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The anorexia of ageing: Physiopathology,prevalence, associated comorbidity and

mortality. A systematic review

Article in Maturitas · February 2013

Impact Factor: 2.94 · DOI: 10.1016/j.maturitas.2013.01.016 · Source: PubMed

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4 authors, including:

Vincenzo Malafarina

Clinica Los Manzanos, Lardero, La Rioja

32 PUBLICATIONS 246 CITATIONS

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Lucía Gil-Guerrero

Orden Hospitalaria San Juan de Dios


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Raquel Iniesta

King's College London


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Available from: Vincenzo Malafarina

Retrieved on: 22 April 2016

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V. Malafarina et al. / Maturitas74 (2013) 293–302 295

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APPETITE

PSYCHOLOGICALENVIRONMENTAL

DRUGS3

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α MSH1

ALZHEIMER’SDISEASE

INTESTINE

PANCREASADIPOSE TISSUE

EXERCISE

SENSES

GLP-1

CCK

LEPTIN

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RESISTIN

ADIPONECTINGASTRIC EMPTYING

GIP

PYY

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OBESTATIN

OXYNTOMOULI

TASTEDECLINE

SWALLOWINGPROBLEMS

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IL1 β

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GHRELIN

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NPY1

MCH2

AgRP1

STOMACH

SMELL REDUCEDDEPRESSION

LOSS OF PLEASURE INFOOD

HYPOTHALAMUS

HYPOTHALAMUS

Fig. 1. pathogenesis of anoxia of ageing. Central and peripheral hormones, psychological and environmental factors, medical and pharmacological factors and habits linkedto the regulation of appetite in elderly people. 1 Neurons in the hypothalamic arcuate nucleus. 2 Neurons in the lateral hypothalamic area. 3 Morley JE. American Journal of ClinicalNutrition1997;66:760–73. MSH,alphamelanocyte-stimulatinghormone; AgRP,agouti-related protein;CART, cocaine-and amphetamine-regulated transcript;CCK,cholecystokinin; GLP-1, glucagon-like peptide 1; GIP,glucose-dependent insulinotropic polypeptide; IL-1, interleukin-1; IL-6,interleukin-6; MCH,melanin-concentratinghormone; NPY,neuropeptide Y; PYY, peptide YY; TNF-, tumour necrosis factor-alpha. Thesolid line indicates inhibition, thedashed line indicates stimulation.

Potentiallyrelevant citation:

PubMed n=142

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n=22

After duplicates removedn=162

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Secondary anorexia: n=10Other: n=10

Full-text articles assessed foreligibility: n=46

Studies included in qualitativesynthesis: n=27

Full-text articles excluded: n=19

Repeated data: n=2

No anorexia: n=17

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Fig. 2. Flow-diagram of literature search.


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statistically higher values in anorexic elderly people than in non-anorexic elder people [16].

An increase in basal values was observed in both younger andolder subjects following a preload meal. The differences were notstatistically significant in one study [11], whereas in three stud-ies the increase observed was statistically higher in older subjects[12–14]. SerraPratet al., conversely,observeda statisticallygreaterincrease in younger subjects than in older ones[15].

Ghrelin is the main orexigenic hormone, secreted by the cells atthe bottom of the stomach. Ghrelin levels increase in fasting con-ditions and fall rapidly after the ingestion of food[17]. The levels of ghrelinobservedinthestudiesvariedgreatly.Ingeneral,thestudiesdid not specify whether they measured total ghrelin, the acylated(active) form or the non-acylated (inactive) form. Most of the stud-ies observed similar levels of ghrelin in young and elderly subjects[18–21], althoughonefoundminimallyhigherlevelsinelderlypeo-ple [15] and another lower levels in elderly people than in youngsubjects [11]. Two studies found plasma ghrelin concentration inolder subjects to be significantly lower than that in younger peo-ple [22,23]. Two studies observed no difference in basal levels of ghrelin following a preload meal [20], and a further study observedno changes in elderly subjects and a reduction of ghrelin levels inyoung subjects [18]. Some of the authors observed a decrease inghrelin levels following a preload meal compared with fasting lev-els, with the difference not being significant in one case[11] andsignificant in another [15]. One study reported slightly conflictingresults, with an increase of ghrelin compared with fasting valuesonly in young subjects, although the differences were not statisti-cally significant [23].

SerraPratetal.presenttheresultsofastudywithrepeatedmea-surements design type after two years [39]. The authors observethat low baseline levels of ghrelin are associated with a loss of strength, as measured by the hand grip, with a worsening of the Barthel index, and an increased risk of malnutrition, calcu-lated using the Mini Nutritional Assessment-Short Form (MNA-SF).Although the authors do not present the data about the numberof deaths, commented that the women who died during the two

years had baseline ghrelin lowest of women still alive, which is notobserved in men.

