Aging may increase apoptotic events and the susceptibility of the central nervous system to apoptosis. Calorie restriction has been shown to have neuroprotective effects, but the mechanisms in vivo are unknown. We investigated apoptosis and apoptotic regulatory proteins in the brain frontal cortex of 12-month-old ad libitum fed, 26-month-old ad libitum fed, and 26-month-old calorie-restricted (CR) male Fischer 344 rats (CR = 40% restricted compared to ad libitum). We found that specific DNA fragmentation indicative of apoptosis was increased with age (+124%) in the cortices of the brain and that calorie restriction attenuated this increase significantly (-36%). We determined levels of ARC (apoptosis repressor with a caspase recruitment domain), which inhibits caspase-2 activity and also attenuates cytochrome c release from the mitochondria. We found a significant age-associated decline in ARC level, which was attenuated in the brains of the CR rats. In accordance with the changes in ARC expression observed, calorie restriction attenuated the increases in cytosolic cytochrome c and caspase-2 activity with age and suppressed the age-associated rise in cleaved caspase-9 and cleaved caspase-3. However, neither age nor calorie restriction had any effect on caspase-3 and caspase-9 activities. This data provides evidence for an increased incidence of apoptosis in rat brain with age and evidence that calorie restriction has the ability to attenuate this. Furthermore, our data suggest that calorie restriction provides neuroprotection through ARC by suppressing cytochrome c release and caspase-2 activity.