Mechanisms of Ageing and Development 196 (2021) 111476

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Mechanisms of Ageing and Development

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

Effects of n-3 EPA and DHA supplementation on fat free mass and physical
performance in elderly. A systematic review and meta-analysis of
randomized clinical trial
Mariangela Rondanelli a, b, Simone Perna c, Antonella Riva d, Giovanna Petrangolini d,
Enrica Di Paolo e, Clara Gasparri f, *
a
IRCCS Mondino Foundation, Pavia, 27100, Italy
b
Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, 27100, Italy
c
Department of Biology, College of Science, University of Bahrain, Sakhir Campus, P.O. Box 32038, Bahrain
d
Research and Development Unit, Indena, Milan, 20139, Italy
e
General Geriatric Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita’’, Pavia, 27100, Italy
f
Endocrinology and Nutrition Unit, Azienda di Servizi alla Persona “Istituto Santa Margherita’’, University of Pavia, Pavia, 27100, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: The most studied n-3 polyunsaturated fatty acids (n-3 PUFAs) are eicosapentaenoic acid (EPA; 20:5n− 3) and
n-3 PUFAs docosahexaenoic acid (DHA; 22:6n− 3), and their intake seem to have a positive effect on skeletal muscle. This
EPA systematic review and meta-analysis aims to investigate the effect of n-3 EPA and DHA supplementation on fat
DHA
free mass, and on different indexes of physical performance in the elderly. Eligible studies included RCT studies
Fat free mass
Physical function
that investigated EPA and DHA intervention. Random-effects models have been used in order to estimate pooled
effect sizes, the mean differences, and 95 % CIs. Findings from 14 studies (n = 2220 participants) lasting from 6
to 144 weeks have been summarized in this article. The meta-analyzed mean differences for random effects
showed that daily n-3 EPA + DHA supplementation (from 0.7 g to 3.36 g) decreases the time of Time Up and Go
(TUG) test of − 0.28 s (CI 95 %− 0.43, − 0.13;). No statistically significant effects on physical performance in­
dicators, such as 4-meter Walking Test, Chair Rise Test and Handgrip Strength, have been found. The fat free
mass follows an improvement trend of +0.30 kg (CI 95 % -0.39, 0.99) but not statistically significant. N-3 EPA +
DHA supplementation could be a promising strategy in order to enhance muscle quality and prevent or treat
frailty.

1. Introduction lifestyle characterized by low physical activity, lack of mobility and an

unbalanced diet, with inadequate amounts of calories and protein, that
Aging is characterized by a decline of muscle mass, documented by could contribute to muscle mass loss (Krzymińska-Siemaszko et al.,
decreased muscle strength and/or physical performance deterioration. 2015).
Muscle weakness could be debilitating for the functional independence Diet and nutritional supplementation may represent a strategy to
of elderly individuals, with increased risk of falls and disability (Krzy­ achieve maintenance of muscle mass (Rondanelli et al., 2015). In
mińska-Siemaszko et al., 2015). The muscle mass preservation and particular, the role of n-3 polyunsaturated fatty acids (n-3 PUFAs) for
function is critical for the adverse outcomes prevention, such as physical improving muscle mass and physical performance parameters was
frailty, mobility disability, and loss of independence in older adults deeply investigated. N-3 PUFAs are a class of long chain fatty acids;
(Smith et al., 2015). Eicosapentaenoic acid (EPA; 20:5n–3) and docosahexaenoic acid (DHA;
The age-related muscle mass decline is due to many different factors, 22:6n–3) have been the most studied n-3 polyunsaturated fatty acids
including hormonal changes, oxidative damage, chronic inflammation, (PUFAs) and can be found in mostly fatty fish. Current recommendations
neurodegenerative changes, drugs taken or the status of diseases. Even a for EPA and DHA intake for general health vary from country to country

* Corresponding author.
E-mail addresses: [email protected] (M. Rondanelli), [email protected] (S. Perna), [email protected] (A. Riva), giovanna.
[email protected] (G. Petrangolini), [email protected] (E. Di Paolo), [email protected] (C. Gasparri).

https://doi.org/10.1016/j.mad.2021.111476
Received 13 October 2020; Received in revised form 18 March 2021; Accepted 22 March 2021
Available online 26 March 2021
0047-6374/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

