Nuclear deformation, a hallmark frequently observed in senescent cells, is presumed to be associated with the erosion of chromatin organization at the nuclear periphery. However, how such gradual changes in higher-order genome organization impinge on local epigenetic modifications to drive cellular mechanisms of aging has remained enigmatic. Here, through large-scale epigenomic analyses of isogenic young, senescent, and progeroid human mesenchymal progenitor cells (hMPCs), we delineate a hierarchy of integrated structural state changes that manifest as heterochromatin loss in repressive compartments, euchromatin weakening in active compartments, switching in interfacing topological compartments, and increasing epigenetic entropy. We found that the epigenetic de-repression unlocks the expression of pregnancy-specific beta-1 glycoprotein (PSG) genes that exacerbate hMPC aging and serve as potential aging biomarkers. Our analyses provide a rich resource for uncovering the principles of epigenomic landscape organization and its changes in cellular aging and for identifying aging drivers and intervention targets with a genome-topology-based mechanism. [Display omitted] • A comprehensive survey of the aging epigenome across the chromatin hierarchy • An overall increase in chromatin entropy and epigenetic instability with aging • Consequent reactivation of PSGs due to heterochromatin erosion during aging • Reactivated PSGs as a hallmark and potential driver of human cellular aging Liu and colleagues surveyed the epigenomic landscape across the hierarchy of chromatin organizations during human stem cell aging, revealing how multifaceted genomic conformational changes associated with aging converge to impact upon senescence, and identified the activation of placenta-specific genes as a hallmark of human cellular aging. [ABSTRACT FROM AUTHOR]