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。我们发现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。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（独立于端粒酶调节）在我们的实验室无法克隆。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。研究还表明，各种局部或全身条件（如缺氧、氧化应激、肥胖和热量摄入）可能影响细胞衰老、端粒酶调节和SIRT蛋白功能，从而调节人类衰老和致癌过程。

Aging is a major risk factor of human cancers. Our project was to elucidate molecular mechanisms of aging and cancer using cellular and animal models. We showed 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) could not be cloned in our laboratory. To understand a link between cellular aging and organismal aging, we studied SIRTs, human homologs of the yeast/worm longevity gene Sir-2 encoding a NAD-dependent protein deacetylase. Our data suggested 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). It was also suggested that various local or systemic conditions (e.g., hypoxia, oxidative stress, obesity and calorie intake) could affect cellular senescence, telomerase regulation and SIRT protein function to modulate human aging and carcinogenesis processes.