but are typically recommend from 250 to 500 mg/day as a combination mean change (Δ-change) and relative standard deviation from baseline,
of both fatty acids. and/or the mean difference among intervention groups vs. control group
An adequate intake from foods in n-3 PUFAs (1.6 g/day and 1.1 g/ concerning body composition (fat free mass) and physical performance
day for men and women, respectively) resulted in a better total-body tests (TUG test, 4-meter Walking test, Chair Rise Time test and handgrip
skeletal muscle mass (SMM) in 111 patients receiving standard hae­ test).
modialysis treatment; on the contrary, a higher dietary ratio of n-6/n-3 Studies in which n-3 EPA + DHA supplementation were combined
PUFAs seemed to be associated with a reduced muscle mass (Wong et al., with other supplements, such as leucine, creatine, vitamin D, whey
2015). A recent review showed that fish consumption could be consid­ protein and/or calcium, were excluded.
ered as “functional food” for elderly with sarcopenia. People should
consume at least three servings weekly in order to have a minimum 2.2. Information sources and data items
intake of 4–4.59 g daily of n-3 PUFAs (Rondanelli et al., 2020).
The positive effect of EPA and DHA intake on skeletal muscle was To identify the studies that were eligible for this meta-analysis, we
widely described by several researchers, conducted either in vitro conducted a computerized search of clinical trials from (2010 to
(Jeromson et al., 2018; Kamolrat and Gray, 2013), in murine models September 2020); in Ovid-MEDLINE EMBASE Web of Science. To
(Kamolrat et al., 2013; You et al., 2010) or in humans (McGlory et al., minimize publication bias, the references cited in the text of the selected
2019; Smith et al., 2015, 2011). The results from recent studies articles were also included in the search.
demonstrate that dietary supplementation with fish oil-derived n-3
PUFAs stimulates muscle protein synthesis and improves muscle mass
and function in sedentary older adults, by mediating cell signaling and 2.3. Search
inflammation-related oxidative damage (Cruz-Jentoft et al., 2020; Gray
and Mittendorfer, 2018). We carried out an electronic search using primarily Medline, Google
Thus, there is a growing evidence that n-3 PUFAs have anabolic ef­ Scholar, Scopus, and the Science Citation Index databases, for studies
fects on skeletal muscle metabolism (Robinson et al., 2018). According published after September 2010, without any language restriction. The
to Di Girolamo et al., the anabolic effect of n-3 PUFAs seem to be in­ search was carried out as follows: “n-3 PUFAs” OR “omega-3” OR “EPA”
dependent from their anti-inflammatory properties (Di Girolamo et al., OR “DHA” AND “muscle mass” OR “fat free mass” OR “sarcopenia” AND
2014). This action is at least partially mediated via increased activation “elderly”.
of mTOR-p70s6k (mammalian target of rapamycin/ribosomal protein
kinase S6) signaling pathways, influencing skeletal muscle mass, in 2.4. Study selection
particular when combined to mechanical stimulation (Smith et al.,
2011). After literature search and filter applications (humans; clinical tri­
The intake of EPA and DHA as dietary supplements appears to be a als), the eligible studies were selected through full-text revision. The
promising, safe and low-cost strategy in the prevention and management selected studies were included in the systematic review; if applicable,
of sarcopenia, especially when combined with healthy dietary patterns the studies were included in the meta-analysis.
and anabolic stimulus by physical activity (Di Girolamo et al., 2014;
Dupont et al., 2019; Robinson et al., 2018). 2.5. Data collection process
Given this background, this systematic review and meta-analysis of
randomized clinical trials aims to assess the effects in elderly individuals The data were extracted in duplicate from all reports and indepen­
of n-3 EPA + DHAs supplementation on fat free mass and on functional dently recorded on a piloted form by 2 authors. The reviewers were not
parameters such as Time Up and Go (TUG) test, 4-meter Walking test, blind to authorship. The following data were extracted from each study:
Chair Rise Time test and handgrip test. (1) patient characteristics (ie, mean age, country, and inclusion and
exclusion criteria); (2) intervention characteristics (ie, daily treatment
2. Methods dose and administration time); (3) control characteristics (ie, placebo
type, daily dose, and administration time); and (4) outcome mea­
The present systematic review was conducted in accordance with the sures. Differences among reviewers related to data extraction were
PRISMA (Preferred Reporting Items for Systematic Review and Meta- resolved by discussion, and a consensus was reached.
Analyses) statement (Moher et al., 2009).
It was performed through the following steps:
2.6. Risk of bias in individual studies
• formulation of the review question: "n-3 PUFAs supplementation and
fat free mass or muscle mass and function"; The risk of bias of each study was assessed using the Cochrane
• definition of participants: elderly women and men; Collaboration Risk of Bias tool (Higgins et al., 2011) and considering as
• search strategy for the identification of relevant intervention studies factors contributing to the study quality the generation of the allocation
that included the effect of n-3 PUFAs supplementation; sequence, the allocation concealment, the blinding of outcome data, the
• analysis of the data through the systematic review and meta-analysis; presence of incomplete data and the selective reporting. These factors
were classified as low risk of bias, high risk of bias, or unclear risk of
bias. Studies with a low risk of bias for at least three items were held as
2.1. Eligibility criteria good; studies with a low risk of bias for at least two items were
considered as fair, and studies with a low risk for no item or only for one
Potentially eligible studies were English written and reported EPA item were regarded as poor.
and DHA treatments in adult and elderly subjects. The search was not
restricted for year of study publication or for the duration of follow-up of 2.7. Summary measures
treatment. Supplementation was administered both in healthy subjects
and in those with diagnosed diseases. The outcomes considered were fat free mass and functional param­
Eligible studies for inclusion in the systematic review were inter­ eters such as Time Up and Go (TUG) test, 4-meter Walking test, Chair
vention studies in humans, targeting older adults. Eligible studies for Rise Time test and handgrip test. The outcomes were expressed as mean
meta-analysis were required to report baseline and follow-up values, the values.

