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Aging is associated with a progressive decrease in appetite and food intake. The reasons for the decline in food intake are multifactorial, and relate to both peripheral and central mechanisms. Current studies about the regulation of food intake suggest that there are many central mediators that control the appetite. To determine the mechanism of age-associated decrease in appetite and food intake, we focused on the age-associated changes of the suppressing and stimulatory effect of some appetite-regulating peptides. At first, we examined cholecystokinin (CCK), one of the typical appetite-suppressing factors. Although sensitivity to CCK is enhanced in old animals, the mechanism underlying this effect has not been elucidated. Next, we focused on the appetite-stimulating peptides, orexin-A, neuropeptide Y (NPY) and ghrelin, which are known to play a critical role in food intake. To determine the age-associated decrease in appetite and food intake, we compared the stimulatory effect of intracerebroventricular administration of orexin-A, NPY and ghrelin. We report the studies of the age-associated changes of appetite-regulating peptides in this review.

Gastric acid secretion in response to chemical stimulation and to mechanical stimulation was investigated in adult and old mice. The protein expression of a proton pump (H(+)-K(+)-ATPase), a marker of parietal cell function, was determined by Western blotting. Acid secretion was stimulated by histamine (500 and 1000 microg/kg) or carbachol (10 and 20 microg/kg). To investigate the response to mechanical stimulation, the stomach was distended by an intragastric injection of isotonic saline (0.5, 1.0, 1.5, and 2.0 ml). Administration of two doses of histamine produced a dose-dependent increase in acid secretion in adult mice, whereas a higher dose of histamine failed to produce a further increase in old mice. Gastric acid secretion, whether produced by carbachol or mechanical stimulation, did not differ between the two age groups. The protein expression of H(+)-K(+)-ATPase was significantly lower in old mice than in adult. Insofar as histamine increases acid secretion via the cyclic AMP (cAMP) pathway in parietal cells, while carbachol and gastric distention do so via the calcium signaling pathway, the cAMP signaling pathway may be more susceptible to aging than the calcium signaling pathway. The decrease in the secretory capacity of acid secretion in the old mice may be partly attributable to a decrease in parietal cell function, as shown by decrease in H(+)-K(+)-ATPase protein expression.

Aging is associated with a progressive decrease in appetite and food intake. The appetite-stimulating peptides orexin A, neuropeptide Y (NPY) and ghrelin are known to play a critical role in food intake. In this study, the stimulatory effect of intracerebroventricular administration of these peptides on food intake was compared among young (4 months old), adult (11 months old) and old (24-27 months old) male Wistar rats. A stainless steel cannula was implanted stereotactically into the left lateral ventricle. After a 7-day recovery period, different doses of orexin A (0.25-3 nmol), NPY and ghrelin (0.03-1 nmol) were injected into the left lateral ventricle without anesthesia. Food consumption was measured at 1, 2 and 4 h after injection. We also examined the plasma levels of acylated and desacyl ghrelin in young and old rats by ELISA. Intracerebroventricular administration of orexin A and NPY stimulated food intake in young and adult rats, but no effects were observed at any dose in old rats. Ghrelin increased food intake in a dose-dependent manner in all groups, and the effect of ghrelin was reduced with advancing age. Neither the acylated nor the desacyl plasma ghrelin level differed significantly between young and old rats. In conclusion, the orexigenic effect of the peptides orexin A, NPY and ghrelin decreased in old rats, and this reduction may have been responsible for the age-related decrease in food intake.

Aging is associated with a progressive decrease in appetite and food intake. Both A and B orexins, expressed in specific neurons of the lateral hypothalamic area, have been implicated in the regulation of sleep and feeding. In this study, the stimulatory effect of intracerebroventricular administration of the orexins on food intake was compared between young (4-mo-old) and old (25- to 27-mo-old) male Wistar rats. A stainless steel cannula was implanted stereotactically into the left lateral ventricle. After a 7-day recovery period, different doses (0-30 nmol) of orexins were injected into the left lateral ventricle without anesthesia. Food and water consumptions were measured at 1, 2, and 4 h after injection. The protein levels of orexin receptors, a specific receptor for orexin-A (OX1R) and a receptor for both orexin-A and -B (OX2R), in the hypothalamus were determined by Western blot analysis and compared between young and old rats. Intracerebroventricular administration of orexin-A stimulated food intake in a dose-dependent manner in young rats. However, no effects were observed at any dose in old rats. The protein level of OX1R in the hypothalamus was significantly lower in old rats than in young rats, although the protein level of OX2R was comparable between groups. Results of the present study indicate that the function of the orexin system is diminished in old rats. The decrease in the OX1R protein level in the hypothalamus could be responsible for orexin-A's lack of stimulation of food intake in old rats.

