Damaging the Biology of Mice to Make them Age More Rapidly Often Tells Us Little of Use

Posted: August 25, 2013 at 2:53 am

Aging is damage: it is the accumulation of broken and obstructed protein machinery and nanoscale structures inside and around our cells. Living beings come with many varied repair systems, so the processes by which damage grows and eventually overwhelms those repair systems is far from straightforward. In that sense aging isn't like the wearing of stone by the weather, or the failure of a non-repairing mechanical system like a car - but it's still all about damage. At the highest level the same mathematical models of damage and component loss that work just fine as aids to understanding failure in complex non-repairing systems like electronics also work just fine for aging.

Every so often a research group feels the need to publicize work in which they damage mice or other laboratory species in ways that cause them to live shorter lives. There are many very subtle ways to alter genes, such as those involved in DNA repair, that produce what is arguably accelerated aging. (Though not everyone thinks that these forms of life span reduction are in fact accelerated aging, but that's a debate for another time and place). The point here is that I think you have to beware of taking it at face value that these research results are relevant to normal aging, or relevant to extending healthy life. You can damage mice with a hammer if you so choose, and it will certainly shorten their life spans, but examining the results won't tell you anything about aging. Similarly, it's the case that near all of the possible ways of interfering in mouse biology via genes and metabolic operation in order to reduce life span are just as irrelevant.

Here is an example of this sort of thing: researchers are producing mice with additional damage in their mitochondria, a component of cellular biology known to be important in all sorts of metabolic processes, and considered to be important in aging, and showing that these mice don't live as long. I don't think that the authors can show that they've proved much of relevance to aging with this study as constructed, however, for the reasons noted above.

Mutations of mitochondrial DNA can hasten offspring's ageing process

In ageing research, mitochondria have been scrutinized by researchers for a long time already. The mitochondria in a cell contain thousand of copies of a circular DNA genome. These encode, for instance, proteins that are important for the enzymes of the respiratory chain. Whereas the DNA within the nucleus comes from both parents, the mitochondrial DNA (mtDNA) only includes maternal genes, as mitochondria are transmitted to offspring via the oocyte and not via sperm cells. As the numerous DNA molecules within a cell's mitochondria mutate independently from each other, normal and damaged mtDNA molecules are passed to the next generation.

To examine which effects mtDNA damage exerts on offspring, researchers used a mouse model. Mice that inherited mutations of mtDNA from their mother not only died quicker compared to those without inherited defects, but also showed premature ageing effects like reduced body mass or a decrease in male's fertility. Moreover, these rodents were prone to heart muscle disease.

As the researchers discovered, mutations of mtDNA not only can accelerate ageing but also impair development: In mice that, in addition to their inherited defects, accumulated mutations of mtDNA during their lifetime, researchers found disturbances of brain development. They conclude that defects of mtDNA that are inherited and those that are acquired later in life add up and finally reach a critical number.

To show relevance, you really need to demonstrate life extension - meaning repair mechanisms for mitochondrial DNA rather than damage mechanisms should be the focus. To shorten life spans through various forms of damage is unlikely to provide anything more than hints and inference when it comes to ways to extend life.

Source:
https://www.fightaging.org/archives/2013/08/damaging-the-biology-of-mice-to-make-them-age-more-rapidly-often-tells-us-little-of-use.php

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