Effects of long-term dietary interventions on pituitary growth hormone-releasing hormone receptor in aging rats and potential mechanisms of action.

Long-term moderate caloric restriction (LTMCR) is a powerful intervention to delay age-related health deterioration. In this study, the effects of 40% caloric restriction (CR), implemented at 8 months with or without protein restriction, and 40% dietary protein restriction alone, implemented at 2 months, were examined on pituitary growth hormone-releasing hormone receptor (GHRH-R) and GHRH sensitivity in 12-20-month-old male Sprague Dawley rats. An increase of the 4-kb GHRH-R mRNA transcript and 4 kb/2.5 kb ratio, the blunting of high affinity GHRH binding sites and a decrease in GHRH-induced cAMP production were observed in old rats. Only 40% CR maintained youthful levels of GHRH-R transcripts and GHRH binding parameters as well as maximal GHRH-induced cAMP production. Moreover, the GHRH-induced capacity of somatotrophs to synthesize/repair DNA in vitro, in the presence of moderate glucotoxic stress (12 mM d-glucose), was maintained in old CR rats. Among the hormonal and metabolic regulators of GHRH-R that were modified by LTMCR, glucose, free fatty acids and glucocorticoids represent promising candidates for future investigation. A better understanding of the molecular and cellular mechanisms by which they regulate the pituitary GHRH-R should help define strategies to mimic the beneficial effects of LTMCR by less demanding interventions.