Muscle- and liver-derived
IGF-1 play important roles in muscle anabolism throughout growth and aging. Yet, prolonged food restriction is thought to increase longevity in part by lowering levels of
IGF-1, which in turn reduces the risk for developing various
cancers. The dietary factors that modulate
IGF-1 levels are, however, poorly understood. We tested the hypothesis that the
adipokine leptin, which is elevated with food intake and suppressed during fasting, is a key mediator of
IGF-1 levels with aging and food restriction. First,
leptin levels in peripheral tissues were measured in young mice fed ad libitum, aged mice fed ad libitum, and aged calorie-restricted (CR) mice. A group of aged CR mice were also treated with recombinant
leptin for 10 days. Later, aged mice fed ad libitum were treated with saline (VEH) or with a novel
leptin receptor antagonist
peptide (Allo-aca) and tissue-specific levels of
IGF-1 were determined. On one hand, recombinant
leptin induced a three-fold increase in liver-derived
IGF-1 and a two-fold increase in muscle-derived
IGF-1 in aged, CR mice.
Leptin also significantly increased serum
growth hormone levels in the aged, CR mice. On the other, the
leptin receptor antagonist Allo-aca did not alter
body weight or muscle mass in treated mice compared to VEH mice. Allo-aca did, however, produce a significant (20%) decline in liver-derived
IGF-1 as well as an even more pronounced (>50%) decrease in muscle-derived
IGF-1 compared to VEH-treated mice. The reduced
IGF-1 levels in Allo-aca treated mice were not accompanied by any significant change in
growth hormone levels compared to VEH mice. These findings suggest that
leptin receptor antagonists may represent novel therapeutic agents for attenuating
IGF-1 signaling associated with aging, and could potentially mimic some of the positive effects of calorie restriction on longevity.