GAIN INSIGHTS INTO OUR SCIENTIFIC FINDINGS
The long-term goal of our research activities is to pave the way towards increasing health during ageing in humans. To reach this objective, our scientists explore the basic causes and processes of ageing by using mice, flies, worms, and fish as model organisms.
With our "research stories" we would like to offer you insights into our work. To this end, we have selected a couple of highlights that have already been published in scientific papers. So please enjoy browsing our short stories.
In this study Prof. Dr. Antebi´s laboratory analysed the timing and regulation of development in the round worm C. elegans. This small worm, about 1mm of length, normally lives in the soil and over the last decades has become a frequently used model organism, not only in ageing research, to explore genetic and developmental aspects.
Subject of the group´s study was a specific gene of the worm encoding the nuclear hormone receptor named "DAF-12". Biochemically speaking, DAF-12 is a protein. Proteins in turn are the "work horses" of organisms. For example, they transport metabolic products, they pump substances through the body, they catalyse processes. The protein DAF-12 is activated upon binding of its ligand called "dafachronic acid". Upon binding, the protein can initiate a specific developmental programme. It does so by inducing the expression of specific small RNAs. These so-called microRNAs in turn downregulate the expression of other genes involved in the development of the worm.
And what happens, when DAF-12 remains without its ligand? Just the opposite: there is no expression of these microRNAs and the roundworm experiences developmental arrest.
How developmental programmes might interact with environmental conditions
These findings are of particular interest in so far as they elucidate a cascade of events that integrate environmental conditions and translate them into the regulation of developmental programmes. In this case, unfavourable environmental conditions like reduced caloric input, high temperature (27°C) and a high population density result in the non-binding of DAF-12 to its ligand and thus lead to developmental arrest.
Ultimately, these events on the molecular level have an impact on the correct and timely execution of the above mentioned developmental programmes. Thus they play a role in the organism´s change from one developmental stage to another or its arrest in the current stage.
In the process described above, DAF-12 acts as a "molecular switch" turning on or off certain target genes that are important for the development of the worm.
This concept is of great general interest as it may represent a universal mode of action as to how developmental processes in multicellular organisms are regulated, like for instance the proper anatomical and functional establishment of certain tissues.
In this study Prof. Dr. Antebi's lab analysed how certain molecules (bile acids) are actually synthesized step by step. Ultimately, the knowledge of the exact synthesis, the proteins and enzymes involved might allow for intervention and pharmacological manipulation of similar processes in higher organisms. In other words: results from this kind of basic research might for example pave the way towards new therapeutic possibilities in humans.
While well known for their role in the absorption of dietary fat, bile acids have also emerged as important signaling molecules. They work through so-called "nuclear receptors": Bile acids bind as a "ligand" to their "receptor" in the nucleus and thereby switch on or off certain genes.
Actually, you might imagine this like a situation where several workers act hand in hand. In the process, everybody has a special job to do and tells the next one in line just when to start. And in the end, the overall task is fulfilled. In our case: the activation or downregulation of certain genes. In the cell, this kind of team work amongst molecules that is needed to control cell functions is called a signalling pathway.
The bile acids regulate development and longevity in the worm
In the roundworm C. elegans, a frequently used model organism in ageing research, the protein called "DAF-12" is such a nuclear receptor for bile acids. And in the worm, those acids are called the "dafachronic acids" (DA). They are known to regulate development and longevity via the (down)regulation of certain genes. However, the exact synthesis of these acid molecules remains unclear - just as much as the exact regulating role of the enzymes involved here is still not entirely understood (generally speaking, enzymes have the job to put things together or take them apart, for example in the process of synthesizing molecules). So the Antebi lab took a closer look.
How a molecular team puts together the bile acid molecules
In this study, the enzymes play a regulating role in biochemical activities in the worm that have to do with the biosynthesis of DA. Part of the molecular team at work here is "DHS-16", a "3-hydroxy steroid dehydrogenase". This long term is the name of an enzyme that is very similar in the worm compared to the same or equivalent protein of other organisms, for example in flies or mice. In our case, it´s this enzyme´s job on the team to reduce a hydroxy/alcohol sidechain (-OH) of one of the intermediate products of the DA synthesis to a keto side chain (=O), if you remember chain gangs from your chemistry class at school ... - see the red boxes in the figure below.
