of elderly subjects from an Italian population. Although the authors did not find an association with longevity, they found that individuals with the Val/Val genotype had significantly higher energy expenditure parameters. Interestingly, the A-IGF1R/Asp- IRS2/Val-UCP2 allele combination was associated with a better metabolic profile, higher energy expenditure parameters, and lower mortality rates in longevity, thus indicating a contribution of Ala55val polymorphism to the regulation of energy balance and survival [76]. The latter and our finding suggest that the 55Val allele might promote longevity by conferring protection towards age-related decline of metabolic rate. It is indeed well-known that human aging is accompanied by a decrease in resting metabolic rate, the largest component of total energy expenditure, which significantly affects disability and morbidity among the elderly [24,77]. On the other hand, long-lived subjects show a preserved metabolic profile being less prone to the metabolic deregulation normally occurring with aging [78]. Accordingly, Rizzo and colleagues [79] reported that compared to aged subjects, healthy long-lived subjects display energy expenditure parameters that are closer to the values of healthy middle-aged adults. In a recent study we demonstrated a correlation between the activity of UCP1 and human survival, and hypothesized a slower decline of energy expenditure with age at the basis of the correlation [43].

UCP4 and UCP5, together with UCP2, are known as neuronal UCPs due to their widespread distribution in the brain [6]. Neurons have a very high metabolic rate and consequently a high production of ROS. Andrews and co-workers observed that neuronal uncoupling activity leads to decreased ROS levels, a decreased Ca2+ voltage-dependent influx and increased local temperature in neuronal microenvironment [88]. We found that only the UCP4 rs9472817-GG genotype negatively impacts on the probability to attain longevity. It has been shown that UCP4 activity can induce an adaptive shift in energy metabolism, from mitochondrial respiration to glycolysis, that helps sustain neurons under conditions of metabolic and oxidative stress [89,90]. Therefore, by decreasing free radical production and stabilizing cellular calcium homeostasis, UCPs expressed in neurons may positively influence neuronal function (synaptic transmission and plasticity) and retard the cellular deterioration associated with aged-related neurological disorders. Accordingly, the expression of UCP4 has been found significantly reduced in brains of subjects affected by Alzheimer disease [91]. Moreover, it was found that CC genotype for rs10807344 of UCP4 gene, not found to be associated in the present study with the longevity phenotype, exerts a protective effect on the occurrence of multiple sclerosis and of leukoaraiosis, a vascular demyelinization of the white matter of the brain [92,93]. Thus, it is likely that variants affecting the UCP4 function might have consequences on the aging of the nervous system, and then might have a potential impact on health and longevity. Due to the fact that rs9472817 is located in intron 8, the exact molecular mechanism responsible for the effect on survival remains to be elucidated. Although it has been reported that intronic SNPs may have an effect on gene expression [94], it is more plausible for rs9472817 to be in LD with some other functional genetic alterations affecting the function of UCP4 and this has consequences on the aging nervous system, leading to the observed detrimental effect of the GG genotype. Further studies are

Skeletal muscle, where UCP3 is mainly expressed, contributes considerably to the basal metabolic rate [80]. We found that carriers of the TT genotype (rs15763), and carriers of the -55 T allele (rs180084) were significantly over-represented among long- lived subjects. The rs15763 is located in the 39UTR of the gene and has no clear functional role so far; on the contrary, the -55 T allele has been associated with a significantly increased gene expression and has been shown to positively modulate the resting metabolic rate of skeletal muscle [81,82]. In addition, the over- expression of UCP3 in muscle cells has been shown to be associated with decreased production of ROS as well as with facilitating fatty acid oxidation [17,83]. The physiological status of the muscle mass reflects a complex equilibrium between nutrition, metabolism and the response to stress. Aging muscle is characterized by a progressive loss of mass and a gradual increase of weakness leading to sarcopenia, a condition associated with physical disability, and with an increased risk of developing disorders such as atherosclerosis, type II diabetes and hypertension [84]. Sarcopenia is closely linked to a decrease in resting metabolic rate as well as to mitochondrial dysfunction and oxidative stress [85]. Therefore, in the context of the proposed functions of UCP3, the physiological consequence of an increased UCP3 activity in skeletal muscle might be to slow down the age related decline of muscle performance as a result of decreased ROS production, an increased protection of mitochondria from lipid peroxidation, and better metabolic efficiency [28,83]. Accordingly, it has been found that mild uncoupling has an impact on cellular aging in human muscles in vivo [86]. This is in keeping with our previous work, where we have shown that the hand grip strength, the most effective death predictor in the elderly, was higher in the carriers of