Nothobranchius furzeri as a new model system for ageing studies

Abstract

Ageing can be defined as the age-progressive decline in intrinsic physiological function, leading to an increase in age-specific mortality rate. To date, the mechanisms responsible for natural variation in lifespan and the evolution of longevity are poorly understood, especially in vertebrates. A major limitation is given by the lack of suitable experimental models for ageing studies in terms of limited survival and genetic manageability. Nothobranchius furzeri is an African annual fish known to be actually the shortest-lived vertebrate raised in laboratory and validated in the last decade as new promising model for ageing research: its lifespan can be modulated by environmental, pharmacological and dietary manipulations, and it shows most of the major ageing markers described in mammals (SA-beta galactosidase, lipofuscin, brain gliosis, etc.); the genome, the transcriptome and the proteome of this species are actually available, and RNA-seq analysis has shown a strong evolutionary conservation of many age-related gene pathways and patterns of transcripts regulation. Moreover, it is amenable to genetic manipulation and in the last years the CRISPR/Cas9 technology has been developed in this organism. In addition, its short lifespan allows to perform longitudinal studies in a manageable time frame, giving the opportunity to investigate the relationship between non-genetic lifespan variation and individual ageing. For all these reasons, this animal model represents an ideal platform to rapidly assess the impact of genetic manipulations on vertebrate ageing and age-associated pathologies. Nothobranchius furzeri is also a model for evolutionary genetics of ageing: indeed, it has been observed that geographic differences in habitat duration led to the evolution of a different rate of senescence and expression of ageing markers in Nothobranchius species from humid versus arid habitats, and finally a clear example of parallel evolution has been demonstrated for different populations belonging to two evolutionary independent Nothobranchius lineages. Finally, Nothobranchius furzeri strains show genetic differences in captive lifespan and a quantitative trait loci (QTL) approach was applied to map loci responsible for lifespan differences. This approach clearly showed that the basis for interstrain differences in lifespan is polygenic and also suggests that heritability of lifespan is low (as observed in humans). Therefore, this fish can be used to investigate the quantitative genetics of ageing.