Abstract
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.
Highlights
Fish of the genus Nothobranchius, so-called killifish, are the fastest maturing vertebrates and have a short lifespan, which is obviously associated with adaptation to the seasonal rains in habitats
The overall number of assembled transcripts was almost proportional to the dataset size
It is not surprising that we found significant sex differences in the brain transcriptomes of fish treated using the nootropic drug
Summary
Fish of the genus Nothobranchius, so-called killifish, are the fastest maturing vertebrates and have a short lifespan, which is obviously associated with adaptation to the seasonal rains in habitats. Subsequent studies have shown that N. guentheri demonstrated changes in the expression of aging biomarkers [7,8,9] making this species suitable for testing anti-aging interventions [10,11] and for studying various aspects of aging, including brain aging [12,13]. Studies on Nothobranchius furzeri, the shortest-lived species of Nothobranchius, have shown several signs of brain aging including reduced learning performances, age-dependent gliosis, and reduced adult neurogenesis [15]. As for other Nothobranchius species, there are still no studies of gene expression alteration during brain aging. We studied the effect of prolonged oral administration of meclofenoxate (MF, known as centrophenoxine) on the transcriptome of N. guentheri aging brain. We juxtaposed the derived results with the observed age-associated gene expression changes for the control group
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