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M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

2.8. Risk of bias across studies these 14, 7 studies were included in a meta-analysis. Fig. 1 shows the
study selection procedure.
The studies selected were critically appraised using “risk of bias” Studies included (Table 1) were all randomized clinical trials (RCT).
based on the study design. According to the recommendations outlined Intervention period lasted from a minimum of 6 weeks to a maximum of
in the Cochrane Handbook, the following criteria were included 144 weeks. The 14 studies included a total of 2220 subjects both women
(Cumpston et al., 2019): “random sequence generation,” “allocation and men. 10 studies (Da Boit et al., 2017; Dasarathy et al., 2015; Deger
concealment,” “blinding of participants,” “incomplete outcome data,” et al., 2016; Gharekhani et al., 2014; Krzymińska-Siemaszko et al., 2015;
“selective outcome reporting,” and “other bias.” We assigned a judgment Murphy et al., 2011; Rolland et al., 2019; Smith et al., 2015, 2011; Wang
related to the risk of bias by answering a prespecified question about the et al., 2017) considered a cohort of men and women (2062 subjects); 3
adequacy of the study in relation to the entry, such that a judgment of studies (Logan and Spriet, 2015; Rodacki et al., 2012; Tardivo et al.,
“low” indicated a low risk of bias, “high” indicated a high risk of bias, 2015) considered a cohort of only women (117 subjects) and one study
and “unclear” indicated an unclear or unknown risk of bias. Two authors considered only men for a total of 23 subjects (Cornish et al., 2018).
independently assessed bias, and any disagreement or misunderstanding 4 studies (Cornish et al., 2018; Rodacki et al., 2012; Smith et al.,
was resolved by discussion until a consensus was reached 2015, 2011) involved healthy older subjects (total of 132 subjects);
three studies (Krzymińska-Siemaszko et al., 2015; Logan and Spriet,
3. Results 2015; Rolland et al., 2019) considered community-dwelling elderly in­
dividuals (1753 subjects); other studies considered patients undergoing
3.1. Studies characteristics hemodialysis (65 subjects) (Deger et al., 2016; Gharekhani et al., 2014),
postmenopausal woman with metabolic syndrome (MetS) (63 subjects)
The literature search retrieved 365 articles through the database (Tardivo et al., 2015), type 2 diabetic patients with abdominal obesity
search and, after filter applications (humans; clinical trials), 29 papers (99 subjects) (Wang et al., 2017) or with nonalcoholic steatohepatitis
were selected through full-text revision. 15 studies were excluded. The (NASH) (Dasarathy et al., 2015), patients with non-small cell lung
14 remaining studies were selected for the current systematic review. Of cancer (NSCLC) who were naive to chemotherapy (40 subjects) (Murphy

Fig. 1. Flow diagram.

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M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

Table 1
Studies included in the systematic review.
First author, year Study design Setting Total Intervention: Parallel Duration of Outcomes of Results about body
daily Number of treatments: the interest composition /
amount subjects (M, Number of intervention physical
of n-3 F;); type of subjects (M, F); performance
PUFAs intervention; type of
Age (mean ± treatments;
ds) BMI (mean Age (mean ±
± ds) ds) BMI (mean
± ds)

