Mechanisms of Ageing and Development 136-137 (2014) 7684

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Mechanisms of Ageing and Development

journal homepage: www.elsevier.com/locate/mechagedev

Nutrition and protein energy homeostasis in elderly

Yves Boirie a,b,c, Beatrice Morio b,c, Elodie Caumon a, Noel J. Cano a,b,c,*
a

CHU Clermont-Ferrand, Service de Nutrition Clinique, F-63003 Clermont-Ferrand, France

Clermont Universite, Universite dAuvergne, Unite de Nutrition Humaine, BP 10448, F-63000 Clermont-Ferrand, France
c
INRA, UMR 1019, UNH, CRNH Auvergne, 58 rue Montalembert, BP 321, F-63009 Clermont-Ferrand cedex 01, France
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Available online 31 January 2014

Protein-energy homeostasis is a major determinant of healthy aging. Inadequate nutritional intakes and
physical activity, together with endocrine disturbances are associated with of sarcopenia and frailty.
Guidelines from scientic societies mainly address the quantitative aspects of protein and energy
nutrition in elderly. Besides these quantitative aspects of protein load, perspective strategies to promote
muscle protein synthesis and prevent sarcopenia include pulse feeding, the use of fast proteins and the
addition of leucine or citrulline to dietary protein. An integrated management of sarcopenia, taking into
account the determinants of muscle wasting, i.e. nutrition, physical activity, anabolic factors such as
androgens, vitamin D and n-3 polyunsaturated fatty acids status, needs to be tested in the prevention
and treatment of sarcopenia. The importance of physical activity, specically resistance training, is
emphasized, not only in order to facilitate muscle protein anabolism but also to increase appetite and
food intake in elderly people at risk of malnutrition. According to present data, healthy nutrition in
elderly should respect the guidelines for protein and energy requirement, privilege a Mediterranean way
of alimentation, and be associated with a regular physical activity. Further issues relate to the
identication of the genetics determinants of protein energy wasting in elderly.
2014 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Elderly
Sarcopenia
Protein metabolism
Energy metabolism
Nutrition
Exercise training

1. Introduction
In 2009, life expectancy without disability stood at 61.3 years
for men in the European Union (EU27), which represents nearly
80% of their life expectancy at birth (76.7 years). Life expectancy
without disability reached 62 years for women, representing
three-quarters of their life expectancy at birth (82.6 years). Thus, a
major challenge of current public health is to ght against the
factors of disability in order to get an extension of life expectancy
without disability. Disability is often associated with a situation
known as frailty, a state of vulnerability that is responsible for an
inability to maintain a normal physiological balance and respond
to stress. Frailty may be the result of dysfunction related to age or
chronic disease. It affects the quality of life, undermines the
autonomy, can compromise life at home without assistance and
lead to institutionalization.

Abbreviations: AA, amino acids; AEE, activity energy expenditure; BEE, basal energy
expenditure; DEE, daily energy expenditure; FFM, fat-free mass; FM, fat mass; REE,
resting energy expenditure; WPIL, whey proteins providing the same amount of
leucine; WPIN, isonitrogenous whey proteins.
* Corresponding author at: CRNH Auvergne, 58 rue Montalembert, BP 321,
F-63009 Clermont-Ferrand cedex 01, France. Tel.: +33 608071109.
E-mail addresses: Yves.boirie@clermont.inra.fr (Y. Boirie),
beatrice.morio@clermont.inra.fr (B. Morio), ecaumon@chu-clermontferrand.fr
(E. Caumon), noel.cano@clermont.inra.fr (N.J. Cano).
0047-6374/$ see front matter 2014 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mad.2014.01.008

Thus, it is crucial to identify frailty at an early stage and take

charge before it alters the autonomy of old people. The main signs
that announce frailty are related to nutrition and activity:
unintentional weight loss greater than 5% in one year, decreased
muscle strength, appearance of unusual fatigue, reduced walking
speed and physical activity. Protein-energy homeostasis is a major
determinant of healthy aging. In community-dwelling people older
than 70 years, 510% are undernourished, and for institutionalized
elderly, this is up to 3065% (van Staveren and de Groot, 2010;
Cereda et al., 2011). It was shown that loss of lean tissues occurs
exponentially with aging (Genton et al., 2011). A low fat-free mass
index appeared as an independent factor of survival in still healthy
old subjects (Genton et al., 2013). Sarcopenia was reported to be
associated with physical disability in old men (Chien et al., 2010).
Reduced nutritional intakes and physical activity, together with
endocrine disturbances such as of low serum levels of dihydroepiandrosterone and, in men, bio available testosterone are
associated with the risk of sarcopenia and frailty (Koutsari et al.,
2009). Restrictive diets in patients over 75 increase the risk of
protein energy wasting and, at an individual level, need to be
reassessed (Zeanandin et al., 2011). Finally, vitamin D deciency
and associated parathormone changes were shown to be
associated with frailty in men (Shardell et al., 2009).
Guidelines from scientic societies mainly address the quantitative aspects of protein and energy requirements in elderly
and aim to prevent sarcopenia and associated osteoporosis

Y. Boirie et al. / Mechanisms of Ageing and Development 136-137 (2014) 7684

(Verschueren et al., 2013). However, recent data have shown body

composition abnormalities such as fat overload, and age-specic
changes in protein, energy and micronutrient metabolism that
could intervene in the risk of malnutrition and deserve qualitative
recommendations for nutrition in elderly aiming at decreasing the
incidence of nutrition-connected chronic diseases (van Staveren
and de Groot, 2010; Luhrmann et al., 2009).

