Abstract
Aging studies using animal and cellular models have uncovered key proteins and pathways central to organismal aging. However, these models differ genetically and physiologically from human aging, posing challenges in translating discoveries to human contexts. In this study, we present a human normal cell aging model based on the development of cytotrophoblasts (CTBs) to syncytiotrophoblasts (STBs) in the placenta. The in vitro-derived STBs from human trophoblast stem cells (hTSCs) recapitulate the maturation and major cellular aging features of in vivo CTB-STB, including multinucleation, hormone secretion, cell cycle arrest, genome instability, epigenetic changes, activation of endogenous transposable elements, and senescence-associated secretory phenotypes (SASPs). Notably, the progressive senescence in the trophoblast system closely matches the predicted aging trajectory of other human tissue stem cells. Known anti-aging molecules, such as mTOR inhibitors and senolytics, attenuate senescence signals in STBs. The established CGA-EGFP reporter hTSC line enables scalable and quantitative screening and identified candidates with it can be further extended to other context-specific aging processes like that of skin fibroblasts. The hTSC-STB system represents a novel physiologically accelerated cellular aging model, bridges the gap between fundamental aging research and interventions, and prioritizes anti-aging candidates for clinical development.