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

Michelangela Barbieri & Virginia Boccardi & Antonietta Esposito & Michela Papa & Francesco Vestini & Maria Rosaria Rizzo & Giuseppe Paolisso

Received: 6 October 2010 /Accepted: 24 January 2011 /Published online: 22 February 2011 # American Aging Association 2011

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 associa- tion 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, 5.26 204.278; 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.

Keywords IGF1R/IRS2/UCP2 haplotype . Metabolic profile . Energy expenditure . Longevity. Mortality rate

Introduction

Several hypotheses have been formulated in order to explain the biological mechanisms of physiological aging. Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents (Ingram et al. 2006). In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer, and cardiovascular disorders) in mammals (Willcox et al. 2007).Whether this occurs in longer-lived species is unknown,

Electronic supplementary material The online version of this article (doi:10.1007/s11357-011-9210-z) contains supplementary material, which is available to authorized users.

M. Barbieri V. Boccardi A. Esposito M. Papa : : F. Vestini M. R. Rizzo G. Paolisso (*) Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Piazza Miraglia

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Naples, Italy e-mail: giuseppe.paolisso@unina

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located in neuronal populations of sub-cortical regions and is involved in autocrine, endocrine and metabolic regulation. High levels of UCP2 protect the immature brain from exocytotoxic cell death by reducing ROS production (Diano et al. 2003) and increased UCP2 expression correlates with neuronal survival, prevents neuronal death, and diminishes brain dysfunction after stroke and brain trauma (Sullivan et al. 2003).

Several experimental evidences suggest that caloric restriction exerts its beneficial effects on longevity through the modulation of the insulin IGF1 signaling pathway (Fontana et al. 2010; Heilbronn and Ravussin 2003; Taguchi and White 2008) and recent association studies on long-lived people have demonstrated that a large array of gene involved in human longevity are in relationship with insulin/IGF1 pathway (van Heemst et al. 2005; Bonafè and Olivieri 2009; Pawlikowska et al. 2009). To this regard, we have previously demon- strated that the G to A transition in exon 16 of IGF1R gene is associated with longevity in an Italian population (Bonafè et al. 2003) and more recently an overrepresentation of heterozygotes for mutation in IGF1R gene has been found among Jewish female centenarians (Suh et al. 2008). Recently, we have also found that subjects with one or two IRS2Asp alleles displayed a greater chance of living between 96 and 104 years of age (Barbieri et al. 2010). Interestingly, IGF1R and IRS2 genes share a regu- latory role on energy metabolism through their impact on glucose and lipid metabolism. Thus, we hypothesized that such genes may interact each other and/or with other genes to reduce the age-related metabolic derangement and that a combination of variants or haplotypes in these genes may increase the chance to reach exceptional survival.

In flies, over-expressing human UCP2 (hUCP2) to adult neurons resulted in increased uncoupled respira- tion, decreased ROS production, decreased oxidative damage and extended life span without compromising fertility or physical activity (Fridell et al. 2005). Furthermore, a very recent study has demonstrated that the absence of UCP2 shortens life span 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).