Although siRNA‐mediated reduction of p16INK4a expression (about 70%) does not accurately recapitulate the reduction of p16INK4a expression (about 20%) that is elicited by the EST2‐p16INK4a axis, our data indicate that reinforcing the outcome of FOXO3 activity in response to HD, that is, by further inhibiting p16INK4a levels, may have therapeutic potential to avoid the harmful effects (maladaptation) of a chronic cellular senescence response in human HD neurons. The gene discussed is FOXO3; the disease is Huntington disease.