These data show that both TLR4 and HDAC2 modulate p16INK4a expression, that the direction of modulation parallels what has been found in human COPD, and that HDAC2 is regulated by TLR4, suggesting that TLR4 prevents senescence, in part, by modulating HDAC2 activation. Here, TLR4 is linked to chronic obstructive pulmonary disease.