The Notho Project
The progress of aging research in vertebrates is hampered by the lifespan of the available model systems (mouse and zebrafish) which is of several years. Only few years ago, researchers from FLI found the Turquois killifish (Nothobranchius furzeri) to have an extremely short lifespan. Now, it is established as new model organism for age research.
The Turquois Killifish
The N. furzeri inhabits ephemeral pools in semi-arid areas with scarce and erratic precipitations and has adapted to the routine drying of its environment by evolving desiccation-resistant eggs that can remain dormant in the dry mud for one and maybe more years by entering into diapause. Due to very short duration of the rain season, the natural lifespan of these animals is limited to a few months and their captive lifespan is likewise short, making them an attractive model system for aging research.
Nothobranchius furzeri has already been used for pharmacological studies of lifespan and also offers the possibility to investigate the genetic mechanisms controlling aging. The FLI is currently developing genetic and genomic resources to use this model system as a tool to investigate the molecular mechanisms controlling aging.
The Nothobranchius project at FLI is a coordinated and synergic effort of three groups:
Biology of aging
Identification of manipulations which lead to life-extension is a milestone towards understanding the biological mechanisms controlling longevity. Due to its short lifespan, Nothobranchius furzeri represents an ideal model system to investigate life-extension. Three different manipulations can retard aging in Nothobranchius furzeri:
Manipulations of environmental factors (e.g. temperature)
Dietary supplementation with small molecules (e.g. resveratrol)
Crossing with longer-lived isolates/subspecies
Aim of the group is to identify other life-extending manipulations, to test the effects of small molecules on longevity and age-related markers and to provide a phenotyping platform to dissect the genetic components controlling differences in aging phenotype in different isolates of N. furzeri.
Aging-associated genes and signaling pathways
Our aim is to use Nothobranchius furzeri to study the biochemical pathways that regulate aging and determine lifespan in vertebrates. Thus, we currently isolate aging-associated genes from N. furzeri and analyze their expression during aging. We also want to compare gene expression between N. furzeri that are subject to various life-extending treatments. Through the manipulation of gene expression we can determine the effects on lifespan. This is for example done by the CRISPR/Cas9 method which we successfully established in N. furzeri.
Finally and as a shared interest with other members of the Nothobranchius project, we want to examine some classical theories of aging/lifespan determination in the new fish model. In that context we have recently begun to analyze the trade-off between mitochondrial activity and lifespan.
Towards genomics of Nothobranchius furzeri
We have initiated projects to sequence a fraction of the N. furzeri genome by whole genome shotgun sequencing using Sanger and 454 sequencing technology. In parallel, we sequence a normalized cDNA library (cooperation with Evrogen, Moscow, Russia). Assembly, annotation and comparison of the sequences with zebrafish (Danio rerio), tetraodon (Tetraodon nigroviridis), medaka (Oryzias latipes), and stickleback (Gasterosteus aculeatus) will provide a basis for further work concerning molecular, biochemical and evolutionary aspects of aging in N. furzeri.
An initial characterization of the N. furzeri genome has been published in Genome Biology.
Our work together with ongoing phenotypic studies and breeding experiments also provides the basis for linkage and QTL analyzes. Both are a prerequisite for the identification of genetic loci controlling life span and age-related traits in N. furzeri. Our long term goal is to find aging relevant genes by positional cloning and their experimental analysis. In combination with a continued systematic analysis of both N. furzeri genome and transcriptome we will contribute to a better understanding of vertebrate aging.
For additional information see NFIN - The Nothobranchius furzeri Information Network.