Oxidative hormesis: Everything bad is good again

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.

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2 comments

  1. I found this very confusing. You would think a restriction in energy would slow it. But then I figure… since it has to draw on its own fat stores for energy (worms have fat too right?) since fat can only be consumed aerobically, that would explain greater respiration.

    How greater respiration extends life is still confusing though. Does this mean that anaerobic energy production is both more damaging in addition to being less efficient?

  2. I am also trying to rectify the contents of this article with existing knowledge. Their key statement is, “…impaired glucose metabolism extends life expectancy by inducing mitochondrial respiration.” For respiration to occur, a mitochondrion needs pyruvate (the product of glycolysis). Without glycolysis, fat must be broken down to get the pyruvate. For fatty acid oxidation, you need activation of the AMP-dependent kinase pathway. Paraphrasing from Schulz et al., ‘Disruption of AMP-dependent kinase abolishes this extended life expectancy due to impared glycolysis.’ The requirement of fatty acid oxidation for this mode of enhanced longevity is consistent with the role of AMK. [Without AMK or glycolysis, I suppose the pyruvate/glucose comes from gluconeogenesis.]

    Basically, restricted glucose results in increased everything else: fatty acid oxidation, mitochondrial respiration, generation of ROS, production of antioxidants to combat the ROS, and longevity. Still, why does restricted glucose result in greater mitochondrial respiration at all? If glucose is plentiful, yet respiration is depressed, presumably the excess pyruvate is going to fat storage? And what happens if you’re getting just the right amount of glucose? How does hormesis relate to homeostasis?

    just the right amount of glucose -> glycolysis, no net fat storage, and intermittent mito. respiration -> ? ROS ? -> ? protection against ROS ? -> ? longevity ?

    It could be that we’re obscuring things by delving too deeply into metabolite analysis. I suspect, if Schulz et al. are correct, that epigenetics are involved: less glucose could *directly* cause greater expression of genes whose products fight the increased ROS, rather than those genes being expressed in response to increased ROS, or decreased glycolysis, or increased fatty acid oxidation, or whatever. The fact is, in times of scarce resources, it benefits an organism to live longer so that it has more opportunity to procreate. So instead of trying to tweak its metabolism, the cell whacks the whole system with a flood of antioxidants (and who knows what else — telomerase maybe?) in an effort to stay alive and healthy as long as possible.

    It’s an immensely complex system, and we’re only able to vary and monitor a few factors at a time. It’s linked not only to our cellular physiologies but to our perpetuation as a species. No wonder it doesn’t make sense.

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