Emeritus Scientific Member - MPI for Biology of Ageing (Former Director)
A major focus of the research group led by Prof. Dr. Linda Partridge is to explore the effects of nutrition and nutrient-sensing signaling networks on the aging process. Insulin, insulin-like growth factor (IGF), and mTOR (the mechanistic target of rapamycin) signaling are central areas of interest, and they provide information about nutrients, stress and growth factors, and regulate gene expression to match costly activities such as growth, metabolism, and reproduction, to current circumstances. An exact understanding of this network provides hints for identifying appropriate targets that might be responsive to new medications to improve health during aging. This would open new preventative options for age-related diseases for which we have no effective substances to slow their progression, such as amyotrophic lateral sclerosis (ALS), a motor neuron disease, and Alzheimer’s Disease.
Our research: Decoding the network of central signaling pathways for insulin, insulin-like growth factor and mTOR opens new options and targets for medical intervention and might contribute to improved health during aging. Metabolic disorders in particular, such as diabetes mellitus type II, result from dysregulation within this network. Other aging-associated diseases, such as Alzheimer’s and amyotrophic lateral sclerosis (ALS), are also associated with these dysfunctions.
The signaling networks have extensive inputs and feedbacks, and can also act systemically to affect other tissues in the body. This results in a complex system where intervention in one area sets off a reaction in others. A deeper understanding of the function of this network will provide answers about control of development, growth, reproduction and different types of stress responses that have an essential effect on metabolism and on the aging process.
Our successes: One of the research group’s greatest successes is the discovery that the mechanisms of aging are evolutionarily conserved during evolution from worms to flies and mammals. Signaling pathways and networks can be modified in these animals, resulting in an extended lifetime and improved quality of life for the organism. These findings suggest that interventions into the insulin and TOR network may also be beneficial for human health and lifespan.
Through their research into age-related functional decline, Prof. Partridge and her team have demonstrated that low activity in the insulin signaling pathway is linked to an improved sleep quality at old age. With advanced age, people often fall asleep during the day but find it difficult to fall asleep and to stay asleep at night. This phenomenon has also been observed in fruit flies. Prof. Partridge’s group was able to demonstrate that sleep quality of the fruit fly Drosophila is considerably improved by feeding Rapamycin, a drug that targets the mTOR signaling pathway. This finding could be applicable to humans and might contribute to improved sleep and consequently also quality of life with advanced age.
Our goals: A central objective of the research group led by Prof. Partridge is a comprehensive understanding of central signaling pathways, including the insulin, insulin-like growth factor and mTOR pathways.
The team also explores Alzheimer’s and motor neuron diseases, and has successfully modified the fruit fly Drosophila with one of the most important genetic risk factors for motor neuron diseases. Describing the mechanisms that can trigger such illnesses under specific genetic preconditions allows possible points of attack for targeted medications to be identified. These findings are truly groundbreaking, as there are no curative therapeutic approaches to date. The team of scientists now plans to investigate these mechanisms further with the ultimate goal of revealing new treatment possibilities for patients suffering from motor neuron and other neurodegenerative diseases.
Our methods/techniques: The scientists around Prof. Partridge work with model organisms like the fruit fly Drosophila and mice. They use genetics, behaviour assays, molecular biology and genome wide expression techniques to study the aging process. Their electrophysiological research methods on the fruit fly are unique at the institute to date.
Figure 1: Drosophila as a model organism to study motor neuron diseases. A hexanucleotide repeat expansion in the human C9ORF72 gene is a major risk factor for frontotemporal dementia and amyotrophic lateral sclerosis. Overexpression of C9orf72 hexanucleotide repeats in the Drosophila eye suggests that toxicity is caused by protein translated from the repeats, but not from the RNA itself.
Figure 2: Heat map showing differential tissue specific proteomics of Drosophila. We detected approximately 6000 proteins in each tissue, revealing highly tissue specific expression profiles in response to reduced IIS.
Figure 3: Drosophila activity monitor. A Drosophila activity monitor allows measuring sleep parameters in fruit flies. Treatment of flies with Rapamycin, an inhibitor of the mTOR pathway, ameliorated the age-related decline in sleep quality.