We tested the effects of a Class I histone deacetylase inhibitor (HDAcI), sodium butyrate (NaBu), on the longevity of normal- and long-lived strains of Drosophila melanogaster. This HDAcI has mixed effects in the normal-lived Ra strain as it decreases mortality rates and increases longevity when administered in the transition or senescent spans, but decreases longevity when administered over the health span only or over the entire adult lifespan. Mostly deleterious effects are noted when administered by either method to the long-lived La strain. Thus “mid- to late-life” drugs may have different stage-specific effects on different genomes of a model organism. A different HDAcI (suberoylanilide hydroxamic acid, SAHA) administered to the normal-lived strain showed similar late-life extending effects, suggesting that this is not an isolated effect of one drug. These data also show that the use of an HDAcI can significantly alter the mortality rate of the senescent span by decreasing its vulnerability, or short-term risk of death, in a manner similar to that of dietary restriction. These studies may help to shed light on the frailty syndrome affecting some aging organisms.