Abstract The effects of aging and long-term caloric restriction (LTCR), on the regulation of neuropeptide Y (NPY) Y1, Y2 and Y5 receptors subtypes, was studied in 20-month-old male rats fed ad libitum (AL) or submitted to a 40% caloric restriction for 12months. [125I]GR231118, a Y1 antagonist was used as Y1 receptor radioligand. [125I][Leu31, Pro34]PYY, a high affinity agonist of Y1 and Y5 subtypes was used in the absence or presence of 100nM BIBO3304 (a highly selective Y1 receptor antagonist) to assess the apparent levels of [125I][Leu31, Pro34]PYY/BIBO3304 insensitive sites (Y5-like) from [125I][Leu31, Pro34]PYY/BIBO3304 sensitive sites (Y1). [125I]PYY(3–36) was used to label the Y2 receptor. In the brain of 3-month-old AL rats, the distribution and densities of Y1, Y2 and Y5 receptors were in agreement with previous reports. In the brain of 20AL rats, a decrease of NPY receptor subtype densities in regions having important physiological functions such as the cingulate cortex, hippocampus and dentate gyrus, thalamus and hypothalamus was observed. In contrast, LTCR had multiple effects. It induced specific decreases of Y1-receptor densities in the dentate gyrus, thalamic and hypothalamic nuclei and lateral hypothalamic area and Y2-receptor densities in the suprachiasmatic nucleus of hypothalamus. Moreover, it prevented the age-induced increase in Y1-receptor densities in the ventromedial hypothalamic nucleus and decrease in the mediodorsal thalamic nucleus, and increased Y2-receptor densities in the CA2 subfield of the hippocampus. These results indicate that LTCR not only counteracts some of the deleterious effects of aging on NPY receptor subtype densities but exerts specific effects of its own. The overall impact of the regulation of NPY receptor subtypes in the brain of old calorie-restricted rats may protect the neural circuits involved in pain, emotions, feeding and memory functions.