Translational Studies Linking Aging and Cancer

描述(申请人提供)：这个项目采用了一种新的策略，由衰老科学的基础研究建议，寻找小分子(药物的前体)，延长健康、年轻的寿命，并对抗与年龄相关的疾病，如癌症。在动物中，许多营养、能量和压力敏感基因的突变延长了年轻和寿命，并预防了与年龄相关的疾病。老龄化研究人员的一个共同梦想是，这些非凡的发现将导致新的方法，使我们在变老时更年轻，更没有疾病。我的实验室进行了一次小分子筛选，希望能让这个梦想更接近现实。我们没有针对单一的衰老调节因子，而是撒下了一张大网，首先筛选了许多长寿动物突变体的细胞以及长寿物种的细胞所共有的一种细胞表型：对多种形式的环境压力的抵抗力增强。当在动物身上进行类似的筛选时，一小部分点击率已被证明可以延长寿命。从104,000种化合物中，我们发现了~50种使培养中的人类原代细胞抵抗氧化应激的物质。有些人还能抵抗其他压力源。我们现在正在问，这些化合物中的哪些可能会激活人类的长寿途径。到目前为止，至少有一些小分子激活了延长动物寿命的途径，至少有一些似乎增加了线虫的抗逆性和寿命。许多长寿突变体的一个特点是抗癌，我们的几个热门药物被预测具有抗癌活性。因此，这就是 筛查策略可能会带来治疗或预防癌症的新方法。我们将通过测试我们的小分子的抗癌活性来探索这一假设。相关性：癌症是一种与年龄相关的疾病，许多延长动物寿命的基因扰动也会延缓癌症的发生。在这项研究中，我们利用我们对衰老的基本生物学知识来开发新的方法来寻找抗癌药物。这些药物还应该增加青春和一般健康。

DESCRIPTION (provided by applicant): This project employs a new strategy, suggested by basic research in the science of aging, to find small molecules (precursors of drugs) that extend healthy, youthful lifespan and combat age-related diseases such as cancer. In animals, mutations in many nutrient, energy and stress-sensing genes extend youthfulness and lifespan and prevent age-related disease. A shared dream of aging researchers is that these remarkable findings will lead to new ways to keep us more youthful and disease-free as we age. My lab has carried out a small-molecule screen in hopes of bringing this dream closer to reality. Instead of targeting a single aging regulator, we cast a wide net by screening first for a cellular phenotype that is shared by cells from many long-lived animal mutants, as well as cells from long-lived species: increased resistance to multiple forms of environmental stress. When similar screens have been done in animals, a fraction of the hits have proven to extend lifespan. From a screen of 104,000 compounds, we found ~ 50 that make human primary cells in culture resistant to oxidative stress. Some confer resistance to other stressors as well. We are now asking which of these compounds might activate human longevity pathways. So far, at least some small molecules activate pathways that extend lifespan in animals, and at least some appear to increase C. elegans stress resistance and lifespan. A hallmark of many long-lived mutants is cancer resistance, and several of our top hits are predicted to have anticancer activity. Thus this screening strategy may lead to new ways to treat or prevent cancer. We will explore this hypothesis by testing our small molecules for anticancer activity. Relevance: Cancer is an age-related disease, and many gene perturbations that extend lifespan in animals also delay cancer. In this study, we use our knowledge of the basic biology of aging to develop new ways to find drugs against cancer. These drugs should also increase youthfulness and general health.