ZMPSTE24 and Hutchinson-Gilford progeria syndrome: Most PIs inhibit Zmpste24, leading to the cellular accumulation of prelamin A.25–27 Impaired biosynthesis of mature Lamin A is associated with several genetic diseases, such as Hutchinson-Gilford progeria syndrome and mandibuloacral dysplasia.28 Zmpste24 mutation causes restrictive dermopathy, a neonatal lethal progeroid disorder.29 Zmpste24 knockout mice exhibit spontaneous bone fractures, reduced BMD, and progressive hair loss.30 Whether the side effects of PIs on senescence are related to the downregulation of Zmpste24 remains uncertain.16