New Genetic Intervention for Healthy Aging

描述（由申请人提供）：研究主题11。干预。胰岛素/IGF-I信号传导减少与几种哺乳动物模型的寿命延长有关，包括卡路里限制的啮齿动物和侏儒突变小鼠。在这些模型中，血清胰岛素和IGF-I水平显著降低，胰岛素对葡萄糖处置的敏感性增加。蛋白酪氨酸磷酸酶1B（PTP-1B -/-）无效突变的纯合子小鼠与热量限制和侏儒小鼠的胰岛素/IGF-1表型非常相似。此外，它们表现出减少的内脏肥胖，这可能是这些抗衰老作用的重要介质，如果这种代谢变化的星座在鼠寿命中是重要的，PTP-1B-/-小鼠似乎有希望作为延长寿命的新的单基因突变模型。该提案的目的是确定PTP-1B-/-小鼠是否可能是长寿突变体，从而为获得R 01资金提供基础，以确定其寿命和健康寿命并探索潜在机制。 具体目的是确定PTP-1B -/-小鼠是否： 1.中位寿命延长，并表现出延迟/减弱的年龄相关病理学。 2.表现出细胞增殖和/或炎症过程减少，这些过程被假设为有助于年龄相关疾病和功能障碍。 3.在整个成年期维持其胰岛素/IGF-I/代谢表型。 如果大多数或所有这些研究的结果都是肯定的，那么它们将表明，消除PTP-1B基因是一种具有延缓衰老的强大潜力的遗传干预。这些数据将使R 01应用程序能够确定这种遗传干预对最长寿命和衰老的影响，并探索其潜在机制。PTP-1B-/-长寿突变体也将为延缓衰老的药物干预提供新的靶点。

DESCRIPTION (provided by applicant): Research Topic 11. Interventions. Reduced insulin/IGF-I signaling is implicated in the extended life span of several mammalian models, including calorie restricted rodents and dwarf mutant mice. Serum insulin and IGF-I levels are markedly reduced and insulin sensitivity for glucose disposal is increased in these models. Mice homozygous for the null mutation of protein tyrosine phosphatase 1B (PTP-1B -/-) closely mimic the insulin/IGF-1 phenotype of calorie restricted and dwarf mice. In addition, they exhibit reduced visceral adiposity, which may be an important mediator of these anti-aging effects, if this metabolic constellation of changes is important in murine longevity, the PTP-1B-/- mouse would seem promising as a new single-gene mutant model of extended longevity. The goal of this proposal is to determine if the PTP-1B-/- mouse is likely to be a longevity mutant, and thus provide the basis for obtaining R01 funding to establish definitively its longevity and healthspan and probe the underlying mechanisms. The Specific Aims are to determine if the PTP-1B -/- mouse: 1. Has an extended median lifespan and exhibits delayed/attenuated age-related pathology. 2. Exhibits reduced cell proliferation and/or inflammatory processes which are hypothesized to contribute to age-related disease and dysfunction. 3. Maintains its insulin/IGF-I/metabolic phenotype throughout adult life. If the results of most or all of these studies are affirmative, they will indicate that nullifying the PTP-1B gene is a genetic intervention with strong potential for retarding aging. These data would enable a R01 application to determine the effect of this genetic intervention on maximal longevity and aging, and to probe its underlying mechanisms. A PTP-1B-/- longevity mutant would also provide a new target for pharmacologic interventions to retard aging.