with age. The effects of NPY administration in humans have not been reported. Therefore, there is currently no convincing evidence for an involvement of NPY in the human anorexia of ageing.36
Galanin
Galanin is a peptide hormone located in the brain and periphery that stimulates food intake. Available animal evidence does not suggest a decline in galanin levels with ageing, and circulating levels do not differ between young and older women.38 Declining galanin levels are therefore unlikely to contribute to the anorexia of ageing, but reduced sensitivity to galanin might. The effect of ageing on stimulation of feeding by galanin has not been reported in humans, but older women (not men) display a reduced growth hormone secretory response to galanin compared with young adults.39
Orexins (hypocretins)
Orexin A and B (hypocretin‐1 and ‐2) are neuropeptides synthesized in the hypothalamus and involved with feeding and sleep. Orexin deficiency causes narcolepsy in animals and humans and hypophagia and weight loss in animals.40 Intracerebroventricular orexin injection dose‐dependently increases food intake in rodents, and orexin antibody reduces food intake (reviewed by Kirchgessner41). Orexin A is the subtype mainly responsible for effects on feeding. The majority of evidence does not support declining orexin activity as a cause of the anorexia of ageing. In a cross‐sectional study of 82 healthy men and women age 23–79, plasma orexin A concentrations increased with age in both men and women, which should favour increased appetite and food intake.40 Studies in mice have found no changes or increases in total brain orexin levels and hypothalamic orexin A receptor levels with increasing age, while a decrease in hypothalamic orexin gene expression in ageing rats has been described.42 In humans, the effects of normal ageing on the levels of the orexin receptors and sensitivity to the effects of orexin are unknown.
Cocaine–amphetamine‐regulated transcript (CART)
CART is a peptide widely distributed in the brain, including the hypothalamus. In animals, central CART administration reduces feeding and blocks NPY‐induced feeding. Sohn et al. reported that arcuate nucleus CART mRNA levels were higher and NPY mRNA levels lower in healthy old than young male rats, whereas testosterone treatment of castrated, older rats significantly lowered CART mRNA levels and increased NPY mRNA levels. This suggests that in males, there is ageing‐related increased central activity of CART and reduced activity of NPY, both mediated by the normal age‐related decline in testosterone. This is an intriguing possibility, but the effects of ageing on CART in female animals have not been reported, nor have those in humans. The evidence that age‐related increases in central CART levels may cause the anorexia of ageing is currently derived from one study in male rodents.43
‘Peripheral’ hormones, including gut peptides
Cholecystokinin (CCK)
CCK is present in the hypothalamus, cortex, and midbrain and is released from the lumen of the intestine in response to nutrients, particularly fat and protein, in the gut. CCK causes contraction of the gallbladder and relaxation of the sphincter of Oddi. Exogenous CCK administration decreases food intake in animals and humans. CCK is a physiological satiety hormone as its suppressive effect on food intake occurs with the administration of doses producing plasma CCK concentrations within the physiological range, and administration of CCK antagonists increases food intake in animals and young adult humans.44 CCK also slows gastric emptying. The satiating effects of CCK appear to increase with age. Most studies in humans have shown plasma CCK concentrations to be higher in healthy older than young adults.30,45 Elderly people with idiopathic anorexia have significantly higher plasma levels and non‐significantly higher CSF levels of CCK than healthy age‐matched controls.36 Intraperitoneal CCK suppresses food intake more in old than young rats and mice. Intravenous CCK‐8 administration has been found to acutely suppress food intake twice as much (31 vs. 15%, p = 0.02) in older than young adult healthy human subjects. The combination of increased circulating CCK concentrations and enhanced sensitivity to CCK suggests that CCK may cause the anorexia of ageing and raises the possibility of using CCK antagonists to increase energy intake in undernourished older people.46
Glucagon‐like peptide‐1 (GLP‐1)
The lining of the intestine releases GLP‐1 in response to nutrient ingestion, particularly carbohydrates. It stimulates insulin secretion and, together with gastric inhibitory peptide (GIP), is one of the incretin hormones. It also slows gastric emptying.30 Administration of GLP‐1 to humans increases feelings of fullness and reduces food intake.47 Studies of the effects of ageing on plasma GLP‐1 concentrations have found either no effect or increased levels in older people.45 Further studies are needed to determine if increased GLP‐1 activity is a cause of the anorexia of ageing.
Peptide YY (PYY)
PYY is a peptide hormone present in the brain and released from the bowels in response to the presence of fat and carbohydrate in the small intestine. PYY is involved in physiological processes such as memory, pain, blood pressure regulation, appetite, and anxiety.48 In rodents, feeding is increased by central PYY administration but decreased by peripheral administration. Intravenous infusion of PYY to normal‐weight and obese humans aged less than 50, in doses that produce postprandial blood levels, reduces short‐term food intake by ∼30%. This suppression may be mediated by the associated suppression of ghrelin levels, whereas leptin, insulin, and GLP‐1 are unaltered. There is currently no evidence favouring alterations in PYY activity as a cause of the anorexia of ageing and no difference in plasma PYY concentrations, fasting and in response to intraduodenal nutrient infusions, between young and older subjects. Because there is a strong negative correlation between fasting plasma PYY levels and BMI in healthy, non‐elderly subjects, studies involving accurate body composition analysis are needed to determine the true effect of healthy ageing on PYY. The effects of ageing on sensitivity to the appetite‐suppressant effects of PYY have not been reported.49
Leptin
Leptin is produced predominantly in adipose tissue and circulates in amounts directly related to the size of fat stores. It suppresses appetite and food intake. Congenital leptin deficiency in humans is a very rare cause of morbid obesity associated with hyperphagia, and leptin treatment produces substantial weight loss in these people. Most obese people, however, have elevated circulating leptin concentrations consistent with their increased fat mass. Leptin resistance is probably a feature of most human obesity, and leptin administration to obese people has resulted in only minor weight loss. Although adipose tissue leptin mRNA expression increases with age in mice and rats, studies in rats and pigs have not found an increase in serum leptin with ageing. Plasma leptin concentrations in humans often increase with ageing, to a large extent because of the increased fat mass that also accompanies ageing. Most studies show that adjustment for fat mass removes this effect.50 This is certainly so in women; but in men, some but not all studies have shown ageing to be associated with an increase in circulating leptin levels, even allowing for fat mass. This appears to be because of age‐related decreases in circulating testosterone concentrations. After adjusting for fat mass, plasma leptin levels in men are inversely related to plasma testosterone, while testosterone therapy reduces and inhibition of testosterone production increases circulating leptin levels.51
Little is known about the effects of ageing on sensitivity to the effects of leptin. Circulating levels of the soluble leptin receptor do not change with age in humans. Resting energy expenditure and carbohydrate oxidation are predicted by fat‐free mass and serum leptin concentration in middle‐aged, premenopausal women, but the relationship between fat store size and plasma leptin is much weaker in older adults. Fasting normally dramatically suppresses plasma leptin concentrations, thus stimulating hunger. Reduced suppression of leptin levels by fasting has been reported in