The impact of mitochondria on aging and lifespan in the short-lived killifish Nothobranchius furzeri

• Applicant: Professor Dr. Christoph Englert, since 1/2016
• Subject Area: General Genetics and Functional Genome Biology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233592434

Mitochondria have been suggested to play an important role in aging for several decades. One observation is that mitochondrial function declines with age in numerous organisms. In humans, age-related mitochondrial dysfunction has been frequently described to accumulate in patients with sarcopenia, metabolic disorders and neurodegenerative diseases. We use the short-lived killifish Nothobranchius furzeri as a model to study the impact of mitochondria on aging. For a vertebrate species, Nothobranchius furzeri has an exceptionally short lifespan of four to ten months and shows typical signs of aging. We recently observed that mitochondrial respiration, ATP content and the amount of respiratory chain complexes III and IV are significantly reduced with age in N. furzeri. We also found that mitochondrial DNA content as well as the expression of the genes Pgc-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha) and Tfam (mitochondrial transcription factor A) are decreased with age. Based on these findings we want to address the following questions in this proposal: 1) Do mutations of the mitochondrial DNA accumulate in N. furzeri with age and contribute to the decline of mitochondrial function?2) Can physical exercise prevent the age-related decline of mitochondrial function and extend the lifespan of N. furzeri?3) Does over-expression of Pgc-1alpha and Tfam improve mitochondrial function and extend lifespan? To identify mutations that have been accumulated with age, we want to analyse the entire mitochondrial DNA of aged animals. Mitochondrial DNA will be first amplified and then sequenced using next-generation sequencing technology. One approach that has been shown to increase mitochondrial function is physical exercise. Preliminary results in N. furzeri suggest that mitochondrial genes are up-regulated in muscle of exercised animals. We want to analyze the short-term and long-term impact of physical exercise on mitochondrial function and lifespan. Another approach to improve mitochondrial function is to over-express Pgc-1alpha and Tfam, which both play an important role in mitochondrial biogenesis. A prerequisite for this approach is the possibility to introduce DNA constructs into the germ line of N. furzeri. Therefore, we recently developed a microinjection protocol and successfully generated transgenic animals. Altogether, these approaches shall give new insight whether increased mitochondrial function is sufficient to delay aging and extend lifespan.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Nils Hartmann, until 12/2015