N = 11 (11 M;) N = 12 (12 M) Decrease of percent

3 g of a n- 3-6-9 body fat, increase of
n-3 PUFAs
PUFAs blend lean tissue mass,
+ resistance + resistance chest press and leg
3 g n-3
training 3 training3 Muscle mass, press strength,
PUFAs
Older men aged ≥ times/week; times/week; muscle strength improvement of
(Cornish et al., 2018) RCT (1.98 g 12 weeks
65 y old Age: 71.4 ± 6.2 Age: 70.9 ± 5.0 and functional timed-up-and-go and
EPA, 0.99
ability 6-minute walk
g DHA)
distance due to
BMI: 27.5 ± 4.2 BMI: 27.7 ± 3.5 resistance exercise.
n-3 didn’t enhance
these parameters.
N = 27 (14 M, N = 23 (13 M,
13 F) 10 F)
n-3 PUFAs 3 g safflower oil
+ resistance + resistance
Men: similar increase
exercise exercise
in muscle quality in
3 g n-3 training twice training twice
the intervention and
PUFAs weekly; weekly; Muscle mass and
Healthy older placebo groups.
(Da Boit et al., 2017) RCT (2.1 g Age: 69.8 ± 4.0 Age: 71.5 ± 5.1 18 weeks function; sex
adults
EPA, 0.6 for male; 70.5 for male; 70.9 difference
g DHA) ± 3.9 for ± 2.6 for
female female
BMI: 25.1 ± 5.3 BMI: 24.7 ± 2.6
Women: greater
for male; 25.9 for male; 25.8
increase in the
± 4.9 for ± 4.6 for
intervention group
female female
N = 18 (6 M, N = 19 (2 M, There was no
3.6 g n-3 12 F) 17 F) significant change in
Diabetic adults PUFAs n-3 PUFAs; corn oil; body weight or in
Prospective,
with nonalcoholic (2.16 g Age: 49.8 ± Body any of the measures
(Dasarathy et al., 2015) double-blind Age: 51.5 ± 6.9 48 weeks
steatohepatitis EPA and 12.1 composition of body composition
RCT
(NASH) 1.44 g in either of the
DHA) BMI: 34.8 ± 4.6 BMI: 35.7 ± 7.0 groups during the
course of the study
N = 11 (9 M, 2 Attenuation of
N = 9 (8 F, 1 M)
F) forearm muscle
Placebo (not protein breakdown
n-3 PUFAs;
2.9 g n-3 specified); but did not influence
hemodialysis (HD) Change in
PUFAs Age: 53.0 ± skeletal muscle
Double-blind patients with Age: 53.0 ± 9.0 forearm muscle
(Deger et al., 2016) (1.93 g 13.0 12 weeks protein synthesis,
RCT systemic protein
EPA, 0.96 skeletal muscle net
inflammation breakdown
g DHA) protein balance or
BMI: 28.0 ± 7.0 BMI: 35.0 ± 9.0 any component of
the whole-body
protein balance.
N = 25 (13 M, N = 20 (12 M,
Mid-arm muscle Supplementation did
1.8 g n-3 12 F) 8 F)
circumference, not produce
PUFAs n-3 PUFAs; Paraffin oil;
(Gharekhani et al., Single-blind HD treatment for dry body weight significant changes
(1080 mg Age: 56.8 ± Age: 57.2 ± 16 weeks
2014) RCT at least 3 months (after HD in nutrition indices,
EPA, 720 13.1 15.2
treatment), and including BMI, dry
mg DHA) BMI: 23.8 ± BMI: 23.3 ±
BMI body weight, MAC.
3.82 3.24
N = 30 (11 M, N = 20 (4 M, 6 No statistically
1.3 g n-3
19 F) F) significant
PUFAs
community- 1 drop of differences in the
(660 mg
dwelling elderly vitamin E Body analysed components
EPA, 440 n-3 PUFAs;
aged ≥60 y old, solution (11 composition, of body composition,
(Krzymińska-Siemaszko mg DHA
RCT with decreased mg); 12 weeks muscle strength in muscle strength
et al., 2015) +200 mg
muscle mass or at Age: 75.0 ± Age: 74.9 ± and physical nor in physical
other n-3
risk of low muscle 8.23 7.49 performance performance (4-
PUFAs
mass meter Walking Test
fatty BMI: 23.4 ± BMI: 22.9 ±
and Go test) in any
acids) 3.14 3.39
group.
(Logan and Spriet, healthy, 3 g n-3 N = 12 (12 F) N = 12 (12 F) Body Significantly increase
RCT 12 weeks
2015) community- PUFAs (2 n-3 PUFAs; 3 g olive oil; composition, of lean body mass
(continued on next page)

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Table 1 (continued )
First author, year Study design Setting Total Intervention: Parallel Duration of Outcomes of Results about body
daily Number of treatments: the interest composition /
amount subjects (M, Number of intervention physical
of n-3 F;); type of subjects (M, F); performance
PUFAs intervention; type of
Age (mean ± treatments;
ds) BMI (mean Age (mean ±
± ds) ds) BMI (mean
± ds)

