Current Opinion in Clinical Nutrition & Metabolic Care:
AGEING: BIOLOGY AND NUTRITION: Edited by Tommy Cederholm and John E. Morley
Pathophysiology of the anorexia of aging
Morley, John E.
Division of Geriatric Medicine, Saint Louis University School of Medicine, St Louis, Missouri, USA
Correspondence to John E. Morley, MB, BCh, Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238 St Louis, MO 63104, USA. Tel: +1 314 977 8462; e-mail: firstname.lastname@example.org
Purpose of review: Anorexia represents a major problem for older persons leading to weight loss, sarcopenia, functional decline, and mortality. There is increasing information on the pathophysiological mechanisms that lead to anorexia.
Recent findings: Increasing evidence has shown the importance of gastrointestinal hormones (ghrelin, cholecystokinin, and glucagon-like peptide) and adipokines in producing the anorexia of aging. Numerous neurotransmitters have been shown to be involved in this aging anorexia, but evidence in humans is lacking.
Summary: The early recognition of anorexia of aging is important to allow intervention and prevent functional deterioration in older persons. Screening tests for anorexia have been developed. New approaches to managing anorexia are being tested.
The concept of the anorexia of aging as a physiology occurrence to allow adaptation to the decrease of energy expenditure and loss of muscle mass that occurs with aging was first described in 1988 . The extension of this concept was that this physiological anorexia made older persons who developed a variety of diseases, particularly vulnerable to developing severe anorexia and weight loss . A recent European study suggested that the anorexia of aging was present in 21.2% of persons over 65 years of age [3▪]. The physiological anorexia in older persons occurs to a greater degree in men than women. In addition, the anorexia of aging itself plays a role in the development of sarcopenia and frailty [4–7]. In older persons, anorexia and the subsequent weight loss have been epidemiologically associated with a variety of poor outcomes, including hip fracture, impaired physical function, institutionalization, and increased mortality [8–10]. This appears to be true even in moderately obese individuals and has been termed the ‘obesity paradox’ [11,12]. There are numerous factors involved in the anorexia of aging and this article will explore recent studies attempting to delineate the causes of the anorexia of aging.
THE SENSORY SYSTEM
Food represents a major sensory delight for humans. The enjoyment of food involves its visual presentation, smell, and taste, as well as its ability to relieve hunger. Olfactory function declines most dramatically with age . This is due to a reduction in mucus secretion, thinning of the epithelium, and a decline in the regeneration of olfactory receptor cells . Medications are particularly likely to increase dysgeusia when there is inhibition of the cytochrome P450 metabolism system and the efflux transporter P-glycoprotein. Drugs then alter taste through the intravascular taste system . Visual impairment occurs both from age-related decline in vision and due to diseases such as cataracts and age-related macular degeneration.
Overall changes in sensory function result in a relatively small decrease in food intake, but over a number of years this can result in an appreciable weight loss . Taste enhancers have been found to have a small effect on reversing the anorexia of aging . Enhancement of the dining room and food presentation has been shown to improve food intake in nursing homes, attesting to the importance of vision as a sensation playing a role in appetite . Buffet dining and the use of snack carts and ice-cream parlors have also improved food intake. With aging, changes in food preferences and choices appear to be influenced more by social forces than by sensory changes .
THE GASTROINTESTINAL TRACT AND SATIATION
The involvement of the gastrointestinal tract in producing satiation involves antral stretch, the rate of gastric emptying, the release of gastrointestinal hormones, and feedback to the central nervous system, through the ascending fibers of the central nervous system. Older persons have a delay in gastric emptying when they ingest large meals . This delay in gastric emptying is associated with an increase in satiation in older compared to younger persons. In addition, aging is associated with a decrease in fundal compliance leading to more rapid antral filling and increased central stretch . This decrease in fundal compliance is due to a decrease in fundal relaxation to nitric oxide with aging . When the stomach is bypassed by utilizing an intraduodenal tube, food has less of a satiating effect in older persons . Liquids are rapidly emptied from the stomach without producing significant antral stretch. For this reason, it has been demonstrated that oral liquid supplements given at least an hour before the meal result in greater food intake in older persons .
Animal studies have suggested that gastrointestinal hormones have a greater satiation effect in older animals [24▪]. In older humans, cholecystokinin (CCK) levels have been found to be elevated at baseline and after a meal compared to levels found in younger individuals [25,26]. The elevation of CCK has not been found in all studies . It has been suggested that this is dependent on the volume of food ingested. CCK infusion has a greater satiation effect in older than in younger persons .
Glucagon-like peptide 1 (GLP-1) is a potent anorexic hormone that also slows gastric emptying [28,29]. A high fat meal that produced more satiation in older persons also increased GLP-1 levels more than those in younger persons . Other gastrointestinal hormones that produce satiation still need to be studied to provide comparisons between the effects on satiation in young and old persons.
Ghrelin is a gastrointestinal hormone that is produced from the fundus of the stomach. It releases growth hormone from the pituitary and it stimulates feeding by activating nitric oxide synthase in the hypothalamus . A number of studies have examined the effect of aging on ghrelin. In general, these studies suggest a small decrease in ghrelin levels in older compared to younger persons [32,33]. The active ghrelin (acetylated) levels tend to be lower than deacetylated ghrelin in older persons . The recovery of ghrelin following a meal is less pronounced in older compared to younger persons . The expected increased ghrelin levels in malnourished older persons are not present [33,34], although they also show less suppression following a preload .
