Mittwoch, 13. Mai 2015

The oxidative stress theory of aging - concepts and limitations

What do we know about the involvement of oxidative stress in disease?
Definitely not enough. The speakers at MiP-School London reminded us that researchers use the term "ROS" as explanation to hide behind with little explanatory value. Berry Halliwell (3,4) and Mike Murphy (6) gave fascinating talks on this topic. I would like to add a more biogerontologic perspective.

A deep mechanistic understanding of how ROS regulate lifespan might be called for, but I don't think we should over-emphasize detailed understanding in the field of aging as a whole. Gerontology is difficult. There are enough basic questions still unanswered. (Is calorie restriction a universal mechanism? Are current models of mouse lifespan extension redundant/convergent? etc.)

Historically, progress has come from rather crude phenotypic screens. Calorie-restriction was discovered before the Second World War, using mice without fancy molecular biology. To me, the whole Interventions Testing Programme is one big, naive phenotypic screen (readout = dead mice). The rationale for some of the tested compounds is almost cringe-worthy. Guess what? It's the most successful programme in the world, yielding multiple promising leads. Particularly, Rapamycin. To propose a test of rapamycin as a CR-mimetic we do not need to understand the underlying biology in any detail. Unsurprisingly, the first data on the mTOR pathway was generated using simple phenotypic screens in yeast and 6 years after the rapamycin lifespan study in mice, we still do not understand the mTOR pathway very well. The big invention by the ITP, and others like Spindler, were perfect animal husbandry combined with a modicum of understanding.

Given how little we understand about aging, the naive phenotypic screen will remain a worthwhile strategy. Knowing "just enough" is often quite useful. However, the naive approach to the oxidative stress theory of aging has produced conflicting results. Is it time to re-consider some of the basics?