Mitochondrial uncoupling protein extends lifespan

One key source of aging — oxidative damage — comes form the very air that we breathe. Mitochondrial oxidative phosphorylation is essential for cellular ATP production, but inevitably results in the formation of reactive oxygen species (ROS), which in turn oxidize macromolecules including DNA.

We recently learned that mitochondrial uncouplers — compounds that cause proton leakage across the mitochondrial membrane and thereby separate oxidative phosphorylation from the electron transport chain — can reduce the production of ROS. Indeed, treatment with uncouplers reproduces many of the other hallmarks of calorie restriction (CR), including decreased steady-state oxidative damage to DNA and protein, lower blood sugar and triglycerides, and — crucially — extended lifespan.

Chemicals aren’t the only way to uncouple ox/phos from electron transport. Mammalian genomes encode uncoupling proteins (UCP), generally expressed in tissues involved in thermogenesis, such as the mitochondria-rich “brown fat” that maintains body temperature during rodent hibernation and proteins the brainstem of human infants. (When electron transport is uncoupled from the proton gradient, the lost energy is dissipated as heat.)

A new study has shown that expression of one specific UCP is associated with enhanced longevity and decreased oxidative stress in the mouse. From Andrews & Horvath:

Uncoupling Protein 2 regulates lifespan in mice

The long-term effects of uncoupled mitochondrial respiration by uncoupling protein 2 (UCP2) in mammalian physiology remains controversial. Here we show that increased mitochondrial uncoupling activity of different tissues predicts longer lifespan of rats compared to mice. UCP2 reduces reactive oxygen species (ROS) production and oxidative stress throughout the aging process in different tissues in mice. The absence of UCP2 shortens life span in wild type mice, and, the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals. Thus, UCP2 has a beneficial influence on cell and tissue function leading to increased lifespan.

The most surprising result is that UCP2 mutants have shorter lives, implying that mitochondrial uncoupling is a key mechanism for controlling oxidative stress throughout the lifespan.

The results from the genetic cross with the Sod2 mutant is consistent with what we already know about mitochondrial uncoupling: Without Sod2 (encoding mitochondrial superoxide dismutase), ROS production and oxidative damage increase, causing premature aging). Higher levels of UCP2 (resulting from overexpression) would cause uncoupling, which decreases the production of ROS, and in turn presumably decreases the oxidative load on the Sod2 mutant.



  1. I have read reports that flies and fruit flies expressing the human UCP2 gene have extended longevity. Caloric restriction upregulates UCP2 too, I believe.

    Overexpression of UCP2 apparently is not beneficial when at least some stressors are present. For example –

    It seems that there must be some fitness drawback to excess UCP2. Otherwise, numerous species would have acquired the trait.
    Is this related to the “Indy” mutation in fruit flies, or CLK-1 in mice?
    Are there any supplements that are mito-uncouplers (e.g., BHT)?

  2. But hang on: none of this shows that UCP2 “regulates longevity,” let alone that it “extends lifespan.” It shows a cross-species ASSOCIATION with longevity, which is an interesting hypothesis-generator, but nothing more; and it shows that knocking it out SHORTENS longeivity — but there’s not much that you can knock out of an animal that DOESN’T shorten longevity, at least in real-world conditions. “Premature aging” is a petitio principii; as Michael Rose concisely put it, “Until you show me that you
    can postpone aging, I don’t know that you’ve done anything. A lot of
    people can kill things off sooner, by screwing around with various
    mechanisms, but to me that’s like killing mice with hammers — it
    doesn’t show that hammers are related to aging.” See also Rich Miller’s “‘Accelerated aging’: a primrose path to insight?” (PMID: 15038817).

    If you want to show that UCP2 “extends lifespan” (or even “regulates longevity”), what you do is you selectively boost its activity, by pharmacological or transgenic means, and watch what happens.


    Exp Gerontol. 2008 Dec;43(12):1061-8.

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

    McDonald RB, Walker KM, Warman DB, Griffey SM, Warden CH, Ramsey JJ, Horwitz BA.

    Department of Nutrition, One Shields Avenue, University of California, Davis, CA 95616, USA.

    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 expression UCP2 (UCP2KO) or UCP3 (UCP3KO), and wild-type C57BL/6J mice (WT-Control) … [and] 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 [848 d], than that observed in Negative-TG or WT-Control[725 d]; 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 [989 & 925 d, respectively].

    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.

    PMID: 18854208 [PubMed – in process]
    The increase in mean LS is interesting, but absent any effect on maximal longevity, this seems to be pretty good evidence that, despite its *association* with longevity across species in CR, UCP2 does not in fact have any lifespan-extending effects — or, quite possibly, that it only has such effects in combination with an entire network of other changes, which coincide with it in rats vs mice and CR vs AL rodents.

    Confounders: the UCP3 upregulation might somehow have masked a benefit — but to go back to the original association studies underlying this experiment, both UCP2 *and* UCP3 are upregulated by CR. Also, none of the cohorts in this experiment (except for the ones on CR) lived as long as the ~1200 d benchmark established for this strain’s max LS in studies by Walford, and repeated in Weindruch’s and in Spindler’s labs, amongst others, so it’s possible that none of the mice can display their longevity because of something about the lab conditions etc.

    But certainly, no evidence has been presented that UCP2 *does* extend (or “regulate”) lifespan — and what data is available, suggests that it does not.


  3. Yes, you are right. There is a missing piece from the equation – UCP1. In order to have extended life span you also need a down-regulation of UCP1 present in CR. Overexpressed UCP2 and UCP3 are only “associated” with longevity when without down-regulated UCP1. Maybe that’s why they call them a family(Pun intended). You have the “full house” familial association in two occasions – with CR and with Ambient Hypoxia, both are directly linked to longevity.

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