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.
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