Biological Mechanisms of Ageing

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.

Lowered activity of the nutrient-sensing insulin/insulin-like growth factor (IGF)/target of rapamycin (TOR) signalling (IIT) network can extend lifespan and improve health during ageing in budding yeast, C. elegans, Drosophila, mouse and, possibly, humans. The IIT network senses nutrient status and matches nutrient-consuming activities, such as growth, reproduction, metabolism and stress responses. We unravel the mechanisms by which reduced IIT improves health, the role of memory of signalling status, and how IIT protects against neurodegeneration.

Dietary restriction (DR) can extend healthy lifespan in diverse animal species including rhesus monkeys. Aspects of human health are also improved by DR, but most humans find the regime impossible to maintain. We are therefore investigating mechanisms mediating the health benefits of DR, to identify potential drug targets, by identifying nutrients that induce DR, the mechanisms by which they are sensed, the consequent changes in physiology, and the mechanisms involved in long-term memory of diet.

Age is the major risk factor for cancer, cardiovascular disease and neurodegeneration. We use both natural neurodegeneration and fly models of Alzheimer's, Parkinson's and motor neuron disease to understand the mechanisms leading to pathology, the ways in which ageing acts as a risk factor, and potential mechanisms that could reverse pathology.

Research areas

Nutrient-sensing Pathways and Ageing

Healthy lifespan of laboratory animals can be substantially increased by genetic and pharmacological interventions that decrease activity of the insulin/Igf/TOR (IIT) network. However, reduced IIT activity can have pleiotropic effects, such as diabetes and impaired wound healing and immune response. IIT also affects growth, fecundity, metabolism and stress responses. Therefore, our key aims are to discover modulations that improve health with the fewest side-effects, as well as to determine the molecular mechanisms at work and the timescales upon which they act.

We recently found that Ras-ERK signalling increases fly lifespan.

First results of this research area/topic have been published in
Slack, C., Alic, N., Foley, A., Cabecinha, M., Hoddinott, M.P. & Partridge, L. 2015. The Ras-Erk-ETS signalling pathway is a drug target for longevity. Cell 162, 72-83.

Click here to see a video of the authors summarizing their paper.

Two important questions at the molecular level are how gene expression in specific tissues is altered by lowered IIT, and how these changes contribute to amelioration of ageing. Lowered IIT has pleiotropic effects, complicating identification of mechanisms specifically extending lifespan. Two fly models may allow us to disentangle this: (1) Deletion of three Drosophila insulin-like peptides greatly extends lifespan, but only in the presence of the symbiotic bacterium Wolbachia pipientis, which does not affect other phenotypes resulting from reduced IIS. (2) Ablation of the insulin producing cells (IPCs) extends lifespan, but only in the presence of dfoxo, which leaves other reduced IIT phenotypes unaffected, except xenobiotic resistance, which is controlled separately from lifespan.

First results of this research area/topic have been published in
Grönke, S., Clarke, D.-F., Broughton, S., Andrews, T.D. & Partridge, L. 2010. Molecular evolution and functional characterization of Drosophila insulin-like peptides. PLoS Genet. 6, e1000857.
Slack, C., Giannakou, M.E., Foley, A., Goss, M. & Partridge, L. 2011. dFOXO-independent effects of reduced insulin-like signaling in Drosophila. Aging Cell. 10, 735-748.

Prominent players in control of ageing control are the well known Forkheadbox-O (FoxO) transcription factors, that also mediate cellular processes like apoptosis and autophagy in response to environmental cues. FoxO factors are downstream components of the IIS (insulin/IGF signalling) pathway and are fundamental to extend lifespan in different model organisms under low IIS. Tissue specific overexpression of FoxO in C. elegans (DAF-16) and Drosophila melanogaster (dFOXO) is sufficient to extend the lifespan of both organisms. Furthermore, different FoxO polymorphisms have been associated with long-lived populations in humans. This project investigates their role in ageing in Drosophila and the mouse

Increased expression of genes involved in xenobiotic metabolism, and also increased resistance to xenobiotics, are common correlates of lifespan-extension by reduced IIT and other interventions. One hypothesis is that the ameliorated ability to metabolize toxic compounds leads to the life span extension. We are investigating this idea through manipulation of hormone nuclear receptors in the fly.

The study is done in collaboration with Dr Dan Magner and Prof Adam Antebi (Department for Molecular Genetics of Ageing, MPI for Biology of Ageing).

Tissue Regeneration is an essential homeostatic mechanism that maintains barrier integrity after damage. Disruption and delay of tissue regeneration may results from chronic disease (exp. diabetes mellitus, vascular disease) as well as ageing processes. Delay of wound repair in aged tissue or under pathophysiological conditions increases mortality and reduces life expectancy. The morphogenesis of the wound healing process (immediate response, inflammatory response, new tissue formation, tissue remodelling) in different organisms is well documented and shows various overlapping phases from insects to mammals. However, many of the underlying molecular and cellular mechanisms are still unclear.

To investigate the influence of ageing on the processes of epithelialisation during wound healing we use Drosophila as a model system. We will study epithelial cell migration during dorsal closure in the embryo and wound healing during both larval and adult stages of long- and short-lived Drosophila mutants. We focus on changes in cell adhesion, cell polarity and cell shape using live confocal imaging techniques to characterise these processes with high spatial and temporal resolution in wild type and mutant conditions. This will enable us to detect changes caused by ageing related processes.

The project is undertaken in cooperation with Prof Maria Leptin at University of Cologne.

Nutrition and Health during Ageing

Dietary restriction (DR), a reduction in food intake that falls short of malnutrition, increases health during ageing in almost all organisms tested, including rhesus monkeys. DR animals are protected against most functional decline and ageing-related disease. However, DR has downsides, including impaired wound healing and vulnerability to viral infection. We aim to identify the mechanisms mediating the health benefits of DR in Drosophila and mice.

