Ongoing Exploration of Mitochondrial Uncoupling

Mitochondria are the power plants of your cells: they toil to turn food into ATP, used as fuel by the cell. In recent years, the eye of the research community has turned towards the process of mitochondrial uncoupling, whereby the processing of food is uncoupled from the generation of ATP. The result is less ATP and more energy in the form of heat - this is a part of the temperature regulation process in mammals, for example. It also appears to be important in calorie restriction, and therefore possibly important to longevity and aging.

Research is still in full swing, however, and the vision of how mitochondrial uncoupling fits into the big picture of metabolism and aging is present incomplete. A number of natural uncoupling proteins (such as UCP1, UCP2, and UCP3) as well as manufactured uncoupling drugs like DNP have been investigated with contradictory results. The following items provide a sampling of the confusion.

Mitochondrial Uncoupling and Tissue Aging:

Mitochondrial uncoupling is much as it sounds; a feedback mechanism in which processing is disconnected from ATP production; energy from food goes elsewhere, as heat for example. Because this affects free radical production, it seems to be important in tissue aging: "Faster aging is predicted in more active tissues and animals because of greater reactive oxygen species generation. Yet age-related cell loss is greater in less active cell types, such as type II muscle fibers. Mitochondrial uncoupling has been proposed as a mechanism that reduces reactive oxygen species production and could account for this paradox between longevity and activity. ... These results reject respiration rate as the sole factor impacting the tempo of cellular aging. Instead, they support mild uncoupling as a mechanism protecting mitochondrial function and contributing to the paradoxical longevity of the most active muscle fibers.

More Building of Better Mice:

We were a little bit disappointed because we had hoped uncoupling in muscle would slow aging, but maximum lifespan didn't increase. However, the odds of reaching that maximum lifespan did improve in the uncoupled mice. ... mice with [increased UCP1] were more likely to live longer, presumably because they were able to avoid age-related diseases. One result appeared in all of the experiments: Decreasing body fat and inflammation in the animals by accelerating muscle metabolism with uncoupling protein delayed death and diseases, including atherosclerosis, diabetes, hypertension and even cancer.

Ouroboros On Mitochondrial Uncouplers:

The DNP treated mice ate the same amount of food as control mice but had lower body mass [and] showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. ... Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan.

Uncoupling extends life, except that it doesn't - depending on how you go about it, which suggests that greater complexity is, as always, hidden under the hood. I noticed a paper today that adds weight to the negative side, though in a way that leaves the door open for further ambiguity:

Characterization of survival and phenotype throughout the life span in UCP2/UCP3 genetically altered mice:

In the present investigation we describe the life span characteristics and phenotypic traits of ad libitum-fed mice that overexpress UCP2/3 (Positive-TG), their non-overexpressing littermates (Negative-TG), mice that do not express UCP2 (UCP2KO) or UCP3 (UCP3KO), and wild-type C57BL/6J mice (WT-Control). We also included a group of C57BL/6J mice calorie-restricted to 70% of ad libitum-fed mice in order to test partially the hypothesis that UCPs contribute to the life extension properties of CR.

Mean survival was slightly, but significantly, greater in Positive-TG, than that observed in Negative-TG or WT-Control; mean life span did not significantly differ from that of the UCP3KO mice. Maximal life span did not differ among the ad libitum-fed groups. Genotype did not significantly affect body weight, food intake, or the type of pathology at time of death.

Calorie restriction increased significantly mean and maximal life span, and the expression of UCP2 and UCP3. The lack of difference in maximal life spans among the Positive-TG, Negative-TG, and UCP3KO suggests that UCP3 does not significantly affect longevity in mice.

So, to summarize that last paper: calorie restriction increases UCP2 and 3 - which is one of the reasons that aging researchers become interested in the uncoupling process - but getting rid of UCP2 or UCP3 entirely doesn't seem to do much. There is an agreement that more uncoupling helps resist age-related degeneration to some degree without extending maximum species longevity. Questions remain as to whether uncoupling is important in calorie restriction, and how DNP is extending longevity if uncoupling proteins have no effect in that regard.


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