Coupled with uncouplers: the curious case of lifespan.

THE SEARCH FOR THE PHILOSOPHER’S STONE, purported to be able to transform lead to gold and bestow upon the owner eternal life, has occupied the imagination of humans for centuries. Whereas, to the best of our knowledge, nobody ever made substantial progress toward the first objective, Andrews and Horvath in the current issue of this Journal provide stimulating new insights into what makes some organisms live longer than others. In this issue of AJP Endocrinology and Metabolism, Andrews and Horvath (1) address the question of uncoupling protein-2 (UCP2)’s involvement in determining lifespan by using both a loss-of-function and a gain-of-function approach. The authors showed a significant reduction in longevity in mice lacking UCP2 compared with wild-type mice with intact UCP2 action. In the gain-of-function model, the longevity of mice carrying the human UCP2 transgene were compared with wild-type controls with no difference being observed. With the caveat of small sample sizes for a longevity study, the authors provide evidence that a lack of UCP2 is deleterious to lifespan. In order to critically assess the impact of UCP2 on reactive oxygen species (ROS)-induced damage and lethality, the authors used a model of extreme oxidative injury, the manganese superoxide dismutase (SOD2)-deficient mouse, which does not usually live beyond three weeks of age. SOD2 / mice display rapidly exacerbated mitochondrial injury in metabolically active tissues, resulting from the inability to convert superoxide to the less harmful oxygen and hydrogen peroxide (15). In this extreme model of oxidative injury the authors demonstrate a protective role for UCP2, with SOD2 knockout mice with intact UCP2 surviving significantly longer than the doubleknockout mice. Additionally the over-expression of UCP2 significantly increased survival in the SOD2 knockout mice. While it is clear from these studies that UCP2 plays a minor role in determining longevity compared with SOD2, the results are indicative of the two mechanisms acting in concert to reduce mitochondrial ROS levels. Many variables correlate with life expectancy in such a way that they could theoretically be mediators of longevity; however, as yet no definitive surrogate markers predicting duration of life have been found. One of the early observations was that body size correlates very well with life expectancy, with a few notable exceptions. This is paired with the observation that as size decreases metabolic rate increases (12), leading to theories that life expectancy may be tied to metabolic rate. From this observation came the “free radical” theories of aging (9), which postulated that increased metabolic rate leads to an increase in the production of ROS by the electron transport chain and that shorter lifespans resulted from increased oxidative damage to DNA, thereby impairing its ability to replicate. Although an attractive theory, there are a number of solidly observed and well reported phenomena for which it does not account. 1) Exercise, while increasing metabolic rate, does not shorten the lifespan of rats (10); 2) in Drosophila, metabolic rates show no correlation with lifespan (13), and in mice increased metabolic rate is associated with increased lifespan (18); and 3) exceptionally long-lived naked mole rats have only a modest reduction in metabolic rate, which is unable to solely account for a lifespan roughly 10 times that of a mouse (6). It is clear that, while metabolic rate and ROS play some part in aging, there are additional factors that influence lifespan. One theory proposed by Brand (5) is the “uncoupling to survive” theory, which proposes that one mechanism by which an organism can reduce free radical production, especially that of superoxide, is by increased rates of mitochondrial uncoupling. During oxidative phosphorylation, ROS production occurs at two points of the electron transport chain: complexes I and III. ROS generation at complex III is likely dependent on high membrane potential (14), and one critical way of lowering membrane potential is to allow protons to cross the inner mitochondrial membrane uncoupled from ATP production. Brand notes that a large number of species, of widely divergent body sizes, show a consistent rate of uncoupled respiration in the range of 15–25% of basal metabolic rate and, as this occurs in ectotherms as well as endotherms, is unlikely to be solely a thermogenic mechanism (5). There is evidence to suggest that higher levels of uncoupling are beneficial when it comes to aging. Outbred MF1 mice with high metabolic rates live longer and have higher rates of mitochondrial proton conductance, a difference mediated, at least in part, by UCP3 (18). Swiss Webster mice treated with low doses of the uncoupling agent 3,4-dinitrophenol showed increased mean lifespan and metabolic changes similar to those seen in caloric restriction (7), the only intervention that reliably increases lifespan (4). Although UCP2 has been shown to be an important signaling molecule in a number of situations (2, 17, 20), a possible role in increasing longevity for UCP2 specifically has only recently gained attention. It has been shown that during -oxidation UCP2 plays an important role in the utilization of fatty acids, a pathway likely to be of importance during caloric restriction (2). Additionally, UCP2 is induced by ROS (8), and its expression levels parallel ROS production levels (3), making it an attractive research target for proponents of the uncoupling to survive theory of aging. The elegant and striking data from mouse mutants with gain or loss of UCP2 function presented by Andrews and Horvath in their current paper outline a distinct role for UCP2 in longevity; however, there are some recently published results which give a slightly different message. McDonald et al. (16) report that UCP2 / mice lived significantly longer than UCP / mice. Although Andrews and Horvath did not investigate the longevity of heterozygous animals, these data are less reassuring that UCP2 has a role in increased longevity. However, McDonald et al. did report that mice carrying the human UCP2/UCP3 transgene have significantly longer mean and median lifespans than both their non-transgene-expressing littermates and wild-type controls. Interestingly, though, the Am J Physiol Endocrinol Metab 296: E619–E620, 2009; doi:10.1152/ajpendo.00060.2009.