SHIP2: A ‘‘NEW’’ Insulin Pathway Target for Aging Research Giulia Accardi, 1 Claudia Virruso, 1 Carmela Rita Balistreri, 1 Fabrizio Emanuele, 2 Federico Licastro, 3 Roberto Monastero, 4 Elisa Porcellini, 3 Sonya Vasto, 5 Salvatore Verga, 2 Calogero Caruso, 1 and Giuseppina Candore 1 Abstract Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate met- abolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardio- vascular disease, as well as Alzheimer’s disease (AD), all characterized by chronic inflammatory status. On the other hand, extensive abnormalities in insulin and insulin-like growth factor I (IGF-I) and IGF-II signaling mechanisms in brains with AD have been demonstrated, suggesting that AD could be a third form of diabetes. The Src homology domain-containing inositol 5-phosphatase 2 (SHIP2) has an important role in the insulin pathway because its over-expression causes impairment of insulin/IGF-1 signaling. Because some single- nucleotide polymorphisms (SNP) of the gene encoding SHIP2 were significantly associated in T2DM patients with metabolic syndrome and some related conditions, we decided to conduct a case–control study on this gene, analyzing AD and T2DM subjects as cases and young, old, and centenarians as controls. Our results suggest a putative correlation between the the rs144989913 SNP and aging, both successful and unsuccessful, rather than age-related diseases. Because this SNP is an insertion/deletion of 28 bp, it might cause an alteration in SHIP2 expression. It is noteworthy that SHIP2 has been demonstrated to be a potent negative regulator of insulin signaling and insulin sensitivity. Many studies demonstrated the association of the insulin/IGF1 pathway with aging and longevity, so it is tempting to speculate that the found association with SHIP2 and aging might depend on its effect on the insulin/IGF-1 pathway. Introduction A ging is an ineluctable process resulting from the interaction among genetic, epigenetic, stochastic, and lifestyle factors. 1,2 However, in vivo studies in model ani- mals demonstrate that single genetic mutations are able to modulate life span. The insulin-like growth factor-I (IGF-I) pathway seems to be correlated to human life span, and its homologs are closely conserved in the main experimental models such as yeast, nematode, and fruit fly in which mu- tations in genes encoding proteins involved in this pathway affect life span. 3 Insulin is the most potent anabolic hormone and is essential for appropriate tissue development, growth, and maintenance of whole-body glucose homeostasis. Insulin resistance (IR) reflects impairments in the insulin signaling pathway, but the molecular mechanisms implicated are not so clear, although the inflammatory process is involved. IR is one of the features of metabolic syndrome, a pre-diabetic status. 4,5 Interestingly, strong evidence suggests that systemic in- flammation and central adiposity contribute to and perpet- uate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovas- cular disease, as well as Alzheimer’s disease (AD), all characterized by chronic inflammatory status. 6–12 In 2005, a group of American scientists hypothesized that AD could be a third form of diabetes. They demonstrated extensive ab- normalities in insulin and IGF-I and IGF-II signaling mechanisms in brains with AD, showing that although each of the corresponding growth factors is normally made in central nervous system neurons, the expression levels are markedly reduced in AD. 13 1 Immunosenescence Unit, Department of Pathobiology and Medical and Forensic Biotechnologies and 2 Clinical Nutrition Unit, Bio- medical Department of Internal and Specialty Medicine, University of Palermo, Palermo, Italy. 3 Department of Experimental Diagnostic and Specialty Medicine, University of Bologna, Bologna Italy. 4 Department of Experimental Biomedicine and Clinical Neurosciences and 5 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy. REJUVENATION RESEARCH Volume 17, Number 2, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/rej.2013.1541 221 Rejuvenation Research 2014.17:221-225. Downloaded from online.liebertpub.com by Calogero Caruso on 04/16/14. For personal use only.