The Effect of Meclofenoxate on the Transcriptome of Aging Brain of Nothobranchius guentheri Annual Killifish.

Annual fish of the genus Nothobranchius are promising models for aging research. Nothobranchius reproduces typical aspects of vertebrate aging, including hallmarks of brain aging. Meclofenoxate (MF) is a well-known compound that can enhance cognitive performance. The drug is prescribed for asthenic conditions, trauma, and vascular diseases of the brain. It is believed that MF is able to delay age-dependent changes in the human brain. However, until now, there has been no study of the MF effect on the brain transcriptome. In the present work, we performed an RNA-Seq study of brain tissues from aged Nothobranchius guentheri, which were almost lifetime administered with MF, as well as young and aged control fish. As expected, in response to MF, we revealed significant overexpression of neuron-specific genes including genes involved in synaptic activity and plasticity, neurotransmitter secretion, and neuron projection. The effect was more pronounced in female fish. In this aspect, MF alleviated age-dependent decreased expression of genes involved in neuronal activity. In both treated and untreated animals, we observed strong aging-associated overexpression of immune and inflammatory response genes. MF treatment did not prevent this effect, and moreover, some of these genes tended to be slightly upregulated under MF treatment. Additionally, we noticed upregulation of some genes associated with aging and cellular senescence, including isoforms of putative vascular cell adhesion molecule 1 (VCAM1), protein O-GlcNAcase (OGA), protein kinase C alpha type (KPCA), prolow-density lipoprotein receptor-related protein 1 (LRP1). Noteworthy, MF treatment was also associated with the elevated transcription of transposons, which are highly abundant in the N. guentheri genome. In conclusion, MF compensates for the age-dependent downregulation of neuronal activity genes, but its effect on aging brain transcriptome still cannot be considered unambiguously positive.

Multifaceted Nothobranchius.

Annual killifish of the genus Nothobranchius are seeing a rapid increase in scientific interest over the years. A variety of aspects surrounding the egg-laying Cyprinodontiformes is being extensively studied, including their aging. Inhabiting drying water bodies of Africa rarely allows survival through more than one rainy season for the Nothobranchius populations. Therefore, there is no lifespan-related bias in natural selection, which has ultimately led to the decreased efficiency of DNA repair system. Aging of the Nothobranchius species is studied both under normal conditions and under the influence of potential geroprotectors, as well as genetic modifications. Most biogerontological studies are conducted using the species Nothobranchius furzeri (GRZ isolate), which has a lifespan of 3 to 7 months. However, the list of model species of Nothobranchius is considerably wider, and the range of advanced research areas with their participation extends far beyond gerontology. This review summarizes the most interesting and promising topics developing in the studies of the fish of Nothobranchius genus. Both classical studies related to lifespan control and rather new ones are discussed, including mechanisms of diapause, challenges of systematics and phylogeny, evolution of sex determination mechanisms, changes in chromosome count, occurrence of multiple repeated DNA sequences in the genome, cognitive and behavioral features and social stratification, as well as methodological difficulties in working with Nothobranchius.