dwelling older g EPA, 1 g Age: 66.0 ± 1.0 strength and and physical function
women aged DHA) BMI: 26.3 ± 1.0 physical function (decreasing Timed
60− 76 years old Get Up and Go Test).
BMI: 27.9 ± 1.3
N = 16 (9 M, 7 N = 24 (12
patients with
Open-label F) M, 12 F)
nonsmall cell lung 2.2 g n-3 Body composition
study with 69 % of Standar of
(Murphy et al., 2011) cancer (NSCLC) PUFAs n-3 PUFA; 6 weeks against SOC during
control patients in the care (SOC)
naïve to (EPA) chemotherapy
group FO group Age: 64.0 ±
chemotherapy Age: 63.0 ± 2.1
maintained or 1.8
gained muscle
compared with
29 % of
patients in the
SOC group.
Four patients in
the SOC group
became
BMI: 27.3 ±
BMI: 26.2 ± 1.1 sarcopenic
1.2
over the course
of
chemotherapy
whereas no
patients in the
FO group
became
sarcopenic.
Group 1 (n =
15): 2 g/die
Group 3 (N =
Fish oil + 90
15): strength
days of
training; FO supplementation
strength
along with strength
training.
training improved
Group 2 (n =
0.7 g n-3 the response of the
15):fish oil 60
PUFAs neuromuscular
days before Age: 64.9 ± 1.0 Muscle strength
Healthy older (0.4 g 90 or 150 system. However,
(Rodacki et al., 2012) RCT strength and functional
women EPA and days supplementation
training; capacity
0.3 g with FO for an
Age: 63.8 ± 1.4
DHA) additional period
for Group 1;
BMI: 25.4 ± 1.6 pretraining did not
63.3 ± 2.0 for
cause any additional
Group 2
effects.
BMI: 27.7 ± 1.3
for Group 1;
25.7 ± 1.1 for
Group 2
Group 3 (N =
Group 1 (N = 420): placebo
422): n-3 + the
PUFAs multidomain
intervention;
No significant
Group 2 (N =
differences at 3-year
417): n-3 Group 4 (N =
Muscle strength follow-up were
non-demented, PUFAs + the 420): placebo
1.025 g n- (chair stand test, observed in the
older, and multidomain alone;
3 PUFAs handgrip), repeated chair stand
community- intervention;
(Rolland et al., 2019) RCT (800 mg 144 weeks walking speed test score and
dwelling, older Age: 65.7 ± 4.7
DHA, 225 (performed on a handgrip test
people aged ≥ 70 y for Group 1; Age: 75.1 ± 4.2
mg EPA) 4-mcourse) and between any of the
old 75.5 ± 4.5 for for Group 3;
balance tests three intervention
Group 2
groups and the
75.1 ± 4.4 for
placebo group.
BMI: 26.3 ± 4.1 Group 4BMI:
for Group 1; 26.0 ± 4.0 for
26.2 ± 4.3 for Group 3; 26.0
Group 2 ± 3.9 for Group
4
Healthy older 3.36 g n-3 N = 8 (5 M, 3 F) N = 7 (5 M, 2 F) Rate of muscle Supplementation
(Smith et al., 2011) RCT adults aged ≥65 y- PUFAs n-3 PUFAs; Corn oil; 8 weeks protein synthesis increases muscle
old (1.86 g Age: 71.0 ± 1.0 Age: 71.0 ± 2.0 and the anabolic anabolic signalling
(continued on next page)

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M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

Table 1 (continued )
First author, year Study design Setting Total Intervention: Parallel Duration of Outcomes of Results about body
daily Number of treatments: the interest composition /
amount subjects (M, Number of intervention physical
of n-3 F;); type of subjects (M, F); performance
PUFAs intervention; type of
Age (mean ± treatments;
ds) BMI (mean Age (mean ±
± ds) ds) BMI (mean
± ds)

EPA, 1.5 signalling activity and the

g DHA) cascade insulin/amino
BMI: 25.6 ± 1.0 BMI: 25.7 ± 1.7 acid–mediated
increase in muscle
protein synthesis
N = 29 (10 M, N = 20 (5 M, Thigh muscle n–3 PUFA therapy
19 F) 10 F) volume, increased thigh
3.36 g n-3 n-3 PUFAs; Corn oil; handgrip muscle volume, and
Healthy 60− 85-y- PUFAs Age: 68.0 ± 5.0 Age: 69.0 ± 7.0 strength, one 1-RM muscle
Double-blind
(Smith et al., 2015) old men and (1.86 g 24 weeks repetition strength, but didn’t
RCT
women EPA, 1.5 maximum (1- affect body weight,
g DHA) BMI: 26.1 ± 4.1 BMI: 25.3 ± 4.2 RM) muscle total-body fat mass,
strength, body fat or the intermuscular
mass fat content
N = 33 (33 F) N = 30 (30 F) Significant reduction
Postmenopausal 0.9 g n-3 Diet + n-3 in BMI and waist
Diet alone;
woman with PUFAs PUFAs; Body circumference in
Prospective
(Tardivo et al., 2015) metabolic (0.54 g Age: 55.1 ± 6.6 Age: 55.0 ± 7.3 24 weeks composition, both groups without
RCT
syndrome (aged EPA, 0.36 muscle mass (%) significant changes
45− 70 y-old g DHA) BMI: 32.8 ± 4.7 BMI: 32.0 ± 4.6 in body fat or muscle
mass.
2.4 g n-3 N = 49 (15 M, N = 50 (20 M,
PUFAs 34 F) 30 F) No significantly
type 2 diabetic
Double-blind (1.34 g n-3 PUFAs; Corn oil; Body changes in body
(Wang et al., 2017) patients with 24 weeks
RCT EPA and Age: 64.6 ± 5.5 Age: 66.3 ± 5.1 composition composition during
abdominal obesity
1.07 g the intervention
BMI: 25.4 ± 2.6 BMI: 25.9 ± 2.8
DHA)

