1 Immunosenescence Unit, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo , Palermo, Italy .
Rejuvenation Res. 2014 Apr;17(2):221-5. doi: 10.1089/rej.2013.1541.
Strong evidence suggests that systemic inflammation and central adiposity contribute to and perpetuate metabolic syndrome. All of these alterations predispose individuals to type 2 diabetes mellitus (T2DM), cardiovascular 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.
强有力的证据表明，系统性炎症和中心性肥胖导致并使代谢综合征持续存在。所有这些改变使个体易患 2 型糖尿病（T2DM）、心血管疾病以及阿尔茨海默病（AD），所有这些疾病的特征都是慢性炎症状态。另一方面，在 AD 大脑中已经证明了胰岛素和胰岛素样生长因子 I（IGF-I）和 IGF-II 信号转导机制的广泛异常，表明 AD 可能是第三种形式的糖尿病。Src 同源结构域含肌醇 5-磷酸酶 2（SHIP2）在胰岛素途径中具有重要作用，因为其过表达会导致胰岛素/IGF-1 信号转导受损。由于编码 SHIP2 的基因的一些单核苷酸多态性（SNP）在 T2DM 患者的代谢综合征和一些相关疾病中与代谢综合征显著相关，我们决定对该基因进行病例对照研究，将 AD 和 T2DM 患者作为病例，将年轻、年老和百岁老人作为对照。我们的研究结果表明，rs144989913 SNP 与成功和不成功的衰老之间存在潜在相关性，而不是与年龄相关的疾病。由于该 SNP 是 28 bp 的插入/缺失，它可能导致 SHIP2 表达的改变。值得注意的是，SHIP2 已被证明是胰岛素信号和胰岛素敏感性的有效负调节剂。许多研究表明胰岛素/IGF1 途径与衰老和长寿有关，因此推测与 SHIP2 和衰老有关的发现可能取决于其对胰岛素/IGF-1 途径的影响。
