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Mitohormesis and supplementation


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I've just read "Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)" [1], and am starting to worry about all the supplements many of us take.


I'd love to get others' views on this topic. Myself, I'd like to be as supplement-free as possible, but, obviously, many supplements wouldn't likely interfere with hormesis in a deleterious way.


It would be great if there were a way to measure the effect of supplements on mtDNA function -- well, there are ways, but I mean: a way that's not hugely expensive and is accessible to the average CR'er.




[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036400/

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First: whether they're right or wrong, the use of putatively antioxidant dietary supplements by CR practitioners simply falls out of it. It's not even really all that clear that most putative antioxidants reduce oxidative stress anywhere outside of the blood (and their effect is limited even there, and sometimes doesn't even manifest except under conditions of very high ox stress, such as smoking, diabetes, or intense physical exercise), and nearly no dietary antioxidant has ever been shown to interdict free radicals inside the mitochondria (mt): first, there are trafficking, colocalization, and coantioxidant issues, and second, ROS are short-lived and antioxidants by definition eager to sacrifice themselves, so if they're going to quench something its going to happen well before they reach the mt.


Second, they're wrong ;) . CR and other interventions may well increase mtROS production in C. elegans and Drosophila, but in mammals CR quite reliably reduces mtROS production in multiple tissues, and reduces the rate of accumulation of mtDNA deletions with age (in part through the aforementioned reduction in mtROS, and in part by reducing the content of DHA and other highly unsaturated fatty acids in the mitochondrial membrane (to which the mtDNA loop is physically attached, so that mtROS that hit the membrane initiate a lipid peroxide chain reaction that can ultimately propagate to and damage mtDNA).(1)


If you look through the paper, you'll see that while they talk about mice, all their actual evidence of mitohormetic effects are from C. elegans and Drosophila. I've said it many times before (and am copy-pasting it here):


Although you have no doubt seen many breathless press reports about studies done in simple model organisms like the roundworm C. elegans and the fruit fly D. melanogaster, which allegedly show us important things about the aging process, the fact is that we have to look at all such research with almost complete skepticism until it is replicated at least in a mouse, because the mechanisms driving aging in these organisms and the means that are effective to retard them, are quite different from those of mammals.


Fruit flies, for instance, don't develop cancer, their entire bodies are composed of postmitotic cells, don't have hearts or circulatory systems as they occur in mammals and thus don't suffer heart disease or atherosclerosis, they don't accumulate mitochondrial mutations as they age, and there are a zillion things (including many dietary and genetic antioxidant manipulations, or even putting the little pests in the 'fridge!) that extend their lives that just don't work in mammals.


Similarly for the roundworm: C. elegans' mature bodies are composed entirely of cells that don't divide, so they don't develop cancer; they don't have hearts or circulatory systems as they occur in mammals and thus don't suffer heart disease or atherosclerosis; they don't live long enough to accumulate mitochondrial DNA deletions, or several other key forms of molecular and cellular damage that contribute to aging in mammals; they almost always die of starvation due to failure of the muscles in their pharynx; and they have the capacity to enter into the "dauer state," a kind of deep suspended animation, when challenged with food withdrawal or a range of other stressors, which likely confounds any data on extended fasting periods.


Even studies in mice don't always translate directly to humans -- look at all the failed cancer drugs that cure the disease in mice -- but they're a much better start!


They also have a whole section on animals with impaired insulin/IGF-1 signaling, which (aside from not necessarily translating straight across the board to CR) says absolutely nothing 'mitohormetic' -- it's a bizarre non sequitur.





1: Pamplona R, Barja G. Highly resistant macromolecular components and low rate of generation of endogenous damage: two key traits of longevity. Ageing Res Rev. 2007 Oct;6(3):189-210. Epub 2007 Jul 13. Review. PubMed PMID: 17702671.

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