Age-related cognitive impairments compromise the functional capacity of aging individuals, and create major individual and societal costs. Therefore, understanding the mechanisms underlying cognitive aging is of great importance. The neurotransmitter dopamine (DA) supports molecular mechanisms of various cognitive functions. Aging-related decline in dopaminergic neuromodulation contributes to cognitive aging. Genes and environmental factors are the two major forces that may be responsible for the often larger between-person differences in cognitive functions among older compared to younger adults. Environmental and lifestyle factors can influence gene expression through epigenetic mechanisms, such as DNA methylation. Based on initial evidence, we test whether higher DNA methylation of DA-related genes in blood, reflecting lower gene expression, is associated with (1) older age, (2) interindividual differences in and decline of DA receptor availability in the living human brain, (3) impaired cognitive and brain functioning in old age, and (4) a disadvantageous lifestyle (i.e., physical inactivity, poor cardiovascular health). Taken together, this program of research will determine the role of DA DNA methylation as a mechanism of change underlying aging-related decline in DA and cognitive functioning. Overall, our findings will contribute to a better understanding of individual cognitive and brain aging trajectories.