than correlation.

Posted by: Anonymoose at December 12th, 2017 8:59 AM

One research article estimated there are 10 DNA breaks per cell every day on average. Because you have a couple trillion cells in your body, it is a huge task to repair every single-stranded and double-stranded DNA break in your entire body. Thus, I think we have to rely on our DNA repair genes to fix the damage. Unfortunately, the repair genes slow down with aging, so much DNA does not get repaired in the elderly. Many of these repair genes and enzymes require energy to operate and fix broken DNA strands. And, of course, the repair genes have to be activated by other genes like SIRT1.

Posted by: Biotechy at December 12th, 2017 2:16 PM
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