Further Support for the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes 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 function as regulators of energy homeostasis and antioxidants. 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 in 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 affects 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, heart and adipose tissue while UCP3 is expressed in muscles and Brown Adipose Tissue and UCP4 is expressed in neuronal cells), our results 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 the 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 maintaining energy homeostasis), and by a gradual decrease in the ability to mount a successful stress response [21,22]. These physiological changes are typically associated with changes in body composition (i.e., an 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, as mitochondria are 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 supported 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 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.

Gene Function symbol dbSNP ID Physical location annotation 

UCP2 rs660339 C/T exon 4 Ala55Val 
rs659366 G/A 5' -proximal region 2866 G/A 
UCP3 rs15763 C/T 3'UTR 
rs1800849 C/T 5' -proximal region 255 C/T 
UCP4 rs9472817 C/G intron 8 
rs10498769 C/G 3'UTR 
UCP5 rs2235800 A/T intron 7 
rs5975178 C/T 5' -proximal region 

Given the tissue-specific expression of UCP genes, it seems likely that they may affect the senescence of different tissues with important effects on the overall aging process and consequently on lifespan. Thus, the goal of the present study was to assess both the primary effects of single loci and gene-gene interactions to test the hypothesis that other UCP genes may contribute to survival at a very old age either independently and/or through complex genotype-phenotype associations in case-control studiesCovariates [49]: This test was based on the score test and has been implemented in the R package RobustSNP. In the present study, the robust association test proposed by So and Sham was applied to estimate the association between the variability in the UCP genes and the probability of reaching advanced ages. In each test, we included sex and Body Mass Index (BMI) as covariates. The analyses were carried out by dividing the sample into two specific age classes obtained according to the survival function of the Italian population from 1890 onwards [44]. The two thresholds of longevity used to define these age classes were 88 years for men and 91 years for women.

SNPs selection: Polymorphisms within the UCP genes were selected from literature data, and using information from online databases such as NCBI dbSNP and HapMap. SNP selection was based on allele frequency, position, and functional effects. For each gene, the selected SNPs are reported in Table 1.

From the z-statistics of these models, we observed that carriers of the T allele at rs660339 and rs1800849 (dominant models) significantly influenced the probability of being part of the oldest group (positive scores). For the recessive models, homozygous subjects for the T allele at rs15763 variation also increased the probability of being part of the oldest group, while this probability was significantly decreased (negative score) for homozygous subjects with the T allele at rs9472817.