Battling human neurodegenerative pathologies, and their pervasive societal impact, is a global enterprise. Ageing is universally associated with marked decrease of neuronal function, and susceptibility to neurodegeneration. In human populations, this is manifested as an ever-increasing prevalence of devastating neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease, stroke, several ataxias, and other types of dementia. Development of therapeutic interventions against such maladies is becoming a pressing priority. Notably, age-associated decline of neuronal function is evolutionarily conserved in diverse organisms, including the lowly worm Caenorhabditis elegans, signifying commonalities in the underlying molecular mechanisms. However, while age-related deterioration of the nervous system is a universal phenomenon, its cellular and molecular underpinnings remain obscure. This research programme aimed to address this fundamental problem. We implemented an interdisciplinary approach, combining the prowess of C. elegans, a highly malleable genetic model, which offers a precisely defined nervous system, with state-of-the-art optical imaging and microfluidics technologies, to monitor and dissect neuronal quality control mechanisms during ageing. Given the pronounced bioenergetic demands and exceptional endurance of neurons throughout life, we focused on mitochondrial maintenance and turnover. Our objectives were four-fold. First, establish a state-of-the-art super-resolution microscopy unit, coupled with a microfluidics platform for high-throughput imaging and manipulation of specific neurons, in vivo. Second, use the facility to monitor the fate of neuronal mitochondria during ageing. Third, examine the contribution of mitophagy in long-term neuron survival. Fourth, conduct both genetic and chemical compound screens for modifiers of mitophagic activity in neurons, towards augmenting mitochondrial quality control and resistance to neurodegeneration. Ultimately, we will investigate the functional conservation of key isolated factors in more complex mammalian ageing models. Together, these studies led to unprecedented understanding of age-related breakdown of neuronal function and provided critical insights with broad relevance to human health and quality of life.