Glucagon-like peptide-1 (GLP-1) is a hormone produced by thesmallintestineinresponsetofoodintake,especiallycarbohydrates;it delays gastric emptying and inhibits appetite [24]. The variousstudies diverge in their observations: some have shown similarfasting levels in elderly and young patients [11,14,21], while oth-ers have reported slightly lower values in elderly subjects [25] oreven higher levels [13], although the differences were not statisti-cally significant in the latter two studies. Almost all of the studiesagree that GLP-1levels increase after a preload meal in both elderlyand young people [11,13,21,25] and in two cases the levels werestatistically higher in elderly subjects than in young ones [14,21].

Insulin, in addition to being one of the principal hormones

involved in glucose metabolism, acts, like leptine does, at thehypothalamic level, reducing appetite by inhibiting cells in thearcuate nucleus and stimulating the lateral hypothalamic area[26]. Several studies assessed fasting levels of insulin and thechanges in these levels following various stimuli – for exampleoralor intraduodenalfoodadministration or intravenousCCK – andobtained slightly differing results. Some authors observed similarbasal values in elderly andyoung subjects [15,18,21,25], whileoth-ers showed statistically higher levels in elderly subjects comparedwithyoungones [11,20,22,23], andMacIntoshetal.observedstatis-tically higherbasallevels of insulin in young subjects[12]. Ofthesixstudiesthatexaminedinsulinlevelsfollowingapreloadmeal,threeobserved an increase in both elderly and young subjects[11,21,25]and the other three found statistically higher levels in elderly sub-

jects [15,18,20]. Again, the study conducted by MacIntosh et al.

diverged from the rest of the studies, as they observed that, fol-lowing intravenous CCK, insulin levels were statistically higher inyoung subjects than in elderly subjects [12].

Martínez et al. studied two groups of elderly people with andwithout anorexia and found, in the anorexic group, statisticallyhigher levels of CCK in plasma and lower levels of -endorphin,and statistically lower levels of somatostatin and-endorphin incerebrospinal fluid (CSF) [16]. L evels of neuropeptide Y (NPY) werestatistically higher in both the plasma and the CSF of the anorexicsubjects.

There are few data regarding elderly people and three appetite-inhibiting hormones: leptine, produced by the adipose tissue, theglucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY), produced in the intestine.

3.3.2. Motility

Studies on intestine transit have demonstrated an increasein frequency and amplitude of isolated pyloric pressure waves(IPPWs) [27] in elderly people compared with younger people, anincrease in the time gastric emptying takes [28] and a decrease inmaximum contraction of the gallbladder [14]. Allthese factors maycontribute to thefeeling of satiationfollowing a meal. Thecomplete

intestine transit time does not change with age.

3.3.3. Regulation of ingestion

In two studies was assessed caloric intake in basal conditionsand after a test meal [29,30]. The authors observed that the intakeintheelderlywaslowerafterthetestmeal.Evensothetotalamountofcaloriesconsumedtheamountofcaloriesofthemealtestplusthecalories of the free meal were statistically larger than the caloriesingested in the baseline situation. Data are conflicting on medium-term and long-term regulation. Young people recover weight lostduring a periodof restrictive dieting and lose weight gained duringahypercaloricdietbyregulatingtheiringestionthereafter,whereasthis was not observed in elderly people[31]. Nevertheless, anotherof the reviewed papers reported how, following a restrictive dietthat brought about weight loss, elderly subjects soon were back tobasal levels of ingestion andtended to recover the weight they lost,which was not observed in young subjects [32].

It is known that activation of opiate receptors in the brain sti-mulates appetite and ingestion, although their role in the feeling of thirst and in the regulation of water ingestion is not clear [10].

MacIntosh et al. found a decrease in ingestion as a responseto naloxone infusion in young people and elderly men, but not inelderly women [33].

3.4. Prevalence and comorbidity

The prevalence of AA among elderly people living in the com-

munity has been reported to range between 15% and 30%, with anoverall higher prevalence in women [34–37]. Prevalence is higherin elderly people in nursing homes, at 31% (27% of men and 34%of women), and in hospitalized patients, at 31.5% (26.7% men and33.3% women) [35]. Cornali et al. observed a prevalence of 15.8% inelderly people dischargedfrom hospital[38]; of those diagnosedashaving AA, 18% were men and 82% were women.