et al., 2011). abdominal obesity without affect body composition during the inter­
The intervention group was settled up to consume n-3 PUFAs cap­ vention (Wang et al., 2017).
sules, from 0.7 g to 3.36 g daily. The control group received placebo A dosage of 2.2 g/die of n-3 PUFAs (EPA) was chosen by Murphy
identical-looking pills, containing mainly corn or olive oil. Mean of age et al. to examine the effect of nutritional intervention with fish oil on
was 65.53 ± 5.0 and 65.90 ± 6.22 years for intervention and placebo weight and body composition against standard of care (SOC) during the
group, respectively; mean of body mass index (BMI) was 26.97 ± 3.44 course of chemotherapy in patients with non-small cell lung cancer
kg/m2 and 27.19 ± 3.64 kg/m2 for intervention group and placebo showing maintenance of weight, muscle mass, and muscle quality
group, respectively. compared with patients receiving SOC. 69 % of patients receiving FO
maintained or gained weight (0–6.7 kg) during chemotherapy, while in
the SOC group, only 29 % of patients maintained or gained weight
3.2. Effects of n-3 EPA and DHA supplementation on fat free mass (0–4.6 kg) (Murphy et al., 2011).
Krzymińska-Siemaszko et al. conducted a study in community-
A dosage of n-3 EPA + DHA from 1 g to 3 g, provided as fish oil dwelling elderly individuals (aged ≥ 60 years old), with decreased
capsules, was considered in various studies. Cornish et al. showed the muscle mass or at risk of low muscle mass. The intervention group was
effectiveness of 3.0 g/die of EPA + DHA (1.98 g of EPA and 0.99 g of administered two capsules daily containing 660 mg EPA, 440 mg DHA
DHA) supplementation, combined with progressive resistance training +200 mg other n-3 PUFAs +10 mg of vitamin E during or immediately
to improve body composition, in healthy older men (aged ≥ 65 years after meals, for a total daily amount of 1.3 g of n-3 PUFA, for 12 weeks.
old). The results of this study revealed a body fat decreased from 31.9 % Using this dosage, no statistically significant differences were observed
to 31.1 %), as lean tissue mass increased from 55.5–56.1 kg. Another in the analysed components of body composition in the intervention or
study (Da Boit et al., 2017) evaluated the gender effects of 3 g/die of n-3 placebo group (Krzymińska-Siemaszko et al., 2015).
PUFAs supplementation on resistance exercise training for increasing in 2 studies (Deger et al., 2016; Gharekhani et al., 2014) were con­
muscle mass in healthy older men and women, showing no differences ducted in patients undergoing hemodialysis (HD) with supplementation
between groups. (Da Boit et al., 2017). of 1080 mg EPA and 720 mg DHA for 16 weeks. The results showed
In the study of Smith et al. (Smith et al., 2011), a daily dose of 3.36 g not-significant changes in nutrition indices, including BMI, dry body
of EPA + DHA fatty acid supplementation (1.86 g EPA, 1.5 g DHA), for 8 weight, and mid-arm muscle circumference (MAC) (Gharekhani et al.,
weeks, showed an increase of muscle anabolic signalling activity and an 2014).
insulin/amino acid–mediated increase in muscle protein synthesis above On a second study, a higher dose of 1.93 g EPA, 0.96 g DHA,
basal, postabsorptive values in healthy older adults aged ≥ 65 years old administered for 12 weeks, was associated with attenuation of forearm
(Smith et al., 2011). The same dosage did not significantly affect body muscle protein breakdown in patients with systemic inflammation, but
weight, total-body fat mass, or the intermuscular fat content, but did not influence skeletal muscle protein synthesis, skeletal muscle net
increased thigh muscle volume (Smith et al., 2015). protein balance. or any component of the whole-body protein balance
A lower dosage of 2.4 g/die n-3 PUFAs (1.34 g EPA and 1.07 g DHA), (Deger et al., 2016).
was administered by Wang et al. to type 2 diabetic patients with

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M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

