A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

Abstract

A large array of gene involved in human longevity seems to be in relationship with insulin/ IGF1 pathway. However, if such genes interact each other, or with other genes, to reduce the age-related metabolic derangement and determine the long-lived phenotype has been poorly investigated. Thus, we tested the role of interchromosomal interactions among IGF1R, IRS2, and UCP2 genes on the probability to reach extreme old age in 722 unrelated Italian subjects (401 women and 321 men; mean age, 62.83±25.30 years) enrolled between 1998 and 1999. In particular, the G/A-IGF1R, Gly/Asp-IRS2, and Ala/ Val-UCP2 allele combination was tested for association with longevity, metabolic profile and energy expenditure parameters. The effect on all-cause and cause-specific mortality rate was also assessed after a mean follow-up of 6 years. The analysis revealed that AAV allele combination is associated with a decreased all-cause mortality risk (HR, 0.72; 95% CI, 0.63-0.91; p=0.03) and with a higher probability to reach the extreme of old age (OR, 3.185; 95% CI, 1.63-6.19; p=0.0006). The analysis also revealed lower HOMA-IR (Diff, −0.532, 95% CI, 0.886-0.17; p= 0.003), higher respiratory quotient (Diff, 0.0363, 95% CI, 0.014-0.05; p=0.001), and resting metabolic rate (Diff, 101.80693, 95% CI, p=0.038) for AAV allele combination. In conclusion, A-IGF1R/ Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity.

Further Support to the Uncoupling-to-Survive Theory: The Genetic Variation of Human UCP Genes Is Associated with Longevity

“…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 Ala 55v al polymorphism to the regulation of energy balance and survival [76]. The latter and our finding suggest that the 55 Val allele might promote longevity by conferring protection towards age-related decline of metabolic rate.…”

“…Recently, Andrews proposed that UCP2 promotes longevity by shifting a cell towards fatty acid fuel utilization thus pointing to a major role of UCP2 in modulating metabolism [75]. This hypothesis is somewhat supported by Barbieri and colleagues [76] who analyzed the Ala 55v al polymorphism in a human cohort 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.…”

Membrane ion Channels and Receptors in Animal lifespan Modulation

“…Mice carrying a hypocretin promoter‐driven UCP2 transgene have a longer lifespan while UCP2 knockout mice exhibit a significantly shortened lifespan (Andrews & Horvath, ; Conti et al, ), strongly supporting that UCP2 is a prolongevity factor. Consistent with the findings in mice, polymorphisms in UCP2 are also associated with human longevity (Barbieri et al, ; Rose, Crocco, De Rango, Montesanto, & Passarino, ). Mechanistically, UCP2 knockout increases the circulating IGF‐1 level, indicating a crosstalk between UCP2 and IIS pathway (Hirose et al, ).…”

Serum levels of uncoupling proteins in patients with differential insulin resistance

“…[ 34 ] Decreased expression of UCP 2 was also associated with obesity, low adiponectin, and high HOMA-IR levels in animals and patients with type 2 diabetes. [ 35 , 36 ] Several studies performed on high-fat-diet-fed UCP 3 −/− transgenic mice demonstrated variable, age-dependent effects on insulin sensitivity. [ 37 , 38 ] This effect was observed in mice fed with a standard, as well as high-fat diet.…”