Background: To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimer's disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS). Materials and methods: The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An "in vivo" MRI biomarker of myelin integrity (transverse relaxation rates; R[subscript 2]) of LMWM was obtained for 38 very healthy elderly adult men (mean age = 66.3 years; SD = 6.0; range = 55-76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test. Results: LMWM R[subscript 2] and CPS measures were significantly correlated (r = 0.515, p = 0.0009), but no significant association between R[subscript 2] and CPS was detected in the splenium (p = 0.409). LMWM R[subscript 2], but not SWM R[subscript 2], was a significant mediator of the relationship between age and CPS (p = 0.037). Conclusions: In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium. (Contains 1 table and 5 figures.)