A smaller dosage of 540 mg EPA, 360 mg DHA was investigated by CI 95 %: -0.39 to 0.99; p = 0.40) (Fig. 2). The forest plot included a total
Tardivo et al. (Tardivo et al., 2015) in postmenopausal women with of 233 subjects (120 in the intervention group and 113 in the control
metabolic syndrome (MetS), aged 45− 70 years old. Supplementation group). The heterogeneity chi square test is not statistically significant
showed a significant reduction in BMI and waist circumference in both (P = 0.60), and it showed that there is no variation in study outcomes.
groups without significant changes in body fat or muscle mass (Tardivo Concerning physical performance parameters, the meta-analyzed
et al., 2015). MD showed a statistically significant improvement in TUG test (-0.28
s; CI 95 %: -0.43 to -0.13; p = 0.0003) (Fig. 3). The forest plot included a
3.3. Effects of n-3 PUFAs supplementation on physical performance total of 92 subjects (49 in the intervention group and 42 in the control
group). The heterogeneity chi square test is not statistically significant at
In the study of Cornish et al. (Cornish et al., 2018), subjects treated the level of P = 0.63 and it showed that there is no variation in study
with n-3 PUFAs improved chest press and leg press strength (increase outcomes.
from 50.5–60.1 kg and from 110.1–150.4 kg, respectively) and Regarding others physical performance parameters, the meta-
timed-up-and-go test (decrease from 6.13 to 5.73 s). However, these analyzed MD showed a not statistically significant improvement in
improvements in physical performance, similar to those on body TUG test (-0.06 s; CI 95 %: − 0.20 to 0.08; p = 0.40) (Fig. 4). The forest
composition, were to be attributed to progressive resistance training and plot included a total of 940 subjects (476 in the intervention group and
not to n-3 PUFAs supplementation exclusively (Cornish et al., 2018). 464 in the control group). The heterogeneity chi square test is not sta­
The study by Da Boit et al. showed that in women who received 2.7 tistically significant (P = 0.77) and it showed that there is no variation in
g/die of n-3 PUFAs (2.1 g EPA and 0.6 g DHA) for 18 weeks, the maximal study outcomes.
isometric torque was greater (34.3 % ± 17.8 %) than in the placebo Furthermore, the meta-analyzed MD showed a not statistically sig­
group (15.8 % ± 10.6 %) (Da Boit et al., 2017). According to Smith et al., nificant improvement in Chair Rise Time test (-0.17 s; CI 95 %: − 0.97 to
24 weeks of 3.36 g/die n-3 PUFAs (1.86 g EPA, 1.5 g DHA) supple­ 0.63; p = 0.67) (Fig. 5). The forest plot included a total of 890 subjects
mentation increased thigh muscle volume and one repetition maximum (447 in the intervention group and 443 in the control group). The het­
muscle strength (Smith et al., 2015). erogeneity chi square test is not statistically significant (P = 0.62) and it
In the study of Krzymińska-Siemaszko et al. (Krzymińska-Siemaszko showed that there is no variation in study outcomes.
et al., 2015), the administration of daily amounts of 1.3 g of n-3 PUFA, Finally, concerning strength, the meta-analyzed MD showed a not
for 12 weeks in community-dwelling elderly individuals with decreased statistically significant decrease in handgrip test (-0.04 kg; CI 95 %:
muscle mass or at risk of low muscle mass, didn’t produce a − 1.31 to 1.24; p = 0.96) (Fig. 6). The forest plot included a total of 915
statistically-significant improvement in muscle strength nor in physical subjects (464 in the intervention group and 451 in the control group).
performance (4-meter Walking Test and Go test) (Krzymińska-Sie­ The heterogeneity chi square test is p < 0.05 and it showed that there is
maszko et al., 2015). Accordingly, even Rolland et al. (Rolland et al., variation in study outcomes.
2019) observed no significant differences in muscle strength and phys­
ical performance, using a similar low dose of supplementation in 3.5. Analysis of publication bias
non-demented, community-dwelling, older people (aged ≥ 70 years
old). In particular, 1.025 g/die n-3 PUFAs (800 mg DHA, 225 mg EPA), There was no evidence of publication bias across the randomized
combined or not with multi-domain intervention (group sessions inte­ controlled trials included in this review as showed by Egger and in
grating advice for physical activity, nutrition, cognitive training, and Table 2.
preventive consultations), was administered for 36 months. No signifi­
cant differences were observed at 3-year follow-up in the repeated chair 4. Discussion
stand test score and handgrip test between any of the intervention
groups and the placebo group (Rolland et al., 2019). This review showed that supplementation, from 6 to 144 weeks of n-
On the contrary, an improvement of physical function (decreasing 3 PUFAs, with a daily dose ranging from 0.7 g to 3.36 g, improved TUG
Timed Get Up and Go Test) was observed by Logan and Spriet (Logan test in a population of middle-aged and elderly adults.
and Spriet, 2015) in a study conducted in healthy, community-dwelling The results concerning the physical performance (4-meter Walking
older (aged 60− 76 years old) administered with 3 g/die of n-3 PUFAs (2 test and Chair Rise Time test), strength (handgrip) test and body
g EPA, 1 g DHA), for 12 weeks. Even the study of Rodacki et al. (Rodacki composition (fat free mass) were not statistically significant.
et al., 2012) demonstrated that the inclusion of a daily dose of 0.4 g EPA The lack of significant improvements in the other investigated vari­
and 0.3 g DHA supplementation in a program of strength training ables was probably due to the limited number of studies considered. In
improved muscle strength and functional capacity in elderly women, addition, the study population was not homogeneous and patients had
more than exercise training alone. no diagnosis of sarcopenia.
Similar to the current findings, a recent review that assessed the ef­
3.4. Meta-analyzed data ficacy of increasing dietary n-3 PUFAs, n-6 PUFAs or mixed total PUFAs
on musculoskeletal outcomes and functional status, in adults aged 40
The meta-analyzed MD (mean differences for random effects) years or older, found no significant modification on fat free (skeletal)
showed a not statistically significant increase in fat free mass (0.30 kg; muscle mass (Abdelhamid et al., 2019). Conversely, according to

