The Aging Brain: Is Misplaced DNA to Blame?

 BY DEREL LOWE

What is "aging", anyway? Everyone immediately knows what you mean when you refer to a person's body getting old, but what's really happening? That question has occupied a lot of researchers over the years, and things are slowly starting to become a bit more clear. And as we learn the details, there's a key shift in attitude that tends to come over you. Without thinking about it much, aging seems like it's inevitable, just something that happens, all the time to everyone, always has and always will. As the narrator of the late Martin Amis' The Information puts it, "Meanwhile, time goes about its immemorial work of making everyone look, and feel, like shit".

Hard to argue with that! But does it have to? Thermodynamically you can blame entropy, creeping disorder spreading through the system, and that really does seem to be what happens (see below). But living systems are not thermodynamically closed - we can in theory put energy into them and repair things, the same way that you can clean your kitchen when things start to pile up in the sink and on the counters. In theory. We actually do have plenty of repair mechanisms on a cellular level, and one of the features of aging is that the repair mechanisms themselves start to fail.

This new paper is a good illustration of what could be going on. The cGAS-STING pathway (which I wrote about here in the context of innate immunity) is constantly checking for the presence of double-stranded DNA out in the cytosol, because it really shouldn't be there. That would normally be the sign of a viral infection (viral DNA floating around), and that's how the body reacts to it (that STING name is short for "stimulator of interferon genes"). There are autoimmune diseases such as lupus where dsDNA gets spread around to the point that it sets off this inflammatory pathway. A lot of cGAS-STING research comes from that direction, and since immunotherapy is such a huge field in cancer treatment these days, this mechanism gets a lot of attention there, too.

Well, another condition that is characterized by a constant inflammatory response (apparently in the absence of infection as well) is. . .aging. It's a clear source of trouble in a number of different tissues - this has been recognized for some time now, and a great deal of work has gone into figuring out why this happens and what might be done about it. Several years ago it was recognized that the cGAS-STING system was a key part of the inflammation seen in microglial cells in the aging brain (and in the brains of people with neurodegenerative diseases). And this new paper has tracked down further details: the reason this inflammatory pathway has been set off is the leakage of DNA from damaged mitochondria in those microglial cells.

This same team had earlier reported small-molecule STING inhibitors, and they found that administering one of these compounds actually did interrupt the inflammatory cascade in a number of different tissues in mice, and specifically seemed to lead to improved cognitive function in aged mice across several different measurements. It's quite a striking effect, and naturally this immediately makes you wonder about using this as a therapy. STING, as mentioned, also seems to be involved in a number of specific neurodegenerative diseases (Alzheimer's, Parkinson's, ALS, frontotemporal dementia and more), and there are certainly possibilities there as well.

As the authors note, there are some broad connections to be made here, and some thing things that have to be differentiated. The biggest connection is between mitochondrial dysfunction (long investigated in the context of aging) and inflammation (likewise!) There really does seem to be a direct link between these two now because of this leakage of mitochondrial DNA into the cytosol. That's a big insight, not least because it places the mitochondrial trouble upstream of the inflammation. But that may not be universal - there are other situations where it could be genomic DNA that is setting off this response, and it doesn't have to be just in microglia, either (but rather in neurons, etc.) But a common theme is cGAS-STING, responding to aging cells as if they were under viral attack and never letting up on the response to it.

As this overview of the work notes, though, we're going to have to take these insights step by step. Mouse cells simply don't live as long as human cells, because mice don't, and insights into aging from a shorter-lived species may or may not translate to human effects (or at least the human effects that we'd like to see!) There's also the potential problem that when you dial down cGAS-STING, you are inevitably dialing down the response to viral infections. It may be that just in the same way that there appear to be tradeoffs between aging and cancer, there may be others between aging and the ability to deal with viruses. But let's find out!

https://www.science.org/content/blog-post/aging-brain-misplaced-dna-blame