Statistical analyses were performed using SPSS software package. All metabolic parameters are presented as mean standard deviation (SD). Due to the well-known effect of age on energy expenditure parameters, to better highlight the diverse role of long-lived vs. control people, the whole study population was subdivided into three age groups. Long-lived subjects (n=82; mean age, 96±3 years) had fasting Rq significantly higher (0.75±0.05 vs. 0.79±0.05; p<0.001) than aged subjectsexpenditure and energy balance (Vidal-Puig et al. 2000). In this study, we found that individuals carrying the Asp/Asp genotype at the IGF1R locus and Val/Val genotype at the UCP2 locus had higher Rq and RMR compared to other genotypes. Furthermore, the AAV allele combination was associated with a decreased all-cause mortality risk, higher probability of reaching extreme old age, lower HOMA-IR, and higher RQ and RMR. These findings suggest that genetic variability in the insulin/IGF1 signaling pathway and UCP2 may play a role in energy expenditure and longevity.

It is important to note that different genetic and/or environmental backgrounds may modulate the effect of a given gene in different populations. Therefore, further studies are needed to confirm these findings and to investigate potential interactions between genes and environmental factors in the regulation of energy metabolism and aging.Expenditure (Astrup et al. 1999; Buemann et al. 2001; Walder et al. 1998). Interestingly, in our study, AAV haplotype has been found to be significantly associated with a lower degree of insulin resistance and higher energy expenditure parameters. This factor is associated with a variety of intermediate phenotypes (hypertension, atherosclerosis, obesity) that strongly affect morbidity, disability, and mortality among the elderly (Facchini et al. 2001). By contrast, humans beyond 85-90 years of age display preserved insulin action, and centenarians are surprisingly insulin-sensitive. 

In accordance with previous studies (Barbieri et al. 2008), a remarkably low insulin resistance (IR), as well as BMI, WHR, cholesterol, and triglyceride levels were found in our long-lived people, confirming that these individuals are less prone to the metabolic derangement normally occurring with aging. Furthermore, as previously demonstrated in a small Italian cohort, despite an age-related decline in energy metabolism parameters, long-lived subjects had greater RQ and RMR compared to aged subjects (Rizzo et al. 2005). It is likely that the overrepresentation of AAV allele combination might help to explain such a peculiar phenotype found in long-lived subjects. In fact, through its effect on insulin resistance and energy expenditure parameters, the AAV allele combination might confer to long-lived subjects a better ability to preserve energy metabolism and delay the age-related metabolic derangement. Indeed, the effect on longevity is supported by the prospective analysis showing that the AAV allele combination is significantly associated with lower all-cause mortality risk.

Recent experimental evidence suggests that the effect of the insulin IGF1 signaling pathway on lifespan may be partially mediated by regulating the expression of uncoupling protein 2 (UCP2) (Bratic and Trifunovic 2010; Andrews et al. 2005). In flies, overexpressing human UCP2 (hUCP2) to adult neurons resulted in decreased oxidative damage and extended lifespan without compromising fertility or physical activity (Fridell et al. 2005). Furthermore, a very recent study has demonstrated that the absence of UCP2 shortens lifespan in wild-type mice, and the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals (Andrews and Horvath 2009). Indeed, no difference in relative mortality risk among UCP2 gene variants was observed in a Dutch cohort (van Heemst et al. 2005).