Cell Senescence, Carcinogenesis, and Aging

衰老是人类癌症的一个主要危险因素。我们的项目是通过细胞和动物模型来阐明衰老和癌症的分子机制。我们已经证明，正常的人类细胞有端粒酶依赖和独立的细胞衰老途径，这两者都作为肿瘤抑制机制。采用定位克隆和功能克隆的方法克隆染色体3p21上的衰老基因（端粒酶hTERT基因的转录抑制因子）和染色体1q42.3上的衰老基因（独立于端粒酶调控）。为了了解细胞衰老和机体衰老之间的联系，我们研究了SIRTs，酵母/蠕虫长寿基因Sir-2的人类同源物，该基因编码一种nad依赖性蛋白去乙酰化酶。我们的数据表明，与酵母或蠕虫相比，人类衰老过程的调控更为复杂，人类SIRT蛋白在不同的细胞位置（即细胞核、核仁、细胞质和线粒体）具有多种功能。我们发现，在哺乳动物细胞衰老和体内衰老过程中，DNA双链断裂（DSB）在细胞中积累，为细胞衰老促进机体衰老的机制提供了重要的见解。我们也在研究不同的局部或全身条件（例如，缺氧，氧化应激，肥胖，卡路里摄入）如何影响上述途径/因素来调节人类衰老和致癌过程。

Aging is a major risk factor of human cancers. Our project is to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We have shown that normal human cells have telomerase-dependent and independent pathways for cellular senescence, which both serve as a tumor suppressive mechanism. The senescence genes on chromosome 3p21 (a transcriptional repressor of the telomerase hTERT gene) and chromosome 1q42.3 (which functions independently of telomerase regulation) are to be cloned by the positional and functional cloning methods. To understand a link between cellular aging and organismal aging, we study SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggest the more complex regulation of aging processes in humans than in yeast or worms and multiple functions of human SIRT proteins at different cellular locations (i.e., nucleus, nucleolus, cytoplasm and mitochondria). We have found that DNA double-strand breaks (DSB) accumulate in mammalian cells during both cellular senescence and in vivo aging, providing important insight into the mechanism by which cellular senescence contribute to organismal aging. We are also examining how various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity, calorie intake) affect the above-mentioned pathways/factors to regulate human aging and carcinogenesis processes.