Fig. 2. Forest plot for randomized controlled trials of n-3 EPA + DHA supplementation on fat free mass (kg) subgroup meta-analysis (n = 223).

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M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

Fig. 3. Forest plot for randomized controlled trials of n-3 EPA + DHA supplementation on Time Up and Go test (s) subgroup meta-analysis (n = 92).

Fig. 4. Forest plots for randomized controlled trials of n-3 EPA + DHA supplementation on 4-meter Walking test (s) subgroup meta-analysis (n = 940).

Fig. 5. Forest plot for randomized controlled trials of n-3 EPA + DHA supplementation on Chair Rise Time test (s) subgroup meta-analysis (n = 890).

Fig. 6. Forest plot for randomized controlled trials of n-3 EPA + DHA supplementation on Handgrip test (s) subgroup meta-analysis (n = 915).

Table 2
Risk of bias for studies included in the meta-analysis according to the Cochrane Risk of Bias Toola.
First author, year Random-sequence Allocation Participant- Outcome- Incomplete Selective Other
generation concealment personnel blinding assessment blinding outcome data reporting bias

Cornish et al., 2018 Fair Fair Fair Unclear Unclear Fair Fair
Da Boit et al., 2017 Fair Fair Fair Unclear Unclear Fair Fair
Dasarathy et al., 2015 Fair Fair Fair Unclear Unclear Fair Fair
Krzymińska-Siemaszko et al., Fair Fair Fair Unclear Unclear Fair Fair
2015
Logan and Spriet, 2015 Fair Fair Fair Unclear Unclear Fair Fair
Rolland et al., 2019 Fair Fair Fair Unclear Unclear Fair Fair
Wang et al. (2017) Fair Fair Fair Unclear Unclear Fair Fair
a
Bias designations by study criteria are indicated by 7 domains with categories including low risk if negative aspects of the study design were not likely to influence
the study findings, high risk if the study design was likely to influence the study findings, or unclear risk if high or low risk could not be assigned because of a lack of
evidence.

another recent review by Tessier et al., supplementation of EPA + DHA muscle is still debated. However, the literature describes some hypo­
doses of around 3 g/die had a positive impact on physical performance, thetic mechanisms: reduction in pro-inflammatory cytokines (anti-in­
muscle strength, and muscle mass in older adults, and this minimal flammatory effects), the stimulation of muscle protein synthesis via the
amount may be required for beneficial effects when provided alone, i.e., mTOR-p70S6k signaling pathway activation, improvement of insulin
not combined with other nutrients (Tessier and Chevalier, 2018). sensitivity, and diminution of mitochondrial reactive oxygen species
The exact mechanism of the anabolic action of n-3 PUFAs on skeletal emission (Dupont et al., 2019).

8
M. Rondanelli et al. Mechanisms of Ageing and Development 196 (2021) 111476

Another point of interest regards the daily dose of n-3 PUFAs sup­ n-3 EPA + DHA supplementation in association with physical activity is
plementation. In fact, the proper dose n-3 PUFAs may represent a useful needed to better understand the potential of n-3 PUFAs to prevent
therapeutic strategy to overcome anabolic resistance for treating sar­ muscle loss in the elderly.
copenia (Stella et al., 2018). In the elderly, high doses of n-3 PUFAs
equal/higher than 1650 mg daily resulted in increased muscle mass, Funding
function, and whole body energetics (Logan and Spriet, 2015; Smith
et al., 2015). In a recent review, it was observed that dosages ranging None.
from 2 to 5 g/die for a minimum of four weeks resulted in improvements
in anabolic signaling efficience and muscle strength outcomes (Tachtsis
et al., 2018). Declaration of Competing Interest
Another important concern is that many studies included in the
current review considered EPA and DHA supplementation concurrent The authors declare no conflicts of interests.
with physical activity, mainly resistance exercise training, so it’s not
clear what the positive effect on muscle mass was due to (Cornish et al., Acknowledgments
2018; Da Boit et al., 2017; McDonald et al., 2014; Rodacki et al., 2012).
In fact, in addition to diet and supplementation, it’s well known that None.
physical exercise has a positive effect on the individual components of
sarcopenia, such as muscle strength (Peterson et al., 2010), muscle
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