Chronic caloric restriction induces forestomach hypertrophy with enhanced ghrelin levels during aging

Abstract

Caloric restriction (CR) is the only preventive intervention that has robust pro-longevity effects in experimental models. Various circulating hormones that regulate the state of negative energy balance may drive the multi-system beneficial effects of the CR phenomenon. Ghrelin, one such stomach-derived circulating peptide hormone stimulates food intake, promotes GH release and inhibits pro-inflammatory cytokines. We have recently demonstrated that ghrelin also reverses agerelated thymic involution. Here, we report that chronic CR in aging mice results in reduction in body weight, and spleen size but remarkably, leads to a significant increase in the size and weight of stomach. The increased size of stomach was largely due to increased size of fundus (forestomach) and also smaller but statistically significant enlargement of antrum. The analysis of serial stomach sections revealed that chronic CR leads to a striking hypertrophy of lamina propria, stratum basale, stratum corneum and the stratified squamous epithelium of forestomach of the aged animals. We also report for the first time that chronic CR during aging significantly increases circulating ghrelin levels as well as total ghrelin production in the stomach and reverses agerelated loss of ghrelin receptor expression in pituitary. Our data suggests that long-term CRinduced increased ghrelin production from hypertrophic stomach in mice may be an adaptive survival strategy in response to sustained negative energy balance that triggers heightened state of food seeking. Taken together, these data provide new insights into the underlying mechanism behind the salutary effects of chronic caloric restriction during aging process.

Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice

“…In line with previous reports showing that plasma ghrelin levels [16] and production of ghrelin in the stomach [17] rise after DR in WT mice, we have shown that 3 months of DR increases protein levels of gastric ghrelin. We also found that hippocampal ghrelin expression was increased in WT mice maintained on DR regimen.…”

“…These findings indicate that certain factors or hormones, which are increased during DR, may be responsible for the beneficial effects of DR. Considering that plasma ghrelin levels rise significantly during DR [16,17], this peptide hormone may be a potential mediator of enhancement of hippocampal neurogenesis induced by DR. However, it is still unclear whether ghrelin is involved in DR-induced hippocampal neurogenesis.…”

Reduction of T cell–derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation

“…20 Interestingly, intrathymic ghrelin expression declines with age and is associated with age-related thymic involution. 12 Thus the reduction of T cell-derived ghrelin in a tissue microenvironment may play a role in regulating the inflammatory cytokines.…”

Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism

“…These findings and the observations that circulating ghrelin levels are increased prior to a meal and during food deprivation and caloric restriction, as well as in disease states such as anorexia and cachexia, but reduced after a meal and in obesity (Ikezaki et al 2002;Liu et al 2008;Shiiya et al 2002;Tschop et al 2001aTschop et al , 2001bVan der Lely et al 2004;Yang et al 2007), strongly implicate ghrelin being involved in the regulatory processes controlling meal initiation, priming metabolic pathways and leading to more efficient calorie storage.…”