A counter-intuitive proposal for a mechanism of lifespan extension comes from Schulz et al., who contend that glucose restriction extends worm lifespan by increasing mitochondrial respiration and thereby the production of reactive oxygen species (ROS).
Wait, you thought that ROS were deleterious? Welcome to the topsy-turvy world of hormesis, the biological equivalent of Was mich nicht umbringt, macht mich stärker, in which a little bit of a bad thing is actually a very good thing. Hormesis is observed in a variety of stress responses, following the general template that low “priming” doses of some stress can increase resistance to subsequent higher “challenge” doses. In the life extension business, some view exercise as a hormetic stress, pushing the body’s limits so that those limits might be further expanded in future; calorie restriction itself has already been proposed to act via hormesis.
Here, the authors propose that decreased glucose causes worms (their model organism) to rely increasingly on mitochondrial respiration. More flux through the mitochondria means more production of ROS. Chronic production of ROS, usually thought to cause aging, here results in hormetic protection — at least, in the authors’ model. In support of their theory, various types of antioxidants actually prevent the life extension that results from glucose deprivation.
I’m going to admit that I find this confusing. “The” mechanism of hormesis (which may or may not be unitary; hence the quotes) is not yet well understood; one can imagine that goosing the machinery of a given stress response machinery might potentiate it in some way, or that low-level activation of a stress response pathway might end up stocking the cell with various sorts of protective molecules (ranging from chaperones or antioxidant enzymes to noncatalytic “cushions” like trehalose).
Usually, however, hormesis comes from acute exposure to stress: even if it’s repeated, there’s a chance for the cells (or the body) to recover before the next challenge. What I’m having a tough time wrapping my head around is how a chronic stress (i.e., elevated ROS levels resulting from lifelong glucose deprivation) could protect the body from another chronic stress that is essentially identical (i.e., elevated ROS levels pursuant to aging). For the model to hold true, it seems that either the system must be exquisitely tuned and the authors were lucky to hit a very narrow “sweet spot”, or ROS production must be increasing resistance to other stresses that are more relevant to C. elegans lifespan than oxidation.