One of the major challenges in aging research is determining whether or not models of cellular or organismal damage and its consequences are in any way relevant to the natural processes of aging. One can hit a brick with a hammer, but that says very little about how bricks weather over the years. One can hit the brick very carefully with the hammer in ways that produce results that look weathering-like, but can that be used to tell us anything about weathering? In cells the line between artificial and natural damage can be hard to pin down, but the fine details of the processes involved always matter. It is easy to break cells and see them become dysfunctional as a result, but hard to determine the relevance of that breakage to natural aging. Even in the example here, in which researchers are trying to achieve something very similar to the consequences of excessive oxidative damage in mitochondria that is observed in aging, it is possible to argue that the methodology used has little relevance to the actual damage of aging in its details, and therefore may not be a useful model.
Researchers have carried out a causal experiment to kick off a mitochondrial chain reaction that wreaks havoc on the cell, all the way down to the genetic level. "I like to call it 'the Chernobyl effect' - you've turned the reactor on and now you can't turn it off. You have this clean-burning machine that's now polluting like mad, and that pollution feeds back and hurts electron transport function. It's a vicious cycle." The researchers used a new technology that produces damaging reactive oxygen species - in this case, singlet oxygen - inside the mitochondria when exposed to light. "That's the Chernobyl incident. Once you turn the light off, there's no more singlet oxygen anymore, but you've disrupted the electron transport chain, so after 48 hours, the mitochondria are still leaking out reactive oxygen - but the cells aren't dying, they're just sitting there erupting."
At this point, the nucleus of the cell is being pummeled by free radicals. It shrinks and contorts. The cell stops dividing. Yet, the DNA seems oddly intact. That is, until the researchers start looking specifically at the telomeres - the protective caps on the end of each chromosome that allow them to continue replicating and replenishing. Telomeres are extremely small, so DNA damage restricted to telomeres alone may not show up in a whole-genome test, like the one the researchers had been using up to this point. So, to see the genetic effects of the mitochondrial meltdown, the researchers had to light up those tiny endcaps with fluorescent tags, and lo and behold, they found clear signs of telomere fragility and breakage. Then, in a critical step, the researchers repeated the whole experiment on cells with inactivated mitochondria. Without the mitochondria to perpetuate the reaction, there was no buildup of free radicals inside the cell and no telomere damage.
Link: https://www.upmc.com...pnas-van-houten
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