2. Characteristics of energy metabolism in elderly

In old people, energy expenditure and insulin sensitivity can be
altered.
2.1. Energy expenditure in elderly
In a cross-sectional study conducted in 529 adults aged 1896
years, the associations between body composition and daily (DEE),
basal (BEE), and activity energy expenditure (AEE) were examined
throughout the adult life span (Speakman and Westerterp, 2010).
DEE was measured by using doubly labelled water, BEE by using
respirometry, and body composition by isotope dilution. AEE was
calculated as DEEBEE, and physical activity level as DEE/BEE. Up
to age 52 years, fat-free mass (FFM) and fat mass (FM) were
positively associated with age in men, but no signicant effect was
observed in women. Subjects aged more than 52 years were
characterized by lower values of FFM, FM, DEE, BEE and AEE. BEE
similarly decreased in women ( 22 kJ/day/year) and men ( 45 kJ/
day/year). It was noticeable that the decrease in AEE was much
greater than the decrease in BEE, showing that physical activity
was strongly dependent on age for those subjects. No relation was
found between age-adjusted physical activity level and FFM
suggesting that, in elderly, greater physical activity was not
associated with higher FFM. Similar longitudinal changes in energy
expenditure, remarkable by the decrease in physical activity, were
observed during a 12-year follow-up of an elderly German
population (Luhrmann et al., 2009). An association between AEE,
appetite and survival was noted among well-functioning, community-dwelling older adults underlining that appetite assessment
could provide important information regarding the risk for health
deterioration and mortality in elderly as in chronic organ diseases
(Carrero et al., 2007; Shahar et al., 2009). In some healthy aging
subjects, the simultaneous decline in physical activity and calorie
intake can result in the lack of variation in body weight (Sarti et al.,
2012).
The decrease in physical activity in elderly is associated with
the occurrence of falls in community-dwelling adults over 50 years
old (Pereira et al., 2013). Consistently, studies of energy expenditure and activity levels using the multisensor SenseWear Pro
Armband1 showed that older men with lower energy expenditure,
lower activity, or greater sedentary time were more likely to
develop a functional limitation (Cawthon et al., 2013). In both
community-dwelling and institutionalized older adults, the
benecial effect of physical activity was demonstrated. As a
matter of fact, physical activity improved different domains of both
the physical and mental components of quality of life questionnaires and decreased depressive symptoms (Salguero et al.,
2010). Resistance exercise, which can increase REE and serum
adiponectin in overweight elderly individuals, may represent an
effective approach for weight management and metabolic control
in overweight elderly individuals (Fatouros et al., 2009). The
determinants of AEE in elderly are poorly understood. Recently,
mitochondrial DNA variation was shown to be associated with
free-living AEE in older persons suggesting that specic mitochondrial DNA complexes, genes, and variants may contribute to
the maintenance of activity levels in late life (Tranah et al., 2012).

77

2.2. Energy metabolism and predisposition to insulin resistance

The size and distribution of fat depots dramatically change
throughout life. Increased body fatness can be largely explained by
changes in energy metabolism favouring the occurrence of positive
energy balance. First, hormonal changes, mainly in women during
menopause (Ferraro et al., 1992; Morio et al., 1997), and agerelated muscle loss (Tzankoff and Norris, 1978) are responsible for
diminished basal metabolism rate. Furthermore, and partially as
the consequence of the rst point, a lower level of physical activity
is an important factor associated to the reduced energy expenditure during aging (Paivi et al., 2010). Increased body fatness is
strongly involved in the development of metabolic disorders in the
elderly. In that context, prevalence of insulin resistance, i.e.
impaired insulin sensitivity, increases in elderly human.
During the past decade, numerous studies have explored the
potential association between the reduction in insulin sensitivity
and the age-related diminished energy-metabolism, with a specic
focus on muscle mitochondrial functioning. Indeed at the whole
body level, insulin resistance is associated to low aerobic tness
and high body fatness, which have been linked to the decrease in
muscle mitochondrial oxidative capacity (review in Phielix et al.,
2011). At the cellular level, insulin resistance has been correlated
to lipid accumulation in myocytes, which could be the result of
deterioration in mitochondrial oxidative capacity (Johannsen et al.,
2012). Debates still exist with regards to the origin of mitochondrial alterations and how they relate to the development of insulin
resistance. This is probably due to the fact that mitochondria are
complex organelles not limited to substrate oxidation and energy
production. However, increasing evidence suggests that changes in
insulin sensitivity and mitochondrial function may not be causally
related, but mutually amplify each other during aging (Karakelides
et al., 2010; review in Phielix et al., 2011). We here briey develop
arguments supporting this conclusion.
Impact of aging on muscle mitochondria functioning. In the
elderly, alterations in energy metabolism may relate to low
mitochondrial oxidative capacity. Most studies in animals
evidenced that mitochondrial oxidative capacity decreases with
aging. By contrast, adverse effects of aging on muscle energy
metabolism in humans are not unanimously accepted (review in
Chanseaume et al., 2010). Several key pathways altered with aging
have been identied. They include decreased mitochondrial
density, mitochondrial oxidative capacity and ATP production
rate. In addition, several studies have shown that a decrease in the
fractional synthesis rate of mitochondrial proteins may participate
to the age-related decline in mitochondrial oxidative capacity
(review in Chanseaume et al., 2010). It remains controversial,
however, whether the reduction in mitochondrial oxidative
capacity is due to a consequence of aging or to unhealthy lifestyle.
Indeed, physical inactivity and insulin resistance are characteristics of the aging process and those two situations can contribute
to the muscle mitochondrial dysfunction related to aging.
Impact of insulin resistance on muscle mitochondria functioning. It
was shown that acute insulin infusion stimulates muscle
mitochondrial protein synthesis (Halvatsiotis et al., 2002; Stump
et al., 2003) as well as mitochondrial biogenesis, oxidative capacity
and ATP production (Stump et al., 2003). Furthermore, insulin
resistance has been related to decreased stimulation by insulin of
muscle mitochondrial protein fractional synthesis rate (Guillet
et al., 2009) as well as mitochondrial ATP production (Stump et al.,
2003; Petersen et al., 2005). An impaired insulin-stimulated
phosphate transport was also reported in muscle, which may
contribute to the defects in insulin-stimulated rates of mitochondrial ATP synthesis (Petersen et al., 2005). Finally, withdrawal of
insulin in type 1 diabetic patients decreased muscle mitochondrial
ATP production rate and expression of oxidative phosphorylation

