1. Research Background:
The aim of the Department of Biological Mechanisms of Ageing is to discover evolutionarily conserved dietary, genetic and pharmacological interventions that can improve health and function during ageing. We investigate the mechanisms at work using an experimental approach that takes advantage of an interplay between the fruit fly Drosophila and the mouse and that paves the way for development of a broad spectrum, preventative medicine for diseases associated with human ageing.
Diet, nutrient-sensing networks such as insulin/Igf/TOR, and drugs that target the network, can all extend lifespan and improve health and function during ageing in diverse organisms. It is becoming clear that the microbiome in the guts of these animals can play a major role in health during ageing and in the responses to anti-ageing interventions. It will be important to understand the interactions between the host, the microbiome, diet and drugs, and to identify the metabolites that mediate the effects.
The aim of much research into ageing is to find ways to improve the quality of life and the health of older humans. It is therefore essential to find out whether discoveries made about ageing in animals also apply to humans. For instance, we have recently discovered that the Ras branch of the insulin/Igf signalling network is important in ageing of Drosophila. It is of high priority now to find out if this is also the case in mice and humans, because there are many powerful drugs against components of Ras signalling because of its importance in cancer.
2. Research questions addresses by the group:
- It has become clear in recent years that the gut microbiome plays a major role in responses to nutrients, drugs and genetic interventions into ageing. The microbiome also changes in composition during ageing, and increasing evidence suggests that the microbiome of younger animals plays a causal role in their youthful health and function. We are therefore analysing the role of the microbiome in health during ageing and the responses to anti-ageing interventions in Drosophila and mice.
- Gene expression changes during ageing, and several lines of evidence suggest that much of the change is a result of compensatory responses to declining tissue function. We have a powerful, new, genome-wide dataset on proteomic changes in different fly tissues during ageing. We now plan to exploit this dataset to identify new pathways and processes that can protect against ageing-related decline.
- Recent work from our lab using the fruit fly Drosophila showed that inhibition of the Ras-Mek-Erk branch of the IIT pathway is sufficient to extend lifespan in flies (Slack et al., 2015; Cell). In collaboration with Prof Eline Slagboom (Leiden University Medical Center) we identified novel protein-altering variants in human genes involved in the Ras-Mek-Erk pathway. These variants were shared among long-lived siblings from families with a history for longevity and may thus be causally related to familial longevity. The aim of the project is to determine whether these novel protein-variants might contribute to longevity in humans by studying their function in human cell culture and in model organisms.
3. Possible projects:
We always discuss possible projects with prospective students before reaching a conclusion about the direction of the research. We are currently offering three projects for interested PhD students:
- The role of the microbiome in ageing
This project will analyse, and test experimentally, the role of the microbiome in healthy ageing in Drosophila and mice and in the responses to anti-ageing intervention, such as dietary restriction, reduced insulin/Igf signalling and drugs.
- The role of the Ras-Erk Signaling pathway in human longevity
This project will be done in collaboration with Prof Eline Slagboom from the Leiden Longevity Study. The project will include CRISPR/Cas9 mediated gene editing and reprogramming of human fibroblasts isolated from long-lived individuals as well as in vivo work in model organisms (fly, mouse).
- Mining tissue-specific changes in protein expression during ageing
This project will mine a powerful, genome-wide, proteomic dataset from Drosophila to formulate and test new hypotheses about mechanisms that can protect against loss of function during ageing.
4. Applied Methods and model organisms:
Fly, mouse, human cells, including stem cells.
We employ a wide range of methods and techniques depending on the research question including:
- Genetics and molecular biology
- Genomics (RNA Seq, ChipSeq, BisulfiteSeq)
- In vivo phenotyping (behaviour, memory, metabolism)
- Drug treatment
- Tissue culture and gene editing of human cells including stem cells
5. Desirable skills and qualifications:
We seek a talented, dynamic, highly motivated young scientist to join our department at the Max Planck Institute for Biology of Ageing. The applicant will hold a master´s degree in biology, molecular biology, biochemistry or a related field and should have strong written and oral communication skills. Experience in one of the following methodologies: Drosophila or mouse in vivo work, genetics, cell culture, microbiome and gene editing is of advantage.
- Tain LS, Sehlke R, Jain C, Chokkalingam M, Nagarajuna N, Essers P, Rassner M, Grönke S, Froelich J, Dieterich C, Mann M, Alic N, Beyer A, Partridge L. A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity-assurance. Molecular Systems Biology, Sep15, 2017
- Castillo-Quan JI, Li L, Kinghorn KJ, Ivanov DK, Tain LS, Slack C, Kerr F, Nespital T, Thornton J, Hardy J, Bjedov I, Partridge L. Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis. Cell Rep. 2016 Apr 19;15(3):638-650.
- Slack C, Alic N, Foley A, Cabecinha M, Hoddinott MP, Partridge L. The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity. Cell. 2015 Jul 2;162(1):72-83.
- López-Otín C1, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013 Jun 6;153(6):1194-217.
- Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010 Jan;11(1):35-46