Phenotypic effects of calorie restriction and insulin-like growth factor-1 treatment on body composition and bone mineral density of C57BL/6 mice: implications for cancer prevention.

Background: Calorie restriction (CR) inhibits carcinogenesis and delays aging. Some anti-carcinogenic effects of CR are mediated by decreased circulating insulin-like growth factor-1 (IGF-1); however, IGF-1 also plays an important role in regulating growth and bone density. Materials and Methods: We quantified tradeoffs involving the CR/IGF-1 axis in C57BL/6 mice by examining body composition and bone characteristics in ad libitum fed, 20, 30 or 40% CR mice that received placebo or recombinant murine IGF-1 delivered with a time-release pellet. After 26 days, carcasses were scanned with a PIXImus II dual-energy X-ray absorptiometer. Results: CR reduced body weight and percent body fat and had non-linear effects on bone density. IGF-1 restored bone density to control levels or greater in the CR mice. Conclusion: Cancer prevention efforts based on CR and down-regulation of the IGF-1 pathway will require consideration of deleterious effects on bone. Calorie restriction (CR) is known to delay aging and carcinogenesis in rodents as well as in several other animal models (1-3). These results have led to intense interest in identifying mechanisms underlying the beneficial effects of CR and in developing preventive and treatment strategies based on these mechanisms (4, 5). Several lines of evidence show that modulation of the insulin-like growth factor-1 (IGF-1) pathway influences carcinogenesis and is a mediator of at least some of the cancer preventive effects of CR. CR animals have lower serum levels of IGF-1 (6) and increased latency and decreased number and size of tumors (7). Compellingly, restoration of IGF-1 levels in CR animals by exogenous administration of IGF-1 accelerates their otherwise delayed tumor development (7). In vitro studies have demonstrated that IGF-1 stimulates the growth of numerous cancer cell lines (8-10), and a number of epidemiological studies indicate that serum IGF-1 levels are positively associated with risk of colon, breast and prostate cancer (11-13). Calorie restriction and changes in body weight are also known to influence bone characteristics. In humans, bone density is positively correlated with body weight (14, 15), and weight loss results in decreased bone density (14). In rodents, experimentally imposed CR reduces bone density (16, 17). IGF-1 is believed to be part of the mechanistic pathway linking body weight and bone density (18, 19). For example, MIDI mice have circulating IGF-1 levels diminished by 60% and have reduced bone density; IGF-1 treatment increases their bone density (20). Together, these observations suggest that efforts to slow aging or prevent cancer via CR or modulation of the IGF-1 axis must take into account the effects of reduced levels of IGF-1 on bone. In the present study, we examined the effects of several levels of CR with and without treatment with recombinant murine IGF-1 on body composition, bone characteristics and serum IGF-1 levels, in order to further characterize