Carriers of the G allele have a diminished resting energy expenditure, while carriers of the G/G genotype have reduced thermoregulatory sympathetic nervous system (SNS) activity. This finding suggests that the attenuation of UCP1-mediated thermogenesis may have a negative effect on energy balance regulation. The survival advantage exerted by the A-C haplotype could then be a consequence of protection towards age-related decline of energy expenditure. These results seem to be in line with those reported by Rizzo et al. (2005) showing that very old individuals have a higher metabolic rate than older individuals. Human cohort studies also support a relationship between advanced age and body temperature (Waalen and Buxbaum, 2011), suggesting that the individual's ability to maintain a lower steady-state body temperature may affect longevity. Although skeletal muscles may play a role in non-shivering thermogenesis (Wijers et al., 2008), the age-related diminished thermogenic activity of BAT might be the primary cause for the loss of thermoregulation (Son'Kin et al., 2010). An analysis of BMI would be crucial to better understand how UCP1 activity affects longevity. Unfortunately, information on BMI was available only for a subgroup of our sample. Therefore, we cannot fully address whether or not UCP1 affects longevity through BMI. Further studies are needed to clarify this point.

Since the preservation of mitochondrial function from oxidative stress represents one of the most important factors for achieving survival for the very old, the specific involvement of UCP1 in reducing ROS production (Oelkrug et al., 2010; Dlaskov et al., 2010) may represent a further mechanism through which mitochondrial uncoupling in BAT can contribute to slowing down aging. The hypothesis that UCP1 haplotypes affect ROS production is currently under investigation.

The present study shows that haplotypic variants in the 5-enhancer region of the UCP1 gene modulate survival, probably by affecting protein levels. This is the first study reporting a significant association between UCP1 genetic variants and human survival; however, additional data are needed. The soundness of our preliminary findings is supported by the consistency between our association and in vitro studies and previous studies in model organisms.

Luciferase activity of the reporter constructs at basal and after stimulation is shown in Fig. 4. A) MCF-7 cells treated with 1 M of Retinoic Acid forThis is a list of references related to the effects of cold exposure and adiposity on adult humans. The references are as follows:

1. Sale, M.M., Hsu, F.C., Palmer, N.D., Gordon, C.J., Keene, K.L., Borgerink, H.M., Sharma, A.J., Bergman, R.N., Taylor, K.D., Saad, M.F., Norris, J.M. (2009). The uncoupling protein gene, UCP, is expressed in mammalian islet cells and associated with acute insulin response to glucose in African American families from the IRAS Family Study. BMC Endocr. Disord.
2. Sell, H., Deshaies, Y., Richard, D. (2013). The brown adipocyte: update on its metabolic role. Int. J. Biochem. Cell. Biol.
3. Son'kin, V.D., Kirdin, A.A., Andreev, R.S., Akimov, E.B. (2013). Homeostatic non-shivering thermogenesis in humans: facts and hypotheses. Hum. Physiol.
4. Sramkova, D., Krejbichova, S., Vcelak, J., Vankova, M., Samalikova, P., Hill, M., Kvasnickova, H., Dvorakova, K., Vondra, K., Hainer, V., Bendlova, B. (2010). The UCP gene polymorphism A-G in relation to DM and body composition in Czech population. Exp. Clin. Endocrinol. Diab.
5. St-Onge, M.P., Gallagher,D.(2010). Body composition changes with aging: the cause or the result of alterations in metabolic rate and macronutrient oxidation? Nutrition.
6.Tan,Q., Yashin, A.I., De Benedictis, G., Cintolesi, F., Rose, G., Bonafe, M., Franceschi, C., Vach, W., Vaupel, J.W. (2001). A logistic regression model for measuring gene longevity associations. Clin. Genet.
7. Tiraby,C.,Tavernier,G.,Lefort,C.,Larrouy,D.,Bouillaud,F.,Ricquier,D.,Langin,D.(2003).Acquirement of brown fat cell features by human white adipocytes. J. Biol. Chem.
8. Valle,A., Santandreu,F.M., Garca-Palmer,F.J., Roca,P., Oliver,J.(2005).The serum levels of β-estradiol, progesterone and triiodothyronine correlate with brown adipose tissue thermogenic parameters during aging. Cell. Physiol. Biochem.
9. van Marken Lichtenbelt,W.D.,Vanhommerig,J.W.,Smulders,N.M.,Drossaerts,J.M.,Kemerink,G.J.(2009).Cold activated brown adipose tissue in healthy men. N. Engl. J. Med.
10. Vijgen,G.H.E.J.,Bouvy,N.D.,Teule,G.J.Jr,Brons,B.P.P.(2011).Brown adipose tissue in morbidly obese subjects. PLoS ONE.
11. Virtanen,K.A.,Lidell,M.E.E.E.E.E.E.E.E.E.E.E.E.(2009).Functional brown adipose tissue in healthy adults. N. Engl. J. Med.
12.Waalen,J.,Buxbaum,J.N.N.(2011).Is older colder or colder older? The association of age with body temperature in individuals. J.Gerontol.A Biol.Sci.Med.Sci.
13. Images of mitochondrial UCP in mouse thymocytes using confocal microscopy. Biochim. Biophys. Acta.
14.Brand,M.D.(2000).Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol.
15. Cannon,B.,Nedergaard,J.(2004).Brown adipose tissue: function and physiological significance. Physiol. Rev.
16.Cannon,B.,Nedergaard,J.(2004).Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans). Int. J. Obes. (Lond) (Suppl.).
17.Cannon,B.,Shabalina,I.G.,Kramarova,T.V.,Petrovic,N.,Nedergaard,J.(2006).Uncoupling proteins: a role in protection against reactive oxygen species or not? Biochim. Biophys. Acta.
18.Crocco,P.,Montesanto,A.,Passarino,G.,Rose,G.(2012).A common polymorphism