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At the onset of post-implantation embryonic development, the specification of human primordial germ cells (hPGCs) marks the preparation to attain the totipotent state through the extraordinary features of extensive epigenetic reprogramming (in terms of DNA demethylation and chromatin reorganization), a mitochondrial bottleneck, and a characteristic gene regulatory network, which are in stark contrast with those of the somatic lineage. Together, they provide for the attribute of immortality to the germ cell lineage, reflecting their significance in transgenerational inheritance. Interestingly, these features are the antithesis of the several hallmark phenotypes of aging, which gradually accumulate in the somatic lineage over time. In this chapter, we discuss the salient features of hPGC development, the hallmarks of aging, the application of cellular reprogramming as a therapeutic route to rejuvenation, and the intriguing translational potential of the lessons learned from the immortal human germline lineage in the field of anti-aging research.