Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCPGenes Is Associated with Longevity

Giuseppina Rose, Paolina Crocco, Francesco De Rango, Alberto Montesanto, Giuseppe Passarino*

Department of Cell Biology, University of Calabria, Rende, Italy

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.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: g.passarino@unical.it

Introduction

The uncoupling activity of UCPs has also been linked to regulation of other more specific metabolic functions [15,16] such as fatty acid oxidation [17], glucose-stimulated insulin secretion [18], whole body energy balance [19], and apoptosis [20]. Human aging is characterized by a gradual reduction in the ability to coordinate cellular energy expenditure and storage (crucial to maintain energy homeostasis), and by a gradual decrease in the in the ability to mount a successful stress response [21,22]. These physiological changes are typically associated with changes in body composition (i.e increase in fat mass and the decline in fat-free mass), and with a chronic state of oxidative stress with important consequences on health status [23–25]. Mitochondrial function is crucial in these processes, being mitochondria the main cellular sites controlling energy metabolism and the redox state. Thus, by promoting fatty acid oxidation, and by reducing ATP and ROS production, the induction of mitochondrial uncoupling through UCPs may also be a critical pathway in the modulation of the rate of aging and lifespan [26–28]. This idea, first proposed by M. D. Brand [26] and termed ‘‘uncoupling-to-survival’’, is now support- ed by several experimental evidences (for reviews see: [27,29,30]). Of interest, targeted expression of exogenous UCP extends lifespan of adult flies [31,32], while mice with higher metabolism live longer and have higher uncoupling activity [33]. Transgenic and knockout mice for Ucp genes show alterations in lifespan [34,35]. Interestingly, it has also been shown that in vivo uncoupling mimics metabolic and lifespan effects of calorie

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. As a consequence stored energy is released as heat. To date, five UCP homologues, UCP1 to UCP5, have been identified in mammals. 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]. UCP2 and UCP3 share a common region on chromosome 11q13. UCP2 is widely expressed in many organs and tissues [2], while UCP3 is principally expressed in skeletal muscle, cardiac muscle, and BAT [3,4]. Finally, UCP4 (6p12.3) and UCP5 (Xp24) are predominantly expressed in the central nervous system and at a lower level in other tissues [5,6]. Unlike UCP1, the physiological role of the other UCPs still remains to be fully elucidated. 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]. Indeed, Ucp-knockout mice have increased levels of ROS and show signs of increased oxidative damage [9–11]. 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].

restriction (CR) [36]. Consistently, mice subjected to CR show an increased expression of Ucp2 and Ucp3 [37,38].

Table 1. Description and localization of selected SNPs in the UCP genes.

and aging emerges from association studies which support a role for UCPs in many age-related phenotypic traits involving alterations in cellular energy homeostasis such as obesity, diabetes and lipid-related diseases [39–41]. We recently performed a population-based study in a human cohort of elderly subjects which demonstrated that UCP3 variability has an impact on hand grip strength, one of the most important hallmarks of human aging [42] and more recently we also found that two variants (A-3826G and C-3740A) in the upstream enhancer region of human UCP1 gene affect the expression of the gene and are correlated with human longevity [43].