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Two variants located in the upstream enhancer region of human UCP1 gene affect gene expression and are correlated with human longevity

Giuseppina Rose , Paolina Crocco, Patrizia D'Aquila, Alberto Montesanto, Dina Bellizzi, Giuseppe Passarino

Department of Cell Biology, University of Calabria, 87036, Rende, Italy



brown fat specific UnCoupling Protein 1 (UCP1) is involved in thermogenesis, a process by which energy dissipated as heat in response to cold stress and excess of caloric intake. Thermogenesis has potential for body mass control and cellular fat metabolism. In fact, in humans, the variability of the UCP1 is associated with obesity, fat gain and metabolism. Since regulation of metabolism is one of the key- in lifespan extension, we tested the possible effects of UCP1 variability on survival.

pathways in lifespan extension, we tested the possible effects of UCP1 variability on survival. Twopolymorphisms (A-3826GandC-3740A), fallingintheupstream promoterregionofUCP1,wereanalyzed in a sample of 910 subjects from southern Italy (475 women and 435 men; age range 40–109). By analyzing haplotype specific survival functions we found that the A-C haplotype favors survival in the elderly. Consistently, transfection experiments showed that the luciferase activity of the construct containing the A-C haplotype was significantly higher than that containing the G-A haplotype. Interestingly, the different UCP1 haplotypes responded differently to hormonal stimuli. The results we present suggest a correlation between the activity ofUCP1 andhuman survival,indicating onceagainthe intricacyofmechanismsinvolved inenergy production, storage and consumption as the key to understanding human aging and longevity.

1. Introduction

(Adams et al., 2008). Moreover, in response to certain stimuli such as cold exposure and sympathetic stimulation, human white adipocytes can acquire the features of brown cells (Tiraby et al., 2003). Furthermore, starting from the first study by Nedergaard et al. (2007), a series of reports provided evidence for the presence of active adipose tissue in adult humans (Zingaretti et al., 2009; Virtanen et al., 2009; Cypess et al., 2009; van Marken Lichtenbelt et al., 2009; Saito et al., 2009; Nedergaard et al., 2011). In addition, Yoneshiro et al. (2010) have reported that BAT is involved in cold-induced thermo- genesis in healthy adult men, and thus contributes to whole-body energy expenditure. It may therefore be inferred from these

The UnCoupling Protein 1 (UCP1), also known as thermogenin, belongs to a family of anion transporters located in the inner membrane of mitochondria. By allowing the leak of protons through the inner mitochondrial membrane of Brown Adipose Tissue (BAT), UCP1 uncouples fuel oxidation from ATP synthesis. UCP1 activation leads to thermogenesis, which allows energy to be dissipated as heat in response to cold stress and excess caloric intake (Lowell and Spiegelman, 2000; Cannon and Nedergaard, 2004).

(2010) have reported that BAT is involved in cold-induced thermo- genesis in healthy adult men, and thus contributes to whole-body energy expenditure. It may therefore be inferred from these observations that BAT thermogenesis may have a role in human adult whole-body metabolism, and therefore also in aging and longevity.

There is a huge body of evidence indicating that UCP1-mediated thermogenesis in brown fat in rodents significantly contributes to control of body temperature, body weight, energy expenditure, glucose and lipid metabolism (Sell et al., 2004; Cannon and Nedergaard, 2010; Kozak et al., 2010). Moreover, since a consequence of the mitochondrial uncoupling is the lowering of the mitochondrial membrane potential, a potential role for thermogenin in preventing excessive production of mitochondrial reactive oxygen species (ROS) has also been proposed (Cannon et al., 2006; Oelkrug et al., 2010; Dlasková et al., 2010).

Aging is a very complex phenomenon, largely influenced by an increased susceptibility to energy imbalance (Roberts and Rosenberg, 2006). The dysregulation of energy intake and the progressive decline of all components of energy expenditure (that is, obligatory, activity induced and facultative thermogenesis) with advancing age has been well established (Roberts and Rosenberg, 2006; Manini, 2010). The decline of resting metabolic rate (RMR), which represents the largest componentofenergyexpenditure,istypicallyassociatedwithchanges inbodycomposition(i.e.increaseinfatmassandthedeclineinfat-free mass). However, the analysis of energy expenditure shows that after adjustment for differences in fat mass and fat-free mass, the body composition accounts for asmallproportionof the ageassociatedRMR

In humans, UCP1 has been thought to be exclusively expressed in BAT which is well developed only in newborns and young children. However,somerecentstudieshaveshownthatUCP1isalso expressed,

⁎ Corresponding author. Tel.: +39 0984492931; fax: +39 0984492911. E-mail address: pinarose@unical.it (G. Rose).

0531-5565/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2011.07.011

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