There is agreement that AA is more prevalent in older age[34–38] and that it tends to occur in people with disabilities anddependencyfortheactivitiesofdailyliving(ADL) [34,35,37], aswellas in people with a higher comorbidity index [35–37]. Anorexicelderly people overall seem to have worse cognitive deterioration[34–37], worse oral health (expressed as fewer natural teeth andmore difficulty in chewing) [34,35], and more depression [34–38].Table 2 is a summary of themain comorbidities associated with AA.

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300 V. Malafarina et al. / Maturitas 74 (2013) 293–302

T a b l e

2

C o m o r b i d i t y a s s o c i a t e d w i t h a n o r e x i a o f a g e i n g .

A u t h o r

A g e ( m e a n ±

S D )

A D L

C o g n i t i v e i m p a i r m e n t

D e p r e s s i o n

C o

m o r b i d i t y i n d e x

A n o r e x i a

N

o a n o r e x i a

A n o r e x i a

N o a n o r e x i a

A n o r e x i a

N o a n o r e x i a

A n o r e x i a

N o a n o r e x i a

A n

o r e x i a

N o a n o r e x i a

S c o r e , m e a n ±

S D

C P S ( m e a n ±

S D )

( % )

L a n d i 2 0 1 2 [ 3 4 ]

8 1 . 0

±

7 . 8

8

0 . 1

±

7 . 4

* *

5 . 3

±

2 . 4

4 . 5

± 2 . 7 * * *

2 . 7

±

2 . 2

2 . 3

±

2 . 1

* * *

6 1

5 6 * *

N A

N A

> 2 l o s t A D L ( % )

M M S E ( m e a n ±

S D )

G D S ,

( m e a n ±

S D )

( m

e a n ±

S D )

D o n i n i 2 0 1 1 [ 3 5 ]

8 3 . 0

±

7 . 0

7

6 . 6

±

8 . 0

*

5 5 . 5

3 1 . 8

*

1 8 . 5

±

9 . 0

2 3 . 8

±

5 . 0

*

6 . 7

±

5 . 0

4 . 7

±

4 . 0

*

2 . 4 ±

2 . 0

2 . 1

±

2 . 0

*

C P S ( m e a n ±

S D )

( % )

N u

m b e r o f d i s e a s e

L a n d i 2 0 1 0 [ 3 6 ]

8 6 . 8

±

4 . 6

8

5 . 6

±

4 . 9

N S

N A

N A

1 . 1

±

1 . 8

0 . 8

±

1 . 5

N S

3 6 . 5

2 2 . 4

*

2 . 4 ±

1 . 3

2 . 1

±

1 . 2

*

( % )

V á z q u e z 2 0 1 0 [ 3 7 ]

N A

N

A

2 9 . 2

1 3 . 2

* * *

N A

N A

N A

N A

N A

N A

B I ( m e a n ±

S D )

M M S E ( m e a n ±

S D )

G D S ( m e a n ±

S D )

B D

S ( m e a n ±

S D )

C o r n a l i 2 0 0 5 [ 3 8 ]

8 1 . 0

±

7 . 2

7

6 . 5

±

6 . 8

* * *

6 0 . 0

±

2 9 . 2

6 7 . 9

± 2

3 . 6

N S

2 1 . 7

±

5 . 9

2 2 . 7

±

5 . 6

N S

6 . 4

±

3 . 5

6 . 2

±

3 . 4

N S

9 . 9 ±

4 . 3

9 . 1

±

3 . 5

N S

A D L , a c t i v i t i e s o f d a i l y l i v i n g ( s c o r e r a n g e 0 – 7 , a

h i g h e r n u m b e r i n d i c a t e s h i g h e r i m p a i r m e n t ) ; B D S ,

b u r d e n o f d i s e a s e s c o r e ; B I , b a r t h e l i n d e x ; C P S , c o g n i t i v e p e r f o r m a n c e s c a l e ( r a n g e 0 –

6 , a h i g h e r n u m b e r i n d i c a t e s h i g h e r

i m p a i r m e n t ) ; G D S , g e r i a t r i c d e p r e s s i o n s c a l e ; M M

S E , m i n i m e n t a l s t a t e e x a m i n a t i o n ; N S , n o n - s

i g n

i fi c a n t ; N A , n o t a v a i l a b l e .

*

p

< 0 . 0

5 .

* *

p

< 0 . 0

1 .

* * *

p

< 0 . 0

0 1 .

3.5. Mortality

AA has proven to be an independent mortality factor in elderlypeople.