The different responses of the gastrointestinal tract to food in aging are summarized in Fig. 1. Overall, these effects lead to greater satiation by increasing antral stretch, increasing the satiation hormones CCK and GLP-1, and decreasing the levels of the orexigenic hormone, ghrelin. These findings strongly support that changes in the gastrointestinal response to food play a role in producing the physiological anorexia of aging [35▪].
ADIPOKINES AND APPETITE
With aging, there tends to be an increase in adiposity. This leads to an increase in tumor necrosis factor alpha and other proinflammatory cytokines. Cytokines lead to anorexia. Cytokine levels are even more elevated in chronically ill persons, most of whom have some levels of cachexia [36,37]. Chronic low-grade inflammation in older persons leads to increased tryptophan levels [38▪]. This leads to an increased anorexia via serotonin activation.
Leptin is a hormone produced from adipocytes. Leptin decreases food intake. Fasting leptin levels are higher in older compared to younger persons . Elevated leptin levels are associated with weight loss in older persons . Older men tend to have a reduction in testosterone levels . Testosterone reduces leptin levels, explaining the elevated leptin levels and the greater anorexia of aging present in older men. Leptin levels are decreased in cachexia . However, this fall in leptin fails to increase appetite, most probably due to accompanying hypertriglyceridemia producing leptin resistance .
Elevated leptin and cytokines in older persons are seen in association with increased adiposity and play a role in the development of the anorexia of aging.
CENTRAL REGULATION OF APPETITE
Within the central nervous system, appetite is controlled by the interaction of a number of hypothalamic nuclei, that is, ventromedial hypothalamic nucleus (satiety center), the lateral hypothalamic area (hunger center), and the arcuate nucleus. These hypothalamic nuclei interact with other brain areas such as the amygdala and the nucleus tractus solitarius. Over 50 neurotransmitters interact within these nuclei to modulate the feeding drive. These neurotransmitters either increase food intake (orexigens) or decrease food intake (anorexics). Our knowledge of the effects of aging on the appetite regulatory system is predominantly based on studies in old rodents [43,44]. The changes in central neurotransmitters seen with aging are summarized in Table 1. As can be seen from the table, there is, in general, a decrease in mRNA, content, and responsiveness in orexigenic neurotransmitters. Although less data is available for anorexic neurotransmitters, they tend to go in the opposite direction. These findings are displayed graphically in Fig. 2.
The available data for central regulation in humans are very limited. Whereas in animals there is a clear decrease in the orexigenic effect of the kappa opioid peptide, dynorphin , no effect on opioid antagonism of feeding could be demonstrated in humans . In contrast, the diminished role of opioids in thirst with aging could be demonstrated in humans .
PATHOLOGY AND THE ANOREXIA OF AGING
The pathological causes of the anorexia of aging can be broadly divided into psychosocial and medical [24▪]. Recently, Ramic et al.[45▪] showed that loneliness played a role in producing anorexia and malnutrition. Depression is the most common cause of anorexia in older persons both in the community and in institutions [46–49]. The depression-related anorexia is most probably related to the increase in the potent anorectic neurotransmitter, corticotrophin-releasing hormone, which is increased in persons with depression . Late life paranoia results in a decrease of food intake because of the fear of being poisoned. Persons with dementia may increase their food intake early in the disease process but show dramatic increases at the end of the disease course. Anorexia tardive is similar to anorexia nervosa and occurs in older persons who have weight restricted all their life.
Medications play a major role in decreasing food intake in older persons . This effect can be magnified in persons with polypharmacy . Swallowing problems (dysphagia), particularly when associated with aspiration, can lead to a decrease in food intake. Dental problems can lead to a small decrease in food intake. Infections, for example, Helicobacter pylori, tuberculosis, or recurrent urinary tract infections produce anorexia due to elevated cytokines. Cholecystitis is also a cause of anorexia. Persons with Parkinson's disease or functional deterioration find it difficult to feed themselves. It takes up to 45 min to appropriately feed a resident of a nursing home. Therapeutic diets have been demonstrated to decrease food intake and to not be efficacious in improving outcomes in older persons . Inability to shop or prepare food will lead to a chronic anorexia. Chronic conditions such as congestive heart failure (cardiac cachexia) and chronic obstructive pulmonary disease as well as cancer can also present with anorexia.
MANAGEMENT OF ANOREXIA
Based on the high prevalence of anorexia, all older persons should be screened for anorexia, utilizing a simple tool such as the Simplified Nutritional Assessment Questionnaire (SNAQ), which has been shown to have excellent predictive ability of future weight loss and protein energy malnutrition [53,54▪]. Supplementation with a high-quality essential amino acid mix appears to decrease weight loss and improve function even in persons with cachexia [55,56]. In all persons with anorexia, a careful clinical review should be done to try to detect treatable conditions. To date, orexigenic drugs, such as megestrol acetate  or dronabinol , have not proven to have major clinical benefits. Ghrelin agonists and other drugs are being developed to treat anorexia and associated weight loss but are not yet commercially available .
The anorexia of aging has been identified as a true geriatric syndrome. It has both physiological age-related causes and pathological causes. Anorexia in older persons should be identified and vigorously treated as it has a variety of deleterious effects in older persons.
No outside funding was received for the writing of this article.
Conflicts of interest
J.E.M. serves as a consultant for Danone and Sanofi-Aventis and has a research grant from Purina (Nestle).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 111).
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anorexia; cachexia; cholecystokinin; ghrelin; leptin
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