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Y. Boirie et al. / Mechanisms of Ageing and Development 136-137 (2014) 7684

genes despite an increase in whole-body oxygen consumption

(Karakelides et al., 2007). Thus decreased insulin action in skeletal
muscle may contribute to the decline in mitochondrial oxidative
capacity and ATP production.
Impact of sedentary lifestyle on muscle mitochondria functioning.
It is well demonstrated that physical inactivity has adverse effects
on muscle mitochondrial oxidative capacity (Short et al., 2003;
Rimbert et al., 2004). In addition, the inverse relationship between
aging and mitochondrial respiration is no longer valid when young
and elderly subjects are matched for the same level of physical
activity (Barrientos et al., 1996; Rimbert et al., 2004). Thus,
physical activity during lifespan is important in the prevention of
muscle deconditioning and alterations in muscle energy metabolism.
2.3. Guidelines for energy intake in elderly
Prevention of protein-energy wasting. Given the risk of proteinenergy wasting, most guidelines for nutrition in elderly address the
quantitative aspects of energy requirements. It should also be
noticed that most of available data have been obtained in sick but
not healthy elderly people. A simple formula using a factor
multiplying body weight, i.e. 22 kcal/kg/day in under-weight and
19 kcal/kg/day in normal weight sick elderly, was proposed to
predict resting energy expenditure with a condence interval of
the bias was 400 kcal/day (Gaillard et al., 2008a). Guidelines from
the European Society of Clinical nutrition and Metabolism suggested
that the majority of sick elderly patients require at least 1.01.2 g
protein/kg/day and 2030 kcal/kg/day of non-protein energy
(Sobotka et al., 2009). According to current recommendations from
geriatricians, the goal of nutritional support in malnourished elderly
subjects should be to achieve a total energy input of 3040 kcal/kg/
day and a protein intake of 1.21.5 g protein/kg/day, knowing that
nutritional needs vary from person to person and depend on the
physiological and pathological context (Wolfe et al., 2008; RaynaudSimon et al., 2011). The daily energy requirements of healthy older
adults have been poorly studied. Current world-wide recommendations suggest that energy needs of individuals above 50 years are of
1.5 times resting energy expenditure, i.e. close to 30 kcal/kg/day, to be
adapted regarding to physical activity (Pannemans and Westerterp,
1995; Starling and Poehlman, 2000). A simple way to assess whether
energy intake is correct in clinical practice is that the elderly person
has a body mass index more than 21 and maintains a stable weight.
Prevention of metabolic syndrome. Regarding to the risk of
metabolic syndrome in apparently healthy old people, the qualitative characteristics of energy intake appeared of relevance. In
hypercholesterolemic men it has been shown that lifestyle habits
and advice on dietary and exercise habits can affect circulating
biomarkers of lipid metabolism, inammation and vascular adhesion and inuence the development of cardiovascular disease
(Sjogren et al., 2010a). Among persons at high cardiovascular risk, a
Mediterranean diet supplemented with extra-virgin olive oil or nuts
can reduce the incidence of major cardiovascular events (Estruch
et al., 2013). In a large population-based, prospective investigation, a
higher degree of adherence to the Mediterranean diet was associated
with a reduction in total mortality and both death due to coronary
heart disease and death due to cancer (Trichopoulou et al., 2003). In
elderly, adherence to a Mediterranean-like dietary pattern was
shown to reduced the 10-year mortality (Sjogren et al., 2010b). Longchain n-3 polyunsaturated fatty acids were shown to reduce
inammation, to improve insulin sensitivity and to reduce hypertriglyceridemia (Jacobson, 2008; Kelley et al., 2009; Wakutsu et al.,
2010), although their role in the primary and secondary prevention
of acute cardiovascular events remains controversial (Kromhout
et al., 2010; Roncaglioni et al., 2013). Thus, besides quantitative
recommendations aiming to reduce the risk of protein-energy

