Background: The prevalence of dementia and age-related neurodegenerative disease (ND) is increasing and therefore effective prevention and treatment strategies are desperately needed. Dementia and natural ageing are associated with impaired performance on cognitive tasks that rely on the prefrontal cortex (e.g., attention switching task (AST) and mental arithmetic). Further, NDs drastically impair quality of life (QoL) and well-being. This study aimed to investigate the effect of aerobic fitness on cognition and QoL in young and old individuals. Methods: Thirty-six healthy volunteers participated: young (mean ± SD: age 25 ± 7 years; 9 fit, 10 unfit; VO2max >45 mL·kg·min-1 vs. <40 mL·kg·min-1) and old (67 ± 7 years; 10 fit, 7 unfit; VO2max >30 mL·kg·min-1 vs. <20 mL·kg·min-1). During separate visits participants completed an aerobic fitness test (VO2max), cognitive testing (5 tasks; CANTAB software), a paced auditory serial addition task (PASAT) and two QoL questionnaires (RAND-36 and WHO-QoL). Results: ANOVAs revealed slower performance in the AST in the old group (p=0.003). Compared to their unfit counterparts, the old fit group achieved more correct responses with a faster reaction time when they were instructed to respond to the direction of an arrow and ignore conflicting information given about the side (p=0.011; Fig 1). The number of correct responses on the PASAT in the old fit group was greater (p=0.001), whereas fitness effects were not apparent in the young cohort (p=0.123; Fig 2). Finally, physical fitness was positively related to QoL measures in both young and old groups [RAND-36 (overall general health), young (p=0.043), old (p=0.034; Fig 3); WHO-QoL (psychological health subscale), young (p=0.025), old (p=0.138)]. Conclusions: Age-related decline in attention switching was offset by physical fitness. Higher physical fitness also improved mental arithmetic in old participants. Further, physical fitness may significantly improve well-being and quality of life across ages. Taken together, our findings lend further support to the evidence that physical activity may be protective against neurodegenerative disease.