effects. Ageing may be associated with increased satiating effects of serotonin without apparent effects on dopamine or noradrenaline.
Figure 13.1 Overview of the mechanisms involved in appetite regulation.
Figure 13.2 The stimulatory and inhibitory effects of hormones.
Opioids
Endogenous opioids play a role in mediating the short‐term sensory reward response to food. Exogenous administration of opioid agonists increases food intake in animals, and opioid antagonists decrease food intake in animals and adult humans.34 There is evidence that ageing is associated with a reduced opioid feeding drive (reviewed by Horwitz et al.35). Elderly patients with idiopathic, senile anorexia have lower plasma and CSF β‐endorphin concentrations than normal‐weight, age‐matched controls.36 Intraperitoneal (i.p.) morphine injection increases food intake in young but not old mice, whereas i.p. naloxone decreases food intake in young but not older rats. Healthy older men are less sensitive to the inhibitory effects of subcutaneous naloxone on fluid intake than young men,37 and in one small study of feeding in humans, the suppression of food intake by naloxone was non‐significantly greater in the older than young adults: 16 vs. 8%.34 Overall, these results suggest that the stimulatory effect of endogenous opioids does decline somewhat with advancing age and may contribute to the anorexia of ageing. Further work is required to clarify these changes.
Neuropeptide Y
NPY is synthesized in the peripheral nervous system and brain and strongly stimulates food intake. There is preliminary evidence from animal studies that ageing may be associated with reduced NPY activity, perhaps more in males than females. Old rats have lower levels of arcuate nucleus prepro‐NPY mRNA than young rats, and hypothalamic NPY levels decrease with ageing in male but not female rats. Studies in humans, however, suggest, if anything, increased NPY activity with increasing age. CSF NPY levels increase with healthy ageing in women, and plasma and CSF levels are increased in elderly people with idiopathic anorexia. In rats, the feeding response to hypothalamic NPY injections diminishes with ageing, whereas the stimulation of feeding by intracerebroventricular NPY administration in mice does not diminish 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
