Saturday, September 24, 2011

Mitohormesis - Suffocated Mitochondria Live Longer: Scientists Probe Longevity-Effect of Low-Level Stressors.

Image 1: Walter Breuning died in April 2011at the biblical age of 114! And you bet that a man who has seen two world wars has had his share of mitohormetic stress in his life.
As a diligent reader of the SuppVersity you will be familiar with the work of S. Schmeisser and M. Ristow from the Department of Human Nutrition at the University of Jena, here in good old Germany (where not everyone eats Sauerkraut und Weisswurst, even now that the Oktoberfest is in full swing). In previous publications, the scientists have (at least in my mind conclusively) argued against the publicly accepted free-radical hypothesis of aging, which implies that the presence of free radicals is one of the fundamental mechanisms of aging. Now, a few month after the publication of their last review back in May 2011, they are presenting the latest results from their own lab in a paper that is going to be published in the October issue of Hormone and Metabolic Research (Schmeisser. 2011).

Want to live longer? Then you better put another log on the fire

Schmeisser, Zarse, and Ristow used lonidamine (LND), a indazole-3-carboxylic acid derivate, to inhibit cellular respiration in the infamous round-worm (Caenorhabditis elegans) model for aging processes (for a review on the pharmacology, biochemistry and toxicology of lonidamine see Silvestrini. 2008). In essence, they thusly made it more difficult for the cells to "breath", which as you may probably imagine, is a major stressor, which will inevitably increase the formation of purportedly dangerous free radicals (ROS) and should thus increase the aging process, if... yes, if there was any truth to the nonsensical idea that you better sit there, don't eat, don't drink, don't move - in essence - don't live to avoid any potential ROS formation, if you want to extend your lifespan... I guess, you as a self-educated SuppVersity reader won't be surprised that the roundworms did not only survive the "torture" (of life), but - after an initial mitohormetic response, i.e. an adaptational response to the the scientists' effort to suffocate their mitochondria (the initial reduction in oxygen consumption was -37 %!) - thrived on the purportedly life-shortening inhibitor of mitochondrial respiration!
Figure 1: Lifespan of C. elegans treated with 5┬ÁM lonidamine, n-acetyl-L-cysteine (NAC) or both (data calculated based on (Schmeisser. 2011)
As you can see in figure 1, the "pro-oxidant" treatment with lonidamine, of which Schmeisser's, Zarse's and Ristow's data shows that it increased respiration and thus mitochodrial ROS formation, increased both median as well as maximal life-expectancy of the nematodes (roundworms) by ~8% - an increase with statistical significance, as the p-value of p<0.001 (= chances that the increased lifespan observed in the study is just coincidence are <0.1%). The latter cannot be said of either the slight increase in maximal lifespan nor the slight decrease in median lifespan in the group of nematodes that was treaded with n-acetyl-L-cysteine (p=0.17; non-significant) or a combination of the anti-oxidant sulfur-amino acid and lonidamine (p=0.95; absolutely non-significant; cf. figure 1).

These observations may be considered further experimental "evidence" for Schmeisser's and Ristow's previously formulated mitohormesis theory ("evidence" in the sense that the results do not falsify their hypothesis - they do yet falsify the ROS hypothesis of aging). A theory that refutes the idea that the aging process is driven by reactive oxygen species and emphasizes (mitochondrial) adaptation processes to (external) stressors that strengthen, not weaken the organism in the long-run - or as the scientists phrase it:
[...] the induction of endogenous defense mechanisms as a secondary response to a stressful condition is assumed to contribute to longevity [...] a lifetime low dose oxidative stress with a subsequent secondary induction of defense mechanisms could delay the aging process
It is thus the interplay of manageable stress and metabolic adaptation which extends life and not an overall reduction of reactive oxygen species, as the vendors of some "super-potent" anti-oxidants would have you believe. What is still missing though, is a tool which would help us to identify the critical point, where the endogenous adaptation processes cannot keep pace with ever-increasing (mainly) exogenous stressors... in case any scientist finds an answer, I guess you will soon be able to download the respective app on your shiny new iPhone - I just hope that this app will account for the significantly (!) decreased glucose metabolism the iPhone itself will induce in the temporoparietal junction and anterior temporal lobe of the right hemisphere of your brain within less than 30 minutes (Kwon. 2011), as well.