Aging is a major risk factor for neurodegeneration, cancer and heart disease. Understanding what goes wrong with age, in particular how the proteome becomes dysfunctional may help to slow down or prevent these age-dependent diseases. Until recently, it was widely assumed that protein aggregation was mainly restricted to the extensive aggregation of a few hallmark proteins in diseases such as neurodegeneration and systemic amyloidosis. However, we have demonstrated using the model organism Caenorhabditis elegans that during aging in the absence of disease many more proteins are prone to aggregate with age. We will use this physiological protein aggregation as a novel readout to measure the health and age of the organism. Preventing this process will presumably “free up” the cellular systems and keep proteins functional even in an old organism.Overall, we seek to understand how protein homeostasis becomes deregulated with age leading to this widespread protein aggregation. We aim to achieve this by complementary strategies:We will establish a novel method to image protein aggregation dynamics and to determine how the intracellular quality-control systems regulate age-dependent aggregation. Using state-of-the art proteomics, we will distinguish which types of physiological aggregation are controlled by each of the main actors in the quality-control system. Finally, we will open new horizons by performing an RNA interference screen using a novel C. elegans model for extracellular protein aggregation.As many of the mechanisms which control aging in C. elegans are evolutionary conserved in mammals, we predict that our discoveries are relevant to higher organisms including humans. Our long-term goal is to identify novel targets which could be used to develop therapies to prevent diseases related to protein aggregation and to promote healthy aging.