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In recent years, histone deacetylase inhibitors (HDACIs) have been proposed as a budding type of therapeutics with anti-aging effects. Indeed, epigenetic regulatory mechanisms are increasingly appreciated as central to a variety of age-associated processes, and this novel class of drugs targeting epigenetic pathways might be predicted to affect cellular and organismal senescence, genomic instability, and tumorigenesis. This chapter presents an overview of the health-beneficial and life-extending effects of HDACIs, which may be caused by generalized changes in epigenetic regulation of gene expression. Data supporting this hypothesis and other plausible mechanism(s) of HDACIs action are discussed. Overall, findings reviewed in this chapter suggest that uncovering basic genetic mechanisms and metabolic pathways contributing to healthy aging and affected by HDACIs is on the way to the understanding and development of new strategies for treating and preventing age-related human diseases and health span extension.

In this study, we compare the variability of the regulatory region of the Lim3 gene, which plays a key role in the development of the nervous system, in two populations of Drosophila melanogaster inhabiting the cities of Aleksandrov (Russia) and Raleigh (United States). The two population areas are located in different geographic regions and differ in their ecology. A comparison of nucleotide sequences of 16 (2010) and 20 (2011) alleles from the Alexandrov population showed that in both cases the variability level of the untranslated Lim3 region was considerably lower than that of the 5' regulatory region adjacent to the transcription start site. According to quantitative and quantitative parameters of the variability, there was no difference between samples of different years, which indicates the stability of the population inhabiting the northern border of the species areal. The patterns of polymorphic sites are similar in both populations, which suggest a neutral character of the variability found with respect to environmental factors, as well as the importance of nucleotide substitutions in a number of sites of the Lim3 regulatory region with respect to the control of this gene expression.

It is recognized that a stable number of transposable element (TE) copies per genome is maintained in natural populations of D. melanogaster as a result of the dynamic equilibrium between transposition to new sites and natural selection eliminating copies. The force of natural selection opposing TE multiplication is partly relaxed in inbred laboratory lines of flies. The average rate of TE transposition is from 2.6 x 10(-4) to 5.0 x 10(-4) per copy per generation, and the average rate of excision is at least two orders of magnitude lower; therefore inbred lines accumulate increasing numbers of copies with time. Correlations between the rate of transposition and TE copy number have been determined for copia, Doc, roo, and 412 and found to be either zero or positive. Because the rate of transposition is not a decreasing function of TE copy number, TE accumulation in inbred lines is self-accelerating. Transpositions cause a substantial fraction of mutations in D. melanogaster, therefore the mutation rate should increase with time in laboratory lines of this species. Inferences about the properties of spontaneous mutations from studies of mutation accumulation in laboratory lines should be reevaluated, because they are based on the assumption of a constant mutation rate.

We have analysed by in situ hybridization the insertion site polymorphism of the copia, mdg1, mdg3, and P transposable elements in diploid genomes of wild males from a natural population of Drosophila melanogaster. The values of observed average degree of individual heterozygosity for all elements except mdg3 deviate statistically from the values expected by site frequencies, revealing a tendency toward homozygosity as if drift or a structuration in the population was operating. The high degree of heterozygosity for mdg3 which in addition does not deviate from the expected value, suggests that recent high rate of movements has strongly countered the population host effect on this element. Hence, heterozygosity for TEs may well reflect the history of the population, and reveals temporary high rate of site movement existing in natural populations.