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Brazilian Journal of Health Review 17867
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   Effects of aging on resting metabolic rate: A systematic review and
                               meta-analysis
 Efeito do envelhecimento na taxa metabólica de repouso: uma revisão
                      sistemática e meta-análise
DOI:10.34119/bjhrv4n4-266

Recebimento dos originais: 20/07/2021
Aceitação para publicação: 20/08/2021

                         Paulo Roberto Hernandes Júnior
              Graduando em Medicina pela Universidade de Vassouras
                       Instituição: Universidade de Vassouras
  Endereço: Av. Expedicionário Oswaldo de Almeida Ramos, 278, Centro, Vassouras,
                             RJ, Brasil, CEP: 27700-000
                          E-mail: paulorh.eng@gmail.com

                            Bruno Carvalho Brandão
              Graduando em Medicina pela Universidade de Brasília
                      Instituição: Universidade de Brasília
Endereço: Campus Darcy Ribeiro, s/n, Asa Norte, Brasília, DF, Brasil, CEP: 70910-900
                     E-mail: bruno109medunb@gmail.com

                          Patrick de Abreu Cunha Lopes
                       Instituição: Universidade de Vassouras
  Endereço: Av. Expedicionário Oswaldo de Almeida Ramos, 278, Centro, Vassouras,
                             RJ, Brasil, CEP: 27700-000
                        E-mail: patrick.abreu33@gmail.com

                               Amanda Veiga Sardeli
                 Doutora, pela Universidade Estadual de Campinas
                       Instituição: University of Birmingham
  Endereço: Mindelsohn Way, Queen Elizabeth Hospital Research Labs, Birmingham,
                            Reino Unido, CEP: B15 2WB
                        E-mail: amandavsardeli@gmail.com

                           Paula Pitta de Resende Côrtes
                   Mestre, pela Universidade Federal Fluminense
                       Instituição: Universidade de Vassouras
  Endereço: Av. Expedicionário Oswaldo de Almeida Ramos, 278, Centro, Vassouras,
                             RJ, Brasil, CEP: 27700-000
                         E-mail: paulapitta@yahoo.com.br

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ABSTRACT
Objective. To meta-analyze previous literature in order to find a consensus regarding
aging effects on resting metabolic rate (RMR) and to identify the main players in this
process. Methods. Through a search on PubMed eighteen trials comparing RMR between
older and young adults were included for meta-analysis. Results. Older adults had
significantly lower RMR than young adults (-437 kJ/d [-591; 283], p
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determining component of living. The theoretical expectation that individuals who are
most efficient at utilizing energy should survive the longest has been shown by the
negative association between RMR and longevity 2–4. In fact, when RMR is adjusted for
age, sex, and body composition, lower RMR predicts health and longevity, suggesting
that higher RMR is a risk factor for mortality in humans 3,5.
        On the other hand, in human cohort studies show that aging per se reduces RMR,
which is contradictory to previous information, given that aging is the main independent
risk factor for mortality 6. Furthermore, not all studies agree that older adults have lower
RMR than young individuals. The variation in those differences may be related not just
by the known differences in RMR between men and women, but also due to differences
in body composition among older and young adults among the studies.
        It is noteworthy that transient increases in metabolic rate promoted by physical
                                                                     7,8
activity, for example, are expected to be beneficial                       . However, the persistently higher
basal metabolic rate may be harmful, accelerating the disease progression and anticipating
mortality 3,9.
        Many confounding factors such as sex and body fat may lead to these inconclusive
results. Thus, the aim of this study is to meta-analyze previous literature in order to find
a consensus regarding aging effects on RMR, restricting the comparison to health subjects
at baseline condition. The results of this meta-analysis will support a wide range of
research focusing on metabolism, health, and longevity.

2 METHODS
        This review was reported according to PRISMA (Preferred Reporting Items for
systematic Reviews and Meta-Analyses) Guidelines 10.

SEARCH STRATEGY
        The search on PubMed was performed in February 2020. The search combined
the synonyms of aging and metabolism, in which the controlled descriptors were searched
accordingly (MeSh) and the non-controlled descriptors were searched in the titles and
abstracts of the studies. The search targeted cross-sectional studies comparing resting
metabolic rate assessed by indirect calorimetry between young and older adults. There
was no restriction for date of publication, nonetheless only studies written in English
language were selected.

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STUDY SELECTION
       Two reviewers worked on the selection of studies, considering the following
inclusion criteria: (Population) healthy adults; (Intervention/effect) age difference
between groups; (Comparator) younger group; (Outcome) Resting metabolic rate; (Study
type) Observational studies. The exclusion criteria were not original studies, not assessing
resting metabolic rate, comparing children or teenagers, not English Language, animal
study, acute effects, not testing ageing effects, and no access to full texts. Resting
                                                                                                                 11,12
metabolic rate assessed by equation estimates were not accepted to minimize bias
since these equations are not as reliable as indirect calorimetry 13,14. Details of this process
are described in Figure 1.

DATA COLLECTION
        The data collection was performed by two independent reviewers. Means and a
measure of dispersion (standard deviation, standard error or 95%CI) of age and resting
metabolic rate were extracted for each age group. Mean, standard deviation (SD) and
sample number (n) were used for RMR analysis. Standard error (SE) was converted to
SD by the equation SD = SE × (√n) , if SD had not been provided in the original study.
The 95% confidence intervals were converted to SD considering the equation (√n ∗
(UL − LL)/[2 ∗ T. INV (0.05; n − 1)] , where n is the sample size, UL is the upper limit,
LL is the lower limit and T. INV is the function that calculates the left-tailed inverse of the
Student’s T distribution 15.
        Most studies presented their results in kilojoule per day (kJ/d) and thus the main
results were presented in this unit measurement. When studies presented data in
kilocalorie per minute (kcal/min), it was converted to kJ/d by considering 1 kcal is equal
to 4.184 kilojoules, thus the equation was kJ/d = kcal/min * 6024.96 16.
       For subgroup analysis, first, the difference between groups within each study for
mean age and body mass were calculated. These mean differences were clustered in
subgroups of “40yrs” according to proximity of the mean
differences.

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STATISTICAL ANALYSIS
       The outcome measurement was the raw mean difference in resting metabolic rate
(kJ/day) between older and young adults, with its respective 95% of confidence interval.
       One main meta-analysis was performed using Comprehensive Meta-Analysis
software, version 3.3.070. When there was statistical significance for heterogeneity,
randomized effect models were selected and when there was no statistical significance
for heterogeneity, fixed effect models were selected. The inconsistency between studies
was presented as a percentage (I2), based on difference between expected heterogeneity
(df) and true heterogeneity (Q-value). Egger's tests were performed to check the risk of
publication bias in each meta-analysis 17.
       Subgroup analyses were performed to compare sex (men and women), body mass
difference between groups (40yrs). Q tests were applied to group comparisons,
considering 95% confidence. Regression analyses were performed using one single
model for each continuous body composition variables: body mass, body mass index
(BMI), fat mass and fat free mass.

QUALITY OF THE EVIDENCE
       The quality of evidence was assessed by GRADE approach, considering the
evaluation items for observational studies for each of the 3 meta-analyses 18. For meta-
analