Suggesting that Calorie Restriction Primarily Operates on Mitochondrial Function

Mitochondrial damage is important in aging, and a range of evidence suggests it to be perhaps the most important contribution to aging. You might look at the membrane pacemaker theory of aging for example, which points to differences in susceptibility to mitochondrial damage between similar species with divergent life spans, where greater damage resistance correlates to longer life spans.

Mitochondria damage themselves quite readily in the course of the normal operations. They generate the fuel used by other cellular processes, and in the course of doing so also create a flurry of oxidizing compounds - free radicals - that can react with and harm protein machinery. There are natural antioxidant compounds localized to the mitochondria that slow this process down by getting to the free radicals first. Researchers have shown that life span in mice can be extended by boosting the presence of some of these compounds.

It works the other way too; removing or mutating SOD1, one of these antioxidants, shortens mouse life span. Here is an interesting demonstration showing that calorie restriction reverses this effect. That suggests that, while researchers have shown that the benefits of calorie restriction depend on the cellular recycling process of autophagy in some species, the primary mode of operation might be to alter mitochondrial function. Perhaps this occurs through an enhanced autophagic recycling of damaged mitochondria, but other mechanisms are possible:

Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the anti-aging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1-/- mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage.

We found that dietary restriction increased the life span of Sod1-/- mice 30%, returning it to that of wild type, control mice fed ad libitum. Oxidative damage in Sod1-/- mice was markedly reduced by dietary restriction. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1-/- mice fed the dietary restricted-diet compared to Sod1-/- mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver specific pathology, the burden and severity of both neoplastic and non-neoplastic lesions was also significantly reduced in the Sod1-/- mice fed the dietary restricted-diet.

These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1-/- mice that arises from increased oxidative stress/damage.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23459073

Comments

mm, but CR extends the LS of just about every mouse by 30%. So no matter what mechanism(s) CR uses to extend LS should give the same affect here. If SOD1-/- mice lived 70% shorter than WT and CR rescued that completely, then this would be a more convincing argument that CR operates largely through attenuating oxidative stress.

Posted by: Oki at March 7th, 2013 5:23 PM

Rather than viewing ROS as just unfortunate metabolic byproducts, it may be that mitochondrial ROS flux is a pacemaker for development and differentiation. See, for example -

"Mitochondrial involvement in stemness and stem cell differentiation"
http://www.trnres.com/ebook/uploads/loucontent/T_13391546636%20Lou.pdf

It may be a better strategy to interfere with ROS signaling function instead of ROS production.

Posted by: Lou Pagnucco at March 7th, 2013 6:18 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.