Caloric restriction (CR) extends the life-span of various organisms and slows the onset of age-related disorders; however, little is known about the long-term effects of CR per se on bone. In the present study, we have examined the effects of life-long CR vs. AD (ad libitum feeding), mainly on the trabecular bone of proximal tibiae in male C57BL/6 mice and F344 rats. Micro CT scanning of tibiae revealed that CR for 3-9 months caused substantial decrease in 3D-bone volume with structural derangements. Bone histomorphometry revealed the reduced bone mass was due mainly to suppression of bone formation. In db/db mice with defective leptin receptor, CR was unable to decrease bone mass and suppress bone formation. The effect of CR on bone mass was inhibited by administration of a -adrenergic blocker, propranolol. Thus, CR may regulate bone formation through leptin signaling and elevated sympathetic nervous tone. Interestingly, the difference in bone volume between the CR and AD groups disappeared after 1 year of age, and mice and rats on a further extension of CR to natural death maintained higher bone mass than the AD groups, with reduced bone turnover, suggesting that CR slows skeletal aging by regulating the rate of bone turnover. This is the first report, to our knowledge, that has examined the effects of life-long CR on bone metabolism and trabecular microstructure, and documents its contrasting effects during maturation vs. post-maturational, involutional period.