Sources transmission and effects of transcriptional noise in C. elegans ageing

Ageing is a variable process affected by the environment, genes and random chance. The activity of several genes that affect lifespan and ageing are affected by the environment. The goal of this project is determine (1) what leads to fluctuations in the activity level of these genes and (2) the relationship between fluctuations in gene activity and variability in lifespan and ageing. In many species, similar genes and environmental factors contribute to ageing in similar ways. Moreover, variability in gene activity is a universal phenomenon, due to physical laws. Thus research in simple animals such as roundworms can provide general insights on these processes relevant to many species, including humans. We will use powerful experimental tools in the roundworm to dissect the causes of fluctuations in the activity of genes that affect lifespan and ageing, and discern how these fluctuations are linked to variation in lifespan and ageing. These experiments would be very difficult and expensive in other animals such as mice or humans. As an experimental system, roundworms have an established track record of providing insights to many biological processes, including human ageing. We will first measure the fluctuations in gene activity, classify the sources of these fluctuations and determine how these fluctuations are affected by food and temperature. Because these genes communicate with each other in the nervous system, we will next test how the communication process affects the fluctuations. Finally, we will determine whether fluctuations in gene activity lead to variability in ageing. To obtain the large amount of data needed for this work, we will engineer new computerised microscopy systems capable of collecting data ~50x faster than manual work by humans, and other tools to measure muscle decline with age. Together, this research will reveal how fluctuations in gene activity originate and affect ageing and lifespan.

Aging varies from individual to individual due to environmental, genetic and stochastic factors. Powerful genetic and in vivo imaging tools in C. elegans offer unique advantages to study this process. Specific C. elegans neurons respond to environmental cues by changing expression of genes that modulate lifespan and ageing. The transcriptional noise in these processes is completely uncharacterized. How does environmental and transcriptional noise contribute to heterogeneity in aging and lifespan? What are the sources of noise? Are the noises shaped by signalling pathways? Addressing these questions will likely provide fundamental insights into variation in aging in both animal models and humans. Our goal is to determine how transcriptional noises in environmental responses translates to heterogeneity in lifespan and aging in C. elegans, to define factors that contribute to the noises, and to understand how feedback mechanisms shape transcriptional noises. First, we will use a high-throughput quantitative imaging approach to transcriptional noise in three genes implicated in environmental sensing and aging as a function of food, temperature and age. Next, we will identify how signalling among these genes transmit noise, and how feedback mechanisms shape noise in this system. Finally, we will determine if variance in gene expression is correlated with variance in lifespan and other age-related phenotypes, and if expression levels can predict individual ageing and lifespan phenotypes. We will assess ageing by creating new quantitative assays to investigate muscle structure and function with age. Together, these aims will create a conceptual framework for understanding how transcriptional noise created in and shaped by signalling circuits that influence lifespan, and whether these sources of noise are buffered or lead to variation in ageing and lifespan.

This work will advance our knowledge on ageing, and thus has the potential to improve health in ageing populations such as the UK and USA. Similarities in the factors that influence aging indicate that our work will be relevant to mammals including humans. Our work is likely to reveal environment-dependent physiological states that cannot be predicted by genotype alone. In the long term, this may lead to individualized treatments or lifestyle modifications that promote healthy aging in humans, allowing the general populace will benefit from possibilities of enhanced health and quality of life in the face of age. Public health policy makers can use the scientific knowledge of factors that affect age-related declines to increase the effectiveness of their services and policy. A healthier population will have a positive impact on the nation's wealth and culture. The staff working on the projects will be afforded a rare multidisciplinary training opportunity combining molecular genetics, engineering, quantitative imaging and analysis. This diverse training, along with collaborative work and problem solving will be highly applicable to both academic and industry employment. This work will not only strengthen collaborative links between the UK and USA, but also highlight the synergistic interactions between engineers and biologists. Ageing, behaviour and the highly visual aspect of our research has much public appeal and can generate broader interest in science, engineering and research among the public. Dr. Ch'ng has a track record of working with a science museum (The San Francisco Exploratorium) to set up an exhibit. We will publish our work in international journals. We are committed to public engagement and will disseminate our work in layman's terms to reach a wider audience by working closely with our public relations departments. We look forward to sharing our work with the public.