To make a long story short, this is just one step of several in the synthesis. Our enzyme with the long name is one player in the production of the dafachronic acids, which is in fact a 3-4 step enzymatic synthesis, starting from dietary cholesterol:
The identified activities reveal remarkable evolutionary conservation compared to those seen in mammalian bile acid synthesis. Thus, they might provide novel ways to manipulate animal life span and cholesterol homeostasis.
Scientists of the Larsson Lab, together with colleagues of the University of Gothenburg in Sweden and the Max Planck Institute for Biophysical Chemistry, were able to gain high-resolution insights in the scope of nanometers into the genome of mitochondria, the so-called "cellular power plants". One nanometer is the equivalent of a millionth millimetre.
Mitochondria are described as "cellular power plants", because they produce energy in nearly every cell in the (human) body. Since they evolved from bacteria, they harbor their own genome, the mitochondrial DNA. Proteins and DNA are organized as complexes called mitochondrial nucleoids inside the mitochondria. These point-shaped structures can be visualized in the microscope.
The resolution of conventional light microscopes is around 250 nanometers. So far, deeper insights into the structure of nucleoids were impossible. This was a very good reason for the international team to strive for more - and finally reveal these structures with modern super-resolution STED microscopy.
Understanding mitochondrially inherited diseases
The scientists studied mitochondrial nucleoids in different organisms, like human, mouse, African green monkey and potoroo, the latter being a kangaroo/rat-like animal about the size of a rabbit. The measured size of approximately 100 nanometers in average for nucleoids was much smaller than expected. By combining super-resolution microscopy with techniques from the field of molecular biology, the team was able to show that most of the nucleoids harbored just a single molecule of mitochondrial DNA.
This basic important finding will help to provide insights into diseases that are inherited mitochondrially, from mothers to the offspring (mitochondrial DNA is always and only passed on to the next generation by the mother). Furthermore, it is known that there are strong connections between the "cellular power plants" and ageing.
Scientists in the Partridge lab are using a pharmacological approach to delay ageing, using the fruit fly as a model organism.
It has been known for over two decades now that, remarkably, a mutation in a single gene is sufficient to prolong lifespan and ameliorate health in model organisms, such as yeast, worms, flies and mice. The genes involved belong to cellular nutrient-sensing pathways, one of which is called target-of-rapamycin.
In order for humans to benefit from these genetic findings, scientists led by Prof. Dr. Linda Partridge used the fruit fly Drosophila melanogaster to investigate whether drugs acting through this target-of-rapamycin pathway can also have beneficial effects on lifespan, similarly to their genetic mutants.
Rapamycin - a drug discovered in the soil
Rapamycin, the drug investigated, is named after "Rapa Nui", the native translation for the Easter Islands, where the drug was discovered in a soil sample as a bacterial metabolite. Originally, these bacteria secreted rapamycin into the soil in order to stop the growth of competitive fungi, and to absorb as many nutrients as possible themselves.
Anti-ageing effects of rapamycin in flies
Interestingly, flies fed on this drug lived longer than the controls. The target-of-rapamycin pathway plays many important roles, so the scientists needed to establish which specific mechanism was accountable for the longevity effect. The target-of-rapamycin pathway promotes cell growth when nutrients are abundant, but when nutrients become scarce (or when this pathway is inhibited by rapamycin), then cells stop the energetically costly synthesis of proteins and instead start degrading ("recycling") a portion of themselves in order to survive during the stressful period. This process of cellular self-degradation is called autophagy. Interestingly, this study demonstrated that autophagy is essential to achieve the beneficial effects of rapamycin. Another protein essential for the anti-ageing effects of rapamycin is called S6K, and it was demonstrated previously by Prof. Dr. Partridge and Prof. Dr. Dominic Withers that mice carrying a mutation in this gene live longer.
Why research with flies can be applied to mammals
Since flies have relatively short lifespan, scientists were able to uncover the mechanism by which rapamycin slows ageing. Because the target-of-rapamycin pathway is conserved in evolution, this research with flies is very relevant and can be applied to mammals. Indeed, rapamycin is also the first drug shown to extend lifespan in mice. It is also given to humans, not yet in the context of ageing, but as an immunosuppressant and an anti-cancer drug.
Ageing is a topic of great social and economic importance, and many efforts are focussed on understanding and treating the ageing process. According to this study, the autophagy process and the S6K protein are promising targets for drug interventions to improve health and delay disease in the elderly.