Quantitative analysis of a C. elegans TGF-beta and insulin circuit that links food to lifespan

Ageing is affected by exposure to food. Different food levels can either increase or decrease lifespan, but how physiological signals within the body mediate these effects is not clear. Our goal is to understand how the levels of specific hormones from the nervous system change in response to different food levels, and relate these hormonal changes to the changes in lifespan elicited by food. In particular, we want to determine how one hormone could serve as a signal to regulate the activity of other hormones, which in turn modulate the ageing process. By studying the genetic regulation between these hormones, we can understand the role of these hormones in mediating communication between different parts of an animal, the information about the food level that these hormones transmitted, and the routes they take. We will also learn about how the levels of specific hormones are related to different food levels, which will reveal how well animals could distinguish between different food levels to modulate their physiology using these hormones from the nervous system.

To study these processes of communication in detail requires very accurate measurements of the hormone levels in many live animals. Furthermore, to understand the role of these communications in modulating ageing, we need to measure the lifespan of many animals. The roundworm model is ideally suited for these experiments, because it uses similar hormones as humans to modulate its lifespan. This roundworm lives for only a few weeks, thus we can complete our lifespan measurements quickly, in contrast to other animals that could live for months, years or decades. Moreover, there are many experimental tools in this roundworm that allows us to measure and manipulate hormone levels in live animals. Such tools are not always available in other experimental models. We can therefore examine the effects of changing one hormone on other hormones and on lifespan. Our lab has two microscopes with custom-made computerised systems that allows us to examine a hundred roundworms an hour. This automated system speeds up our experiments and allows us to examine the hormone activity in greater detail than is possible by manual methods. We are the only lab in Europe with such a microscope system, due to our collaboration with the engineers that designed it. This roundworm has a very strong track record in ageing research, and several genes involved in human ageing were identified based on discoveries in this roundworm.

From this work, we expect to uncover new knowledge about the hormonal pathways that modulate lifespan in response to food. In the long term, this knowledge can help us understand the physiological responses to food in humans, which in turn can help optimise diets for human health and provide avenues to ameliorate the negative effects of unhealthy diets.

Ageing and lifespan are modulated by food abundance in many species. The relationship between food and ageing has crucial implications for healthy ageing in humans. Powerful genetic and in vivo imaging tools in C. elegans offer unique advantages for studying conserved gene regulatory circuits involved in this process.

Our goal is to understand the information processing mechanisms in conserved gene regulatory circuits that increase or decrease lifespan in response to different food levels. Addressing this question requires a multidisciplinary approach to understand the relationship between food, gene expression and lifespan at a quantitative and mechanistic level. We combine molecular genetics, high-throughput imaging, image processing and computational analysis to dissect a conserved genetic circuit involved in linking food to lifespan. We will measure signals (the changes in gene expression in response to different food level) and variability (the variance in the gene expression) of each gene, as well as the lifespan outputs of this circuit as a function of the food input and gene perturbations. Measuring signals will reveal the response properties of system, while measuring variability will reveal its fidelity and accuracy. We will apply computational methods on our large-scale data to map the input-output relationships for each regulatory step of this circuit. We will also use a decoding algorithm to estimate how well gene expression within this circuit can represent the food input and discriminate between food levels.

Together, this proposed work will reveal how information about the food level is transmitted and transformed within this conserved genetic circuit to modulate lifespan.

Our studies on conserved aspects of nutrition and ageing can open up or guide further research that, in the long term, will help us understand the relationship between diet and ageing in humans. Finding ways for healthy ageing will benefit an ageing society in the UK and other developed countries.

The staff working on this project will have multidisciplinary training combining molecular genetics, engineering, quantitative imaging and computational analysis. This diverse training, along with collaborative work and problem solving will be highly applicable to both academic and industry employment. Our collaboration with the Lu Lab (Georgia Institute of Technology, USA) will not only strengthen collaborative links between the UK and USA, but also highlight the synergistic interactions between engineers and biologists.

Ageing and diets are universal aspects of daily life. By disseminating the outcomes of this research to the general public via press releases upon publication, we can increase scientific awareness on these topic that have broad appeal. We look forward to sharing our work with the public.

High-school students will also benefit from learning about our work and getting involved with our research; it can inspire them to pursue careers in science. To ensure that they benefit, I will be giving annual talks for grade 10 and 11 students at Southbank International. I will also accept one intern per year from this high school to work on simple aspects of the project; I have previously trained such students to perform molecular biology and genetic techniques. I will also conduct one tour of our lab each year for their student and introduce them to a career in science. These are a continuation of on-going activities that I have pursued with Sue Gray (Head of Biology) at Southbank International since 2010.

Some of our computational methods that we develop may also be relevant to "Big Data" driven knowledge industries, since our analyses are based on general approaches. We will look broadly for applications in collaboration with KCL Business.