wasting, present data argue for counselling to elderly people

Mediterranean-like diets providing energy mainly in the form of
fruits, vegetables, grains, olive and sh oils.
3. Characteristics of protein metabolism in elderly
3.1. Whole-body protein turnover
Protein turnover is a continuous and dynamic change in protein
metabolism since tissue proteins are constantly degraded and
synthesized. Protein turnover differs largely between the different
types of organs and even within each tissue so that their relative
contribution to whole body protein turnover depends on the rate of
protein turnover as well as their global protein mass (Guillet et al.,
2004a). In addition, organ protein turnover rates are differently
affected by physiological and disease states and conditions: in the
postprandial period for instance, insulin plays an important
anabolic role for muscle (Boirie et al., 2001a) while in other
situations like inammation protein synthesis is increased in the
liver for acute phase protein synthesis and protein breakdown is
stimulated in the muscle to provide amino acids for body protein
demand and repair (Attaix et al., 2005). Thus in physiological or
disease states, both whole body protein synthesis and breakdown
can be affected and may ultimately determine whether there is
protein accretion or protein loss either at the whole body or organ
(i.e. skeletal muscle) levels.
During the process of aging, synthesis of whole body as well as
specic proteins in muscle is globally lower than in young subjects
during the postabsorptive period (Boirie et al., 1997a). It is
important to note that in the comparison between the results of
different age populations having signicant changes in their body
composition, the data should be expressed as rate per kg lean
tissue instead of per kg body weight, because fat mass contributes
only marginally to whole body protein kinetics. So after correction
for the reduced amount of lean mass, dynamic studies of whole
body protein metabolism performed in the postabsorptive state
have shown no change in whole body protein turnover per unit of
active metabolic tissue between young and old healthy individuals. However, the contribution of muscle protein to whole body
protein metabolism has been reported signicantly reduced in the
elderly, due to their reduced muscle mass and lower myobrillar
protein turnover rate. Consequently, the contribution of nonmuscle proteins, especially visceral tissue proteins whose rates of
protein turnover are more rapid is proportionally greater with
aging (Morais et al., 2006).
3.2. Impact of feeding and splanchnic handling of amino acids
Feeding induces a net protein accretion that normally
compensates protein losses occurring during the postabsorptive
phase (Boirie et al., 1997a). Conceptually, net protein gain may
result from inhibition of proteolysis, stimulation of protein
synthesis or any coordinated changes of these two parameters
leading to a rate of protein synthesis higher than a rate of
proteolysis. It is generally accepted that feeding stimulates amino
acids (AA) oxidation according to the plasma AA level reached, and
decreases whole body protein breakdown, which is mostly
attributed to glucose-induced hyperinsulinemia (Boirie et al.,
2001b; Guillet et al., 2004b). Contradictory results have been
reported in studies on whole body protein synthesis. Indeed,
protein synthesis was stimulated in some studies (Pacy et al., 1994;
Gibson et al., 1996) or did not change in others (Melville et al.,
1989). These apparent discrepancies may partly be explained by
differences in AA availability, as assessed by plasma AA concentrations. For instance, gradual increases in AA concentration by
variable intravenous infusion of AA induce a dose dependent

