On the Road to Measuring the Mutational Damage of Aging
Researchers are now able to compare the mutational damage to nuclear DNA in individual long-lived cells such as neurons, which is a step towards measuring how much of this damage there is and how it varies over time and from cell to cell. That in turn is a step towards getting a handle on whether or not this damage has any meaningful effect over the course of a human life span beyond raising the risk of cancer. For example is the presence of stochastic mutational damage causing large enough alterations in the day to day operation of metabolism across enough cells to matter? There is some debate on this issue, and certainly a lack of good enough data to nail down a proof one way or another.
A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research. The majority of these mutations appear to arise while genes are in active use, after brain development is complete. "We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated." It's not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease.Cells of many shapes, sizes, and function are intimately intertwined inside the brain, and scientists have wondered for centuries how that diversity is generated. Scientists are further interested in genome variability between neurons due to evidence that mutations that affect only a small fraction of cells in the brain can cause serious neurological disease. Until recently, however, scientists who wanted to explore that diversity were stymied by the scant amount of DNA inside neurons: Although researchers could isolate the genetic material from an individual neuron, there was simply not enough DNA to sequence, so cell-to-cell comparisons were impossible. However, technology has become available in the last few years for amplifying the full genomes of individual cells. With plenty of DNA now available, the scientists could fully sequence an individual neuron's genome and scour it for places where that cell's genetic code differed from that of other cells.
The scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. For comparison, the scientists also sequenced DNA that they isolated from cells in each individual's heart. What they found was that every neuron's genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell. What's more, the nature of the variation was not quite what the scientists had expected. "We expected these mutations to look like cancer mutations, in that cancer mutations tend to arise when DNA is imperfectly copied in preparation for cell division, but in fact they have a unique signature all their own. The mutations that occur in the brain mostly seem to occur when the cells are expressing their genes. To what extent do these mutations normally shape the development of the brain, in a negative way or a positive way? To what extent do we have a patch of brain that doesn't work quite right, but not so much that we would call it a disease? That's a big open question."
Link: http://www.hhmi.org/news/study-examines-scale-gene-mutations-human-neurons
This should come as a surprise to exactly no one after the MIT revelations that neurons break and reform their own DNA in the process of learning.
Am I correct in thinking that if DNA mutations do matter in aging beyond cancer then the SENS research foundations approach is sunk?
@Jim: Not necessarily. The forms of aging damage they're aiming to treat can still be far more significant and immediate factors in one's overall health. The hope is that we'll live long enough by fixing these to be around for when we figure out how to fix DNA, too.
And just because DNA damage might be a problem doesn't mean that glucosepane, amyloids, and mitochondrial damage magically go away. It's just one more thing to fix.
@Jim: You are correct. This is to a first approximation the worst possible news that could have arisen out of current medical research with respect to the SENS program.
Mutations associated with errors of replication, even if detrimental to health, are not disastrous to the SENS concept. Such cells could be replenished from stem cells lacking the mutations. The existence, however, of many mutations associated with gene expression in critical populations of non-dividing cells constitutes a crisis for the SENS approach.
I am left to hope there has been some kind of error.
Hi Jim,
First, there's no question in our minds but that DNA mutations (and epimutations too) do matter in aging beyond cancer: the question is when, how, and what the actual biomedical implications are. Within the frame of a currently-normal lifespan, they matter by generating classical senescent cells and causing apoptosis. We can eliminate the functional effects of this damage without having to go so far as to repair the underlying (epi)genetic damage itselfby ablating senescent cells and cell therapy — and, in the case of cancer, by ablating the telomere-maintenance machinery as the ultimate cancer prophylactic.
The question is what happens once all of that damage is removed, replaced, or rendered harmless. There's little doubt that (epi)mutations will eventually accumulate to levels that actually impair tissue function and thus lead to age-related disease and debility for reasons other than the above: the question is when, and what to do about it then. On current evidence, it appears that they have no such effects within the frame of a currently-normal lifespan, and therefore we can put off that question until we have achieved the first comprehensive panel of rejuvenation biotechnologies. At that point, we'll be able to rejuvenate various model organisms as well as we can humans (indeed, we'll have had rejuvenated mice for a couple of decades or more); studying these animals as they age with their first-generation damage repaired will let us see what kind of functional effects (epi)mutations have in rejuvenated, longer-lived mammals within that longer timeframe. We'll have more time to develop strategies to counteract them, because rejuvenated humans will live far longer lives in absolute terms than rejuvenated mice.
If, however, it turns out that they have substantial functional effects within the frame of a currently-normal lifespan, then we need to do that work now so that the first SENS panel is truly comprehensive. The nature of such strategies would depend on the exact functional effects they have: as noted above, we can deal with three such effects indirectly, by removing, replacing, and rendering harmless three of the three downstream functional effects of (epi)mutations known today.
But even direct repair is amenable to the SENS "damage-repair" strategy, such as by "strong" nanotechnology (molecular nanotechnology/atomically precise manufacturing). Indeed, conceptually, direct repair is the most straightforward approach to such damage. But in practice, of course, direct repair would be extremely challenging from the current state of biomedical science, so obviously we'd be in a more comfortable position if either our current thinking is correct, or if any additional emerging effects are remediable by similar indirect means as senescent cells, apoptosis, and cancer with existing or near-term-foreseeable biotechnology.
Ah, I see several others crowded in as I was composing a reply. Slicer's, Seth's, and José's comments are all cogent, although José has highlighted the most challenging scenario.
I wonder if peri-mortem stress might have contributed to the observed mutations? In that case the apparent damage associated with gene expression could be something other than a gradual, life-long process.