Translational Studies Linking Aging and Cancer

描述（由申请人提供）：该项目采用了衰老科学基础研究建议的新策略，寻找能够延长健康、年轻寿命并对抗癌症等与年龄相关的疾病的小分子（药物前体）。 在动物中，许多营养、能量和压力感应基因的突变可以延长青春和寿命，并预防与年龄相关的疾病。老龄化研究人员的共同梦想是，这些非凡的发现将带来新的方法，让我们在衰老过程中保持年轻、远离疾病。我的实验室进行了小分子筛选，希望能让这个梦想更接近现实。 我们不是针对单一的衰老调节因子，而是首先筛选许多长寿动物突变体以及长寿物种的细胞所共有的细胞表型，从而撒下一张广泛的网：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，事实证明，一小部分的点击可以延长寿命。从 104,000 种化合物的筛选中，我们发现了约 50 种化合物可以使培养的人类原代细胞抵抗氧化应激。有些还可以抵抗其他压力源。我们现在要问的是，这些化合物中的哪一种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，并且至少有一些小分子似乎可以增加秀丽隐杆线虫的抗应激能力和寿命。 许多长寿突变体的一个标志是抗癌性，我们的一些热门突变体预计具有抗癌活性。因此这个 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能延缓癌症的发生。在这项研究中，我们利用衰老的基础生物学知识来开发寻找抗癌药物的新方法。这些药物还可以增强青春活力和整体健康。

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.