Twostudies found elderly peoplewith AA to have elevated mor-tality rates. In one of these the corrected relative risk (RR) was1.83 (95% confidence interval, CI, 1.45–2.31) [34]. The same studyfound that the RR was 1.45 (CI 1.01–2.19) when anorexia was notassociated with weight loss, and 1.89 (CI 1.53–2.54) when it wasassociated with weight loss. The other study observed a RR of 2.9(95% CI 1.1–7.4) at 10.5 months [38].

3.6. Treatment

We found few clinical studies of the treatment of AA. Megestrolacetate is a synthetic hormone (progestogen) currently indicatedfor treatment of loss of appetite associated with weight loss in HIV-positive patients whohavecancer.Itisthemoststudieddruginthisfield but results have not demonstrated its efficacy in treating AAand its side-effects limit its use [16,40].

Dronabinol is a synthetic formof delta-9-tetrahydrocannabinol,a natural component of the plant Cannabis sativa, approved for

the treatment of anorexia associated with weight loss in patientswith AIDS, and as an anti-emetic in cancer patients undergoingchemotherapy. We have found no prospective randomized studieswith dronabinol.

CCK inhibitors such as loxiglumide or dexloxiglumide maypotentially be used as treatment for AA, but they are still at anexperimental stage.

4. Discussion

Thereismuchdiversityintheresultsofstudiesonthehormonesthat regulate appetite. This confirms the complexity of the periph-eral and central regulation of appetite. Nonetheless, research mustcontinue along these lines, with particular attention to anorexic

elderly people.One of the most interesting aspects for geriatricians is the high

comorbidity observed in elderly people and how it influences theirclinicalstateand,moreespecially,theirfunctionalstate.Despitethefact that the observational studies included in this review do notallow us to establish causal relationships, they do pose interestingquestions about mechanisms potentially related to AA, which mayserve as a basis forfuture research.The high comorbidity associatedwith AA is a subject of great clinical interest, but here again, moreresearch is required, especially to show which of these comorbidi-ties are causes and which are consequences of AA.

The response to naloxone indicates that opiateregulation is stillimportant and may be a therapeutic target but there is evidenceonly for elderly males.

AA is a clinical problem recognized by geriatricians, butits diag-nosis,complicationsand possible treatmentsare difficult to resolve[41]. It is recognized as a geriatric syndrome, but the factors influ-encing appetite in elderly people are so many and so prevalent thatresearch into its physiopathological mechanisms is difficult.

Nutritional intervention in elderly patients is a matter currentlyunder discussion. For it to be used appropriately, it is imperativethat it is based on an important premise: nutritional interven-tion should begin with the assessment and narrowing down of thepossible causes of malnutrition in an elderly person, and dietarysupplementationshould be instituted only when it hasbeen shownto be necessary should [42].

Before clinicians give dietary advice, they must be aware thatelderly people have slower gastric emptying although they main-

tain normal complete intestinal transit times. Such consideration

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may help to improve the tolerance of and adherence to nutritionaltreatment.

Although an active lifestyle and physical exercise have beenshown to be effective in preventing functional deterioration andloss of muscle mass, it seems there is no relation between physicalexercise and appetite [43–46].

The main limitations of this review are the broad variety in thedesigns of the includedstudies, theirvaryingobjectives,the charac-

teristics of the populations studied and, in the intervention studies,the broad variety of preload meals used in terms of nutritionalcharacteristics, administration route and volume.

5. Conclusions

Almostall the included studies assessed thesecretion of periph-eral hormones related to appetite control in healthy elderly peopleand compared this with secretion in younger people. Future stud-ies should assess the differences between elderly people with andwithout anorexia, to give a better understanding of the physiopa-thological mechanism at the root of appetite loss.

Environmental factors (such as isolation), sensory alterations,poor oral hygiene andpolypharmacy are potentialtargets forinter-ventions aimed at improving ingestion and reducing the risk of malnutrition in elderly people. Research into the treatment of AAshould not focus exclusively on the search for yet another drug tostimulateappetite,inordertoaddittotheexistinglonglistoftreat-ments of elderly patients. Rather, it should focus on an integratedgeriatric assessment, including a nutritional evaluation.

Provenance andpeer review

Commissioned, externally peer reviewed.

Contributors

Dr. Vincenzo Malafarina conceived the idea of the review, per-

formed the bibliographic search and wrote the manuscript. Dr.Francisco Úriz-Otano, Dra Lucía Gil-Guerrero and Raquel Iniestahelped interpreting the data and making comments on the finalversion of the manuscript.

Competing interest

The authors declare no conflict of interest.

Funding

The authors have not received any financial support.

Acknowledgments

We would like to greet the Foundation San Juan de Dios librarypeople (Espluguesde Llobregat, Barcelona),especially Alicia MartínandSílvia Semaan Llurba, for their help in thebibliographic search-ing.

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