Together, these data reveal that cellular senescence may develop during neuronal differentiation in HD, affecting striatal neurons, and that FOXO gene regulation may tip the balance away from the detrimental consequences of cellular senescence via ETS2‐p16INK4a, providing a rationale and strategy for targeting cellular senescence during the early phases of NDs, before the onset of overt neuronal injuries and cell death, a crucial need in HD and other NDs. Here, CDKN2A is linked to Huntington disease.