These studies suggest that the robust ability of UCP2 to control ROS production and restrict neurological disease has a greatest impact on overall aging of an organism, is a good target to restrict age-related deleterious effects associated with ROS and ROS- related mitochondrial dysfunction, and may mediate lifespan. (Andrews 2010). Interestingly, in a recent review, Andrews, evaluating the physiological rele- vance of UCP2 in genetic mouse model, showed that UCP2 promotes longevity by shifting a given cell towards fatty acid fuel utilization thus suggesting that fatty acid regulation and activation of UCP2 are critical aspects of the hypothesis that UCP2 enhances longevity by modulating metabolism (Andrews 2010).

effects of calorie restriction is reduced energy expen- diture with a consequent reduction in the production of reactive oxygen species (ROS; Fontana et al. 2010, Leonie et al. 2003; Taguchi and White 2008). Interestingly, both fast and caloric restriction increase the activity of UCP2 an inner mitochondrial mem- brane protein involved in the regulation of energy metabolism (Andrews 2010; Zhang et al. 2001), mitochondrial biogenesis, fatty acid oxidation, sub- strate utilization and ROS elimination, providing neuroprotective and anti-aging effects (Conti et al. 2006; Bechmann et al. 2002).

In light of such evidences, the presence of mutations in UCP2 gene or regulatory region could contribute to longevity either through the effect on ROS or modulating energy metabolism. Indeed, controversial results came from the literature about functional role of UCP2 gene variants. Three common polymorphisms have been described in the UCP2 gene and have been variably associated with altered body mass index (BMI), changes in energy expendi- ture, and maintenance of body weight after overfeed- ing (Dalgaard and Pedersen 2001; Schrauwen and Hesselink 2002). Most studies have examined indi- vidually either the amino acid substitution of valine (V) for alanine (A) in exon 4 (Ala55Val or A55V) or the 45-bp insertion/deletion variant in the 3- untranslated region (3 UTR I/D) of exon 8, or the

Numerous studies have demonstrated that UCP2, diminishes ROS production in a large number of tissues examined (Echtay 2007; Teshima et al. 2003; Pi et al. 2009; Chevillotte et al. 2007). Within the central nervous system, UCP2 is predominantly

Italian unrelated subjects. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years.

G/A substitution at nucleotide 866 in the 5 upstream region. Results of these studies have been variable (Dalgaard and Pedersen 2001; Schrauwen and Hesselink 2002), with some, but not all (Klannemark et al. 1998), studies showing an association with obesity and energy expenditure (Dalgaard and Pedersen 2001; Schrauwen and Hesselink 2002). In particular, VV genotype, in comparison to those who have the AA or A/V genotype, have a lower degree of uncoupling, lower energy expenditure (Astrup et al. 1999), higher exercise energy efficiency (Buemann et al. 2001), and lower fat oxidation. However, it has been reported that persons with the I/D genotype have an increased basal metabolic rate, increased 24-h energy expenditure and decreased BMI (Esterbauer et al. 2001), as well as a low deposition − index (Walder et al. 1998).Recently, the 866 G-allele has been described to influence UCP2 transcription, to be associated with reduced adipose tissue mRNA expression, reduced transcriptional activity in vitro and in vivo, high BMI, fat mass changes (Yoon et al. 2007), increased risk of obesity (Esterbauer et al. 2001; Argyropoulos and Harper 2002; Vogler et al. 2005), increased insulin response to glucose and reduced risk of T2D (Krempler et al. 2002; Esterbauer et al. 2001; Sesti et al. 2003).

Subjects

Seven hundred twenty-two unrelated Italian subjects (401 women and 321 men, mean age: 62.83± 25.30 year) enrolled between 1998 and 1999, vol- unteered for the study. All participants were followed for mortality until August 1, 2009, with a mean follow-up period of 6 years.

Yashin et al. 1999), in order to assess the impact of specific IRS-2, IGF1R and UCP2 gene variants on longevity, subjects, were then sub-categorized in two groups, by splitting the whole sample at the age of 85: healthy people aged <85 years of age (n=514, mean age=49±16 year) were grouped under the denomina- “ ” tion of control ; healthy people aged from 86 to 104 year; (n=208, mean age=96±4), were collected “ ” in the group of long-lived people .

All subjects were contacted at home or in their institution and examined by physicians previously trained to administer a questionnaire that included cognitive and depression test. No subject used drugs affecting insulin secretion and/or action or plasma lipid level, body composition, resting metabolic rate and respiratory quotient. All subjects that conducted a vigorous physical activity as well as the subjects that were confined to bed were also excluded from the study. Long-lived subjects conducted a sedentary life but were all self-sufficient. After a clear explanation of the potential risk of the study, all subjects gave informed consent to participate into the study, which was approved by the Ethical Committee of our Institutions.