Laboratory rats are normally confined to cages that markedly restrict their physical activity. In these rats, the resting energy expenditure accounts for 90% of the total daily energy expenditure, while the daily physical activity in humans consumes 30% of the total daily energy expenditure. Otsuka Long Evans Tokushima Fatty (OLETF) rats have been developed as a model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity, and obesity is an important factor that induces diabetes in this strain. We implemented a running-wheel exercise regimen that was the equivalent of normal physical activity to provide light exercise for OLETF rats. The purpose of the study was to determine if light exercise improves the age-related decline in energy metabolism and glucose intolerance in OLETF rats. The effects were also compared in control Long Evans Tokushima (LETO) rats. From 12 to 46 weeks of age, the rats performed a running-wheel exercise (3000 m/day). Energy metabolism was determined at 8-week intervals. The typical increase in body weight was significantly decreased in OLETF rats in response to exercise, while no significant effect was observed in LETO rats. Energy expenditure and basal metabolic rate (BMR) per kilogram body weight (not whole-body weight) were increased by exercise in OLETF rats, but not in LETO rats. At 46 weeks of age, after exercise, the blood glucose and hemoglobin (Hb)A1c levels, as well as the plasma levels of insulin, triglyceride, cholesterol, and leptin significantly decreased in OLETF rats, while only the plasma levels of cholesterol and leptin significantly decreased in LETO rats. Light exercise thus appears to be beneficial for preventing age-related decline in energy metabolism and glucose intolerance in OLETF rats.

Female C57BL mice of six different ages (from 6 to 26 months) were given a protein free-diet (PFD) for 1 week and then given a normal diet (ND). Mice were examined for enzyme activities of glutathione S-transferase (GST) in the hepatic cytosol fraction using l-chloro-2, 4-dinitrobenzene (CDNB) as substrate. Enzyme activities were very close among the six different age groups when examined for basal levels as well as after 1 week of PFD. However, a remarkable age difference became manifest when animals were examined 2 days after the start of ND refeeding following 1 week of PFD. In young animals (6, 8 months), activities became much higher than their respective basal levels while in old animals (24, 26 months) enzyme levels remained significantly lower than their basal levels on day 2 of ND refeeding. A significant negative linear correlation between enzyme activities (Y axis) and animal age (X axis) was demonstrated only on day 2 or 3 of ND refeeding, while in control animals or animals given 1 week of PFD diet, no significant correlation could be found between enzyme activities and animal age. We conclude that liver cytosolic GST activity is a function of animal age only after a dietary manipulation such as a PFD and ND refeeding, while basal GST activities remain stable throughout the observation period of animal age., (Copyright 2002 Elsevier Science Ireland Ltd.)

Abstract: Aging is associated with a progressive decrease in appetite and food intake. We focused on the age-associated changes of the stimulatory effect of the appetite-regulating peptide, ghrelin. Food intake and the concentrations of acyl ghrelin and desacyl ghrelin in the plasma and in the stomach were measured with and without overnight fasting in young and old mice. Moreover, the food intake in response to the intraperitoneal administration of graded doses of acyl ghrelin was compared between young and old mice. Fasting drives food intake in young mice, but not in old mice. The concentrations of acyl ghrelin and desacyl ghrelin in the plasma and in the stomach were higher in the old mice than in the young mice. Food intake did not increase in old mice when stimulated by the administration of 1–3nmol of acyl ghrelin, which could produce a significant increase in food intake in young mice. In conclusion, food intake did not increase in old mice after either overnight fasting or the administration of acyl ghrelin. The release and synthesis of ghrelin seem to be rather higher in old mice compared to young mice. These increases might be the results of compensation for the decline of receptor (and/or post-receptor) functions. [Copyright &y& Elsevier]