The average lifespan of humans has immensely increased over the past decades and with it the percentage of elderly in the population. Aging is associated with a progressive decline in numerous physiological processes, ultimately leading to a number of diseases. In particular neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s disease are one of the most prevalent group of age-associated maladies. Huntington’s disease is characterized by the aggregation of Huntingtin, a protein with a poly-glutamine (polyQ) stretch. A polyQ stretch above 35 is considered a high-risk factor for disease outbreak. Yet, human well-being is also chiefly dependent on environmental factors that interface with a variety of quality control mechanisms to sustain overall cellular homeostasis. A healthy lifestyle, including our eating habits, has a large impact on our health- and life-span. Increasing evidence provides a connection between aging, deregulated nutrient sensing and consumption as well as loss of protein homeostasis (or proteostasis for short). However, the role of diet in maintaining cellular and organismal proteostasis and the underlying mechanisms and pathways remain still largely elusive. With this project, we aim to bridge this gap and to identify individual dietary components that influence proteostasis and overall organismal physiology. In parallel, we also aim to identify the mechanisms involved.

Our specific aims are to:

1. identify the specific dietary cues that regulate proteostasis in C. elegans with impact on their health-span and life-span
2. delineate the involved molecular and cellular mechanisms.

To reach the goals, two distinct approaches will be pursued. First, we will use a combination of biochemical fractionation and ‘omics’ approaches to identify the dietary components that favorably (or even adversely) impacts proteostasis in C. elegans expressing different lengths of polyQ. Second, we will perform an RNAi screen using the same animal models reared on different diets to decipher the mechanisms in C. elegans that are regulating proteostasis during aging in relation to dietary cues. Finally, we will investigate the potential impact of the dietary cues and involved mechanisms on life- and health-span.

Taken together, this project will reveal how dietary compounds affect organismal proteostasis and delineate the responsible mechanisms. Understanding the influence of diet in vivo and the affected evolutionary conserved pathways will open new avenues for future research on human physiology and the significance of specific dietary nutrients.