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 ageing rats. Conversely, food intake, fat mass, and insulin action are suppressed less by leptin administration in older than young rats. This suggests that ageing may be accompanied by leptin resistance, which would tend to increase food intake. The impact of human ageing on the effects of fasting on leptin levels and of leptin administration has not been reported.52
Ghrelin
Ghrelin stimulates feeding and growth hormone release. It is present in the hypothalamus, but the main site of production is the gastric mucosa.30 Circulating ghrelin concentrations increase with fasting and diet‐induced weight loss in obese subjects and are elevated in underweight, undernourished young and older subjects. In contrast, circulating concentrations decrease after food ingestion, particularly fat and carbohydrate, and are reduced in obese people. These changes are consistent with compensatory responses to, rather than causes of, these altered nutritional states. It therefore seems unlikely that reduced ghrelin activity contributes significantly to anorexia and weight loss in markedly undernourished older subjects. Nevertheless, the effects of ageing and undernutrition on sensitivity to ghrelin have not been reported, and ghrelin resistance may occur in these states. In support of this, older subjects are less sensitive to the growth hormone (GH)‐releasing effects of intravenous ghrelin (i.v. ghrelin) than young adults.53 The effect of healthy ageing on circulating ghrelin concentrations has not yet been clarified. A possible rationale for a decline in ghrelin levels with age, particularly in men, is the positive association between circulating testosterone and ghrelin concentrations and the increase in plasma ghrelin concentrations that occurs in hypogonadal men in response to testosterone therapy.54 As normal ageing is accompanied by reductions in circulating androgen levels (see the following section), this might have the effect of reducing ghrelin concentrations and thus food intake. One study found a rise in plasma ghrelin concentrations with increasing age, but there was no relationship with age per se when a multivariate analysis was performed, and the study did not include subjects older than 64.55 Two small studies have reported circulating ghrelin concentrations 20%56 and 35%57 lower in healthy older adults (69–87 and 67–91 years, respectively) than young adults, the latter reduction being statistically significant. However, increasing body fat, as indicated by BMI, is associated with decreasing ghrelin concentrations, and the older subjects had higher BMIs than the young subjects in both studies. Neither study included detailed body composition analysis, so the lower ghrelin levels in older subjects may have been because of differences in body composition. Another study found no difference in fasting and postprandial serum ghrelin concentrations between healthy older (mean age 78) and young adults. On balance, the effect of healthy ageing on circulating ghrelin concentrations has not yet been clarified but is probably minimal.58
Insulin
Human ageing tends to be associated with increased fasting and postprandial circulating insulin concentrations.59 Increased insulin activity could, therefore, be a cause of reduced food intake in older people. However, the evidence for a satiating role of insulin is limited. Suppression of food intake by insulin has only been demonstrated in animals and has required central insulin administration at high doses or high‐dose, prolonged peripheral administration. Short‐term, peripheral, euglycaemic insulin infusions have been shown not to affect appetite or food intake in humans.60 Moreover, age‐associated increases in insulin concentrations are due mainly to insulin resistance resulting from increased adiposity and only to a small extent to ageing itself. It seems unlikely that insulin contributes substantially, if at all, to the anorexia of ageing.
Testosterone and other androgens
Circulating androgen concentrations decline with ageing. This may contribute to the development of sarcopenia and the decrease in functional status that occurs with ageing (reviewed by Bhasin61). Whereas androgen replacement therapy (ART) is advocated for men with marked androgen deficiency, there is no consensus for the use of ART in elderly men with less severe ageing‐related declines in androgen concentrations or in elderly women. Studies of androgen replacement have been performed in healthy, older men with androgen deficiency, but although benefits have been seen in muscle mass and, in some cases, strength, as yet there is insufficient evidence regarding improvements in functional status (reviewed by Morley62). Several studies have suggested that there may be benefits from treating older men, particularly if frail, with testosterone therapy. Amory et al.63 gave older men with a mean total testosterone within the normal range 600 mg i.m. testosterone weekly for four weeks before elective knee replacement surgery and found significant increases in the ability to stand postoperatively and trends to improvements in walking and stair climbing, compared with placebo‐treated men. Bakhshi et al.64 gave older men in a rehabilitation programme with low‐normal testosterone levels 100 mgi.m. testosterone or placebo weekly and found significant
