Progressive loss of individual muscle fibers in the elderly is a characteristic hallmark of aging-related muscle wasting condition – sarcopenia. We recently developed a model to address aging-related fiber loss (ARFL) on the basis of Drosophila jump muscle. In this study, the ARFL rates were analyzed in the muscles with depleted chromatin-remodeling factors, histone deacetylases (HDACs). Drosophila and human HDAC3 and HDAC4 share significant homology and are expressed in various muscle tissues. We used RNAi to down-regulate these HDACs in adult flies by means of a jump-muscle specific Gal4 driver. Our results show that the decreased expression of either HDAC3 or HDAC4 strongly promotes muscle fiber loss in aging flies. We hypothesize that this effect might be mediated by changes in HDAC-controlled expression of apoptotic factors. Our study identifies HDACs as important regulators of muscle longevity and survivorship, with potential implications in the development of human sarcopenia.