Abstract
In humans Uncoupling Proteins (UCPs) are a group of five mitochondrial inner membrane transporters with variable tissue expression, which seem to function as regulators of energy homeostasis and antioxidants. In particular, these proteins uncouple respiration from ATP production, allowing stored energy to be released as heat. Data from experimental models have previously suggested that UCPs may play an important role on aging rate and lifespan. We analyzed the genetic variability of human UCPs in cohorts of subjects ranging between 64 and 105 years of age (for a total of 598 subjects), to determine whether specific UCP variability affects human longevity. Indeed, we found that the genetic variability of UCP2, UCP3 and UCP4 do affect the individual's chances of surviving up to a very old age. This confirms the importance of energy storage, energy use and modulation of ROS production in the aging process. In addition, given the different localization of these UCPs (UCP2 is expressed in various tissues including brain, hearth and adipose tissue, while UCP3 is expressed in muscles and Brown Adipose Tissue and UCP4 is expressed in neuronal cells), our results may suggest that the uncoupling process plays an important role in modulating aging especially in muscular and nervous tissues, which are indeed very responsive to metabolic alterations and are very important in estimating health status and survival in the elderly.
Highlights
Un-Coupling Proteins (UCPs) belong to a family of anion transporters located in the inner membrane of mitochondria responsible for uncoupling substrate oxidation from ATP synthesis
Substantial evidence suggests that the ability of UCPs to reduce Reactive Oxygen Species (ROS) and regulate energy utilization underpins the ability of UCPs to promote lifespan in various experimental models [27,28,29,30,35]
In the present study we found that variants in UCP2, UCP3, and UCP4 significantly affect an individual’s chances of becoming ultra-nonagenarians
Summary
Un-Coupling Proteins (UCPs) belong to a family of anion transporters located in the inner membrane of mitochondria responsible for uncoupling substrate oxidation from ATP synthesis. UCP1 (4q28.31), the first member characterized, is predominantly expressed in brown adipose tissue (BAT), where it has a well-established role in cold- and diet-induced thermogenesis [1]. UCP4 (6p12.3) and UCP5 (Xp24) are predominantly expressed in the central nervous system and at a lower level in other tissues [5,6]. It has been hypothesized that these proteins may provide protection from oxidative damage by preventing excessive production of mitochondrial Reactive Oxygen Species (ROS) [7,8]. Ucp-knockout mice have increased levels of ROS and show signs of increased oxidative damage [9,10,11]. Further evidence indicates that activation of UCP2 and UCP3 by ROS leads to a mild uncoupling and to diminished ROS formation [12,13], while their inhibition by purine nucleotides increases membrane potential and mitochondrial ROS production [14]
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