Y. Boirie et al. / Mechanisms of Ageing and Development 136-137 (2014) 7684

stimulation of protein synthesis (Giordano et al., 1996). Similar

interpretation could be done from results obtained with continuous feeding using various amount of dietary protein or AA. Protein
intake above 1.5 g/kg/day, inducing strong hyper aminoacidemia,
generally stimulates protein synthesis (Pacy et al., 1994; Gibson
et al., 1996) while such stimulation was hardly reported with lower
protein intake (Melville et al., 1989). The AA levels may act not only
as substrates for protein synthesis but also as signals to modulate
gene expression (Jefferson and Kimball, 2001). Together all these
data suggest that both AA availability and insulin action are
important determinants of the regulation of protein metabolism.
This is the reason why we developed new strategies to modulate
postprandial plasma AA by studying the impact of different type of
dietary protein and the daily distribution of dietary proteins on the
increase in net protein synthesis. These studies led us to propose
new concepts such as the slow vs. fast protein concept based on
the speed of protein digestion which is able to altered postprandial
protein deposition (Boirie et al., 1997b). The other important
nding was that a pulse vs. spread protein diet, meaning that 80%
of daily proteins are administered in one single meal, is capable of
increasing protein retention in the body of elderly healthy subjects
(Boirie et al., 1997c). These concepts have been applied to optimize
lean body especially muscle protein synthesis as described below
in this review.
However, studying protein kinetics during feeding is complicated since during rst pass of the amino acids coming from the
digested meal proteins, gut and liver will extract variable amounts
of AA according to each AA, implying that the post-splanchnic AA
concentrations differ from dietary AA composition (Deferrari et al.,
1988). Whole-body and splanchnic protein metabolism were
determined in young and older healthy subjects before and during
a standardized meal by using a combination of intravenous and
oral tracers of AA (Boirie et al., 1997a). The pattern of metabolic
response to the meal was similar in young and old men, i.e.
increased ux and oxidation, decreased protein breakdown,
unchanged protein synthesis. However, splanchnic extraction of
dietary leucine was twice as high in elderly men (50% vs. 23%) and
it was inversely related to plasma leucine concentration. This
higher extraction of dietary leucine by the splanchnic tissues
during feeding in older healthy subjects was also conrmed for
phenylalanine (Volpi et al., 1999). The mechanisms of these
disturbances are still unknown but it could potentially lead to a
lower peripheral availability of dietary essential AA for peripheral
tissues like muscle. This higher splanchnic extraction of leucine
may have an impact on inter-organ exchanges of AA as recently
shown for glutamine (Jourdan et al., 2013). It is of interest to note
that, unlike these changes in splanchnic handling observed in
elderly, lower splanchnic tissue extraction of AA have been
reported in chronic kidney disease (Deferrari et al., 1988) and
chronic obstructive pulmonary disease (Engelen et al., 2012).
3.3. Muscle protein synthesis: effect of protein quantity and quality
Muscle loss in elderly subjects may depend upon inadequate
nutritional intake (Houston et al., 2008) and or an impaired
response of skeletal muscle to nutrients, e.g. AA (Guillet et al.,
2004c; Cuthbertson et al., 2005) or hormones like insulin (Boirie
et al., 2001b; Rasmussen et al., 2006). Muscle protein synthesis and
breakdown have been measured in response to oral protein or
intravenous AA infusions in young and elderly subjects. When AA
are infused intravenously, a signicant increase of AA delivery to
the leg, of AA transport, and muscle protein synthesis was reported
irrespective of the age (Volpi et al., 1998). These data suggest that
despite an age-related decline in muscle mass, muscle protein
anabolism can be stimulated by high AA availability in the elderly.
Muscle protein turnover and amino acid transport in healthy

79

young and elderly people were also determined during an oral

administration of an AA mixture. Despite an increased splanchnic
extraction, muscle protein anabolism can be stimulated by an oral
administration of AA or dietary proteins in elderly and in young
subjects as far as the dietary protein intakes or the amount of AA
mixture ingested is high enough to induce a great AA availability
for muscle. From these studies it seems that the amount of AA/
protein intakes is crucial for triggering protein synthesis. Indeed, it
was demonstrated that smaller amount of protein during meal
intake was not able to stimulate muscle protein synthesis as well
as higher doses (Katsanos et al., 2005). This concept of a limited
response to feeding was already demonstrated in animal studies
involving old rodents (Mosoni et al., 1995). This blunted response
of protein synthesis to protein intake also called the anabolic
resistance may be explained by various factors like insulin
resistance, inammation, a reduced leg blood ow but further
research studies are needed to decipher these metabolic alterations in the postprandial period. These studies lead us to open the
question of muscle sensitivity to hormones like insulin or to
substrates like amino acids suggesting that a threshold needs to be
reach to induce muscle protein synthesis and that this threshold
may be higher in the case of inammation (Rieu et al., 2009). It also
demonstrates that substrates delivery has to be controlled by
acting on the plasma availability or blood ow. So the lack of
anabolic response to a complete meal in muscle is likely to
contribute to the development, over the long term, of sarcopenia in
the elderly. Consequently, the age-related loss of muscle mass and
function dening sarcopenia (Cruz-Jentoft et al., 2010) could be
counteracted by integrated interventions including nutritional
intakes, exercise training or hormonal treatments (Walrand et al.,
2011). It was clearly shown that changes in quantitative as well as
qualitative intakes of dietary proteins are able to improve
postprandial muscle protein synthesis. For instance, strategies
aiming at changing daily protein feeding pattern (Boirie et al.,
1997c), speeding-up protein digestion rate (Pennings et al., 2011a)
or supplementing with specic amino acids (Rieu et al., 2006; Wall
et al., 2013) may be benecial to improve short-term anabolic
response of muscle in elderly people. These reports suggest that
designing foods for specic situations like in elderly patients with
chronic diseases may counteract the pathophysiological processes
leading to muscle loss. Recent evidence also indicate that a
multimodal approach combining nutrition, exercise (Pennings
et al., 2011b), hormones, and specic drugs may be a more
appropriate treatment for limiting the development of sarcopenia
with aging, as proposed in muscle wasting associated with chronic
organ diseases (Cano et al., 2011; Pison et al., 2011).
3.4. Guidelines for protein intake in elderly, perspectives
Protein requirements in elderly. At present, protein needs in
elderly have been insufciently studied and, particularly, longterm evaluations are lacking. The recommended dietary allowance
for protein, as promulgated by the WHO and the Food and
Nutrition Board of the United States National Academy of Science,
is 0.8 g protein/kg/day for adults, regardless of age. However, such
a protein load corresponds to be the lowest requirements
acceptable in healthy people (Volkert and Sieber, 2011). In
hospitalized elderly patient, a minimum protein intake of
1.06  0.28 g/kg/day was shown to be necessary to maintain a
neutral nitrogen balance with an energy intake of 1.31 times resting
energy expenditure or greater (Gaillard et al., 2008b). The relationships between dietary protein and changes in total lean mass and non
bone appendicular lean mass were studied in 2066 older communitydwelling men and women during a 3-year follow-up. Participants in
the highest quintile of protein intake (1.2 g/kg/day) lost approximately 40% less lean mass and non bone appendicular lean mass than

