Human Embyryonic Stem (ES) cells are unique in two important aspects. First, they are totipotent (capable of differentiating into any somatic cell type). Second, they are immortal germ-line cells and are, therefore, able to make young cells in vitro for therapy in age-related disease. An important problem to be resolved is how tolerance is to be achieved in transplants made from ES-derived cells. We are pursuing two approaches for tolerance: namely, somatic cell nuclear transfer (using both human and nonhuman oocytes) and the generation of a bank of human ES cells that are homozygous in the HLA region. The relative benefits of these alternatives will be discussed as well as data relating to the cellular lifespan of cells produced by these techniques, and their potential utility in age-related disease including heart disease, immunosenescence, and cancer.