In both Drosophila and mice, specific nutrients rather than overall calories, mediate the effects of DR on health. Reduced intake of protein is important, with essential amino acids (EAAs) of key importance in Drosophila. We have investigated the mechanisms at work in flies and developed a chemically defined diet for Drosophila, which allowed us freely to freely vary EAA ratios in the diet. We used this holidic medium to investigate amino acid-specific effects on food-choice behaviour and report that folic acid from the microbiota is sufficient for Drosophila development.

First results of this research area/topic have been published in
Piper, M.D., Blanc, E., Leitão-Gonçalves, R., Yang, M., He, X., Linford, N.J., Hoddinott, M.P., Hopfen, C., Soultoukis, G.A., Niemeyer, C., Kerr, F., Pletcher, S.D., Ribeiro, C. & Partridge, L. 2014. A holidic medium for Drosophila melanogaster. Nat Methods. 11, 100-105.

This project is done in collaboration with Matthew Piper, Institute of Healthy Ageing, UCL, and Stephen Simpson, University of Sydney.

Ageing and Neurodegeneration

Ageing is the main risk factor for most neurodegenerative disease including Alzheimer's, Huntington's and Parkinson's disease. Using Drosophila, we investigate mechanisms mediating pathology in fly models of Alzheimer's disease (AD) and frontotemporal dementia (FTD) / amyotrophic lateral sclerosis (ALS). We also investigate quality of sleep, which is often disturbed and fragmented in elderly people.

Neurodegeneration in AD is accompanied by aggregation of Amyloid-β (Aβ) peptides and Tau proteins. Aβ peptides are of different sizes in amyloid deposits of AD brains. Aβ43 was recently shown to have high amyloidogenic properties in vitro and is present in AD brains as often as the better-known Aβ42. We investigated the in vivo neurotoxicity of human Aβ43 compared to other Aβ peptides. Using Drosophila, we standardized Aβ mRNA expression and confined it to adult neurons. Aβ43 peptides were highly toxic compared to the normally non-toxic Aβ40 and had a high propensity to self aggregate. Aβ43 peptides also triggered toxicity and aggregation of Aβ40. Aβ43 peptides may thus contribute to pathology in AD.

First results of this research area/topic have been published in
Burnouf, S., Gorsky, M., Dols, J., Grönke, S., and Partridge, L. 2015. Aβ43 is neurotoxic and primes aggregation of Aβ40 in vivo. Acta Neuropathol. 130, 35-47.

The project is done in collaboration with Eckhard and Eva-Maria Mandelkow, DZNE and Caesar, Bonn.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are adult onset, fatal, neurodegenerative diseases. The most common genetic cause of ALS and FTD is an expanded GGGGCC hexanucleotide repeat in the first intron of the C9ORF72 gene. Healthy people carry up to 30 copies of the repeat expansion, while C9orf72 in ALS and FTD patients carry between 400 and 4400.

Three mechanisms have been suggested for hexanucleotide repeat expansion toxicity: (1) Loss of function of the C9orf72 gene, (2) toxic sense and/ or antisense repeat RNA molecules that sequester RNA binding proteins, or (3) toxic dipeptide repeat (DPR) proteins generated by non-ATG-mediated (RAN) translation.

To distinguish between repeat RNA and protein toxicity, we generated transgenic fly lines expressing the pure GGGGCC hexanucleotide expansion, "RNA-only" repeats by introducing stop codons in all sense and antisense open reading frames, and "Protein-only" repeats by using alternative codons to those in the GGGGCC repeat. The pure GGGGCC repeats caused length-dependent toxicity when expressed in the fly eye and drastically shortened lifespan when expressed in the adult nervous system. In contrast, over-expression of the "RNA-only" repeats had no harmful effects, suggesting that the repeat RNA itself is not toxic. Consistently, over-expression of the arginine-rich DPR proteins glycine-arginine (GR) and proline-arginine (PR) caused severe eye defects and shortened lifespan, while the two neutral DPR proteins glycine-alanine (GA) and proline-alanine (PA) caused little or no effect.

First results of this research area/topic have been published in
Mizielinska, S., Grönke, S., Niccoli, T., Ridler, C.E., Clayton, E.L., Devoy, A., Moens, T., Norona, F.E., Woollacott, I.O., Pietrzyk, J., Cleverley, K., Nicoll, A.J., Pickering-Brown, S., Dols, J., Cabecinha, M., Hendrich, O., Fratta, P., Fisher, E.M., Partridge*, L. & Isaacs*, A.M. 2014. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 345, 1192-1194.

Sleep disorders are a common feature of ageing and neurodegenerative disease. Flies, like humans, are more active by day and sleep more at night. As in humans, this pattern deteriorates with age: night sleep becomes interrupted by waking periods, and duration of day sleep increases and of night sleep decreases, collectively known as sleep fragmentation. We tested whether interventions that ameliorate ageing could also prevent sleep fragmentation. Flies mutant for IIT were resistant to age-related sleep fragmentation, with day and night sleep influenced by distinct mechanisms. Day activity was maintained through adipokinetic hormone, dFOXO and octopaminergic signalling, while night sleep was consolidated through TOR and dopaminergic signalling, mediated by the dopamine transporter. We could rescue the night sleep fragmentation of old flies by feeding them rapamycin.

First results of this research area/topic have been published in
Metaxakis, A., Tain, L.S., Grönke, S., Hendrich, O., Hinze, Y., Birras, U. & Partridge, L. 2014. Lowered Insulin Signalling Ameliorates Age-Related Sleep Fragmentation in Drosophila. PLoS Biol. 12, e1001824.