Screening for Stress Resistance Mutations in Mice

The open access paper quoted below provides some insight into increasing sophistication of the work involved in identifying longevity-related genes and proteins in mammals. Many of these have been discovered over the past twenty years, leading to numerous ways to alter the operation of metabolism in order to slow aging and thus extend healthy life. This should probably be considered a part of the bigger picture of progress towards a better understanding of the fine details of biochemistry, however, and not a stepping stone to longer lives for you and I. Slowing aging by building a better metabolism is not a great strategy at this point in time in comparison to working on repair of damage. Researchers know much more about the damage that causes aging than they do about metabolism, so the choice is between easier and more promising lines of research versus much harder work that will produce far less useful results.

Unfortunately for us, since scientists are in the business of gaining knowledge rather than changing the world, most research is in fact directed towards the harder work that will do little to produce meaningful treatments for aging. That is why we need advocacy and grassroots fundraising programs and organizations aimed at changing the strategic direction of aging research.

Longevity is correlated with stress resistance in many animal models. However, previous efforts through the boosting of the antioxidant defense system did not extend life span, suggesting that longevity related stress resistance is mediated by other uncharacterized pathways. We have developed a high-throughput platform for screening and rapid identification of novel genetic mutants in the mouse that are stress resistant. Selection for resistance to stressors occurs in mutagenized mouse embryonic stem (ES) cells, which are carefully treated so as to maintain pluripotency for mouse production.

Initial characterization of these mutant ES cells revealed mutations in Pigl, Tiam1, and Rffl, among others. These genes are implicated in glycosylphosphatidylinositol biosynthesis, NADPH oxidase function, and inflammation. These mutants: (1) are resistant to two different oxidative stressors, paraquat and the omission of endogenous reactive oxygen species (ROS), (3) are capable of generating live mice, and (4) transmit the stress resistance phenotype to the mice. This strategy offers an efficient way to select for new mutants expressing a stress resistance phenotype, to rapidly identify the causative genes, and to develop mice for in vivo studies.


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