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Y. Boirie et al. / Mechanisms of Ageing and Development 136-137 (2014) 7684

did those in the lowest quintile of protein intake (0.8 g/kg/day)

(Houston et al., 2008). Thus, in this long-term study, dietary protein
appeared as mean to decrease the incidence of sarcopenia. Evidence
indicates that protein intake greater than the recommended dietary
allowance can improve muscle mass, strength and function and
maintain body functioning as well as immune status and bone health
(Wolfe et al., 2008). Because elderly people are at increased risk of
illness and malnutrition protein intakes of 1.01.5 g protein/kg/day,
or about 1220% of total caloric intake, have been proposed to
optimize protein intake in terms of health and function (Fukagawa
and Young, 1987; Wolfe et al., 2008; Sobotka et al., 2009; RaynaudSimon et al., 2011).
Protein supply for frail old persons. Few studies addressed the
protein needs of frail elderly. High protein intakes were shown to
decrease the risk of frailty. In a prospective cohort study, 470
women aged 6579 who were free of frailty at baseline were
included (Beasley et al., 2010). Baseline protein intake was
estimated from the food frequency questionnaire. Records of
energy were corrected for measurement error using regression
calibration equations estimated from objective measurements of
total energy expenditure, by doubly labelled water, and dietary
protein, by 24-h urinary nitrogen measurement. After 3 years of
follow-up, 3298 women from the cohort developed frailty. High
protein consumption, as a fraction of energy, was associated with a
strong, independent, dose-responsive lower risk of incident frailty:
a 20% increase in protein intake was associated with a 32% lower
risk of frailty. Thus, incorporating more protein into the diet may
be an intervention target for frailty prevention. The impact of 24
weeks of dietary protein supplementation on muscle mass,
strength, and physical performance has been assessed a randomized controlled double-blind study (Tieland et al., 2012a,b). A total
of 65 frail elderly subjects were included and randomly allocated to
either daily protein or placebo supplementation (15 g protein at
breakfast and lunch). Skeletal muscle mass did not change in the
protein- or placebo-supplemented group following 24 weeks of
intervention, and type I and II muscle bre size did not change.
However, muscle strength increased signicantly in both groups,
with leg extension strength tending to increase to a greater extent
in the protein compared with the placebo group. Physical
performance, as assessed by the Short Physical Performance
Battery test improved signicantly in the protein group but not in
the placebo group (Guralnik et al., 1994). Thus, in this study,
protein supplementation improved physical performance, but did
not increase skeletal muscle mass in frail elderly people (Tieland
et al., 2012a). In frail older adults with low socioeconomic status, it
was also reported that protein-energy supplementation may
prevent the decline of muscle function (Kim and Lee, 2013).
Effects of protein supply manipulations. Following the metabolic
studies mentioned above, a strategy aiming at preventing
sarcopenia by changing daily protein feeding pattern was tested
in a six-week randomized trial (Bouillanne et al., 2013). Pulse
feeding was tested in 66 elderly malnourished or at-risk patients in
an inpatient rehabilitation unit. In the control group, daily dietary
protein was spread over the four meals. In the pulse diet group, 72%
of dietary protein (1.31 g/kg/day on average) was consumed in one
meal at noon. Pulse feeding was signicantly more efcacious than
spread feeding in improving lean mass index, appendicular
skeletal muscle mass and body cell mass index. This study
demonstrated that protein pulse feeding has a positive, clinically
relevant effect on lean mass in malnourished and at-risk
hospitalized elderly patients (Bouillanne et al., 2013). The effects
of slowly digested proteins (caseins) and two rapidly digested
protein supplies (isonitrogenous whey proteins, WPIN, or whey
proteins providing the same amount of leucine as caseins, WPIL) on
protein balance was tested in young and elderly adults (Dangin
et al., 2003). Proteolysis was similarly inhibited whatever the meal

and age groups. Irrespective of age, protein synthesis was higher

with WPIN than with caseins or WPIL. Leucine balance was higher
with caseins than with WPIL in young men, but not in elderly
subjects. In isonitrogenous conditions, leucine balance was higher
with WPIN than with caseins in both age groups, but the
magnitude of the differences was higher in the elderly men. This
suggests that a fast protein might be more benecial than a slow
one to limit protein losses during aging. The same authors showed
that the addition of non-protein energy sources to casein or whey
protein attenuated the differences in both the protein digestion
rate and protein gain (Dangin et al., 2002). Interestingly, and in
contrast to young subjects, whey protein was more effective than
casein in elderly subjects, to limit body protein loss.
Effect of amino acid supplementation. The anabolic effect of
chronically administered leucine has been poorly documented.
Leucine supplementation has not been tested in malnourished
elderly people. In non-malnourished old men, a situation during
which little muscular effect can be expected from nutrition
intervention without exercise, a 3-month supplementation with
7.5 g/day of leucine did not increase muscle mass or strength
(Verhoeven et al., 2012). More recently, it was shown that a
two-week leucine supplementation (12 g/l) improved muscle
meal-induced protein synthesis in older adults consuming
the Recommended Dietary Allowances for protein, but did not
increase fat-free mass (Casperson et al., 2012). Citrulline was
proposed as a new player in the control of protein metabolism both
as a source for arginine production by the kidney and as a signal
agent promoting muscle protein synthesis and function (Moinard
and Cynober, 2007; Faure et al., 2012, 2013). Experimental data
also argue for its possible protective effect on brain function during
aging (Marquet-de Rouge et al., 2012). However, by now, data are
lacking regarding to the use of citrulline in elderly people.
Integrated approach for protein wasting. The efcacy of
nutritional support in terms of protein balance and muscle mass
can be inuence by other factors, underlining the interest of an
integrated approach to nutrition in elderly, including exercise,
anabolic hormones, long-chain n-3 fatty acids and vitamin D
(Walrand et al., 2011). In such a multimodal approach, the
association of exercise with nutritional support is of rst interest
(see below). In men, low bioavailable testosterone is associated
with frailty and osteoporosis (Cawthon et al., 2009). The anabolic
effects of the correction of hypogonadism should also be
considered. Indeed, low-intermediate dose testosterone replacement therapy by different pharmaceutical preparations improved
frailty score in elderly hypogonadal hyperglycaemic patients
(Strollo et al., 2013). A recently reported interest of long chain
polyunsaturated n-3 fatty acids in elderly may be their stimulating
effect on muscle protein synthesis. This anabolic effect was
investigated in older adults during a hyperaminoacidemichyperinsulinemic clamp. Supplementation with long chain polyunsaturated n-3 fatty acids had no effect on the basal rate of
muscle protein synthesis but signicantly augmented the rate of
muscle protein synthesis during the clamp suggesting that they
may be useful for the prevention and treatment of sarcopenia
(Smith et al., 2011). Another nutrient to be considered is vitamin D.
Old people are characterized by a reduced ability to synthesize
vitamin D that is aggravated by the lower sunlight exposure
(Elmadfa and Meyer, 2008). Vitamin D deciency was demonstrated to be associated with a lot of non-bone deleterious effects
including frailty, decreased physical performance, falls and
increased mortality in elderly (Dhesi et al., 2004; Sato et al.,
2005; Shardell et al., 2009; Zittermann et al., 2009). With respect to
muscle protein metabolism, vitamin D appeared to be an actor of
protein synthesis and to inuence muscle function (Campbell and
Allain, 2006; Ceglia, 2008; Moran et al., 2013). Consistently, in a
prospective, double blind, placebo-controlled, randomized trial

Y. Boirie et al. / Mechanisms of Ageing and Development 136-137 (2014) 7684

conducted in institutionalized elderly, a 6-month cholecalciferol

supplementation was able to increase lower limb muscle strength,
in the absence of any regular physical exercise practice (MoreiraPfrimer et al., 2009).
Qualitative aspects of dietary protein. Regarding to the qualitative
aspects of dietary protein, the association between red meat
intake, metabolic syndrome, and serum C-reactive protein as a
surrogate measure of inammation was addressed in a crosssectional study of 482 women aged 4060 years (Azadbakht and
Esmaillzadeh, 2009). Serum C-reactive protein increased across
quintile categories of red meat intake. Concordantly, individuals in
the top quintile of red meat intake had greater odds of having
metabolic syndrome compared with those in the bottom quintile.
This study, that suggested that increased red meat consumption
might be associated with greater risk of metabolic syndrome and
inammation, requires to be conrmed by longitudinal data.
Finally, the benecial effects of milk products have been underlined. Besides their protein content dairy products are an
important sources of calcium, iodine, vitamin B2, zinc, phosphorus,
retinol, and vitamin B12 that make them of special interest in frail
elderly (van Staveren and de Groot, 2010). In some European
countries, three to four servings a day of milk and dairy products
have been recommended (Raynaud-Simon et al., 2011).
4. Role of exercise in maintaining protein energy homeostasis
in elderly
Endurance exercise is the more traditional mean of improving
cardiometabolic health. It has been largely studied in elderly
people as a mean to reduce the age-related alterations in physical
capacities and body composition. The efciency of 24 months
endurance training programs to improve the maximal oxygen
uptake and the maximal aerobic power output is constantly
reported even in elderly individuals (Grimby, 1986). A favourable
impact on fat mass loss was also achieved (Hersey et al., 1994;
Morio et al., 1998). It could be related to the benecial impact of
endurance exercise on insulin sensitivity (Rimbert et al., 2004;
Amati et al., 2009). Regarding the impact of endurance training on
energy metabolism, intervention trials showed that although
progressive endurance training induced a transient increase in
basal metabolic rate and diet-induced thermogenesis of elderly
men and women, total energy expenditure remained constant
throughout the training period (Morio et al., 1998). Those results
suggest that elderly individuals compensatory decrease their
spontaneous activity in response to increased exercise loads.
Furthermore, no obvious benets of endurance training could be
evidenced on lean body mass and more specically on muscle mass
(Suter et al., 1995; Morio et al., 1998; Rimbert et al., 2004).
Contrasting with endurance training, current data indicate that
resistance training of moderate to high intensity is effective to
prevent or slow down the age-related decline in lean body mass
(Peterson et al., 2011) and in muscle mass and strength (Hurley
and Roth, 2000), although high inter-individual variability is
reported in the response to training. Furthermore, resistance
exercise was shown to increase the rate of muscle protein
synthesis in elderly men and women, thus correcting the agerelated impairment in muscle protein metabolism (Yarasheski,
2003). It can be concluded that prolonged resistance training
represents an effective therapeutic strategy to increase muscle
mass and improve functional performance in the elderly (Koopman and van Loon, 2009). In frail elderly people, prolonged
resistance exercise training was similarly reported to be an
effective strategy to improve strength and physical performance.
In the same report, dietary protein supplementation was required
to allow muscle mass gain during exercise training (Tieland et al.,
2012b). Finally, these training programs were also shown to

81

increase total and physical activity related energy expenditure

(Ades et al., 2005; Kirk et al., 2009). Therefore, the contrasting but
complementary effects of resistance and endurance training on
protein energy homeostasis and metabolic health in the elderly
suggest that combined approach would be the most appropriate to
promote or maintain health, autonomy and quality of life (Sousa
et al., 2013; Sillanpaa et al., 2012; Karavirta et al., 2011).
5. Conclusions
Both protein energy wasting and unfavourable dietary regimens leading to fat overload and micronutrient deciencies can
compromise healthy aging. Protein energy wasting is a major issue
in elderly, found in up to 10% of community-dwelling people older
than 70 years and about 50% institutionalized elderly. In elderly
weight loss, is a factor of poor outcome. Weight loss is
accompanied by sarcopenia, a recognized cause of frailty and
disability. In order to ensure adequate intake, appetite and body
weight should be routinely assessed. Possible causes of decreased
food intake should be sought and treated. According to present
guidelines protein and energy intakes in elderly should reach 1.0
1.5 g protein/kg/day and 3040 kcal/kg/day, depending on the
nutritional and health status. High protein intakes (1.2 g protein/
kg/day) were shown to decrease the risk of frailty. Besides the
quantitative aspects of protein load, new strategies to promote
muscle protein synthesis and prevent sarcopenia include
pulse feeding and the use of fast proteins. Long-term clinical
trials are needed to conrm the efcacy of these strategies as well
as the possible benecial effects of the addition of leucine or
citrulline to dietary protein.
An integrated management of sarcopenia, taking into account
the determinants of muscle wasting, i.e. inadequate nutrition, poor
physical activity and deciencies in anabolic factors such as
androgens, needs to be tested in the prevention and treatment of
sarcopenia. Within such an integrated approach of malnutrition,
vitamin D status should be compensated. Similarly, the effects of n3 polyunsaturated fatty acids should be evaluated. As a matter of
fact, they were shown to improve appetite, to reduce the
inammation process and the risk of metabolic syndrome
(Carpentier et al., 2006), and at the myocyte level, to increase
oxidative metabolism, insulin sensitivity (Luquet et al., 2003), and
protein anabolism (Smith et al., 2011). The importance of physical
activity, specically resistance training, is emphasized, not only in
order to facilitate muscle protein anabolism but also to increase
energy expenditure, appetite and food intake in elderly people at
risk of malnutrition. A prior bout of aerobic exercise was shown to
improve the anabolic effect of nutrient intake in older adults
(Timmerman et al., 2012). Physical function and physical activity
are related to feelings of wellbeing and, in dependent subjects,
physical activity was shown to result in positive functional and
psychological effects (Garatachea et al., 2009).
According to present data, healthy nutrition in elderly should
respect the guidelines for protein and energy requirement,
privilege a Mediterranean way of alimentation, and be associated
with a regular physical activity. Such a healthy lifestyle was
recently tested. A composite lifestyle index was calculated that
included the following lifestyle dimensions: physical exercise,
dietary habits, body mass index, smoking and alcohol consumption. In a large cross-sectional trial conducted in healthy elderly
individuals, a healthy life style, the healthiest behaviour, was
assessed by a simple composite index. The following markers of
healthy lifestyle were considered: body mass index <22, a diet
high in fruits, vegetables, low-fat foods and unsaturated fatty acids,
energy expenditure through physical activity >13,000 kcal/week,
no history of smoking and alcohol consumption of 410 drinks per
week. These markers were associated with a better memory score,

82

Y. Boirie et al. / Mechanisms of Ageing and Development 136-137 (2014) 7684

the composite index showing a stronger relationship with memory

scores than single factors (Floel et al., 2008). Although these data
cannot be considered as nutrition guidelines, they argue for a
favourable effect of the association of Mediterranean-like diet with
sustained physical activity.
The identication of the genetics determinants in protein
energy wasting in elderly, as previously shown in chronic diseases
such as chronic obstructive pulmonary disease patients (Wan et al.,
2011), constitutes a promising perspective. A better knowledge of
genotypes at risk of malnutrition may lead to early intervention. A
an example, sequence variations in the regulatory DNA of the
genes coding for important members of the interleukin 1 family are
associated with differential effects on the inammatory response
and consequently may induce different risks of muscle wasting
(Duff, 2006). Similarly, whereas current recommendations target
most of the population to prevent nutritional deciencies,
inclusion of genomic criteria may indicate subpopulations that
may incur differential benet or risk from generalized recommendations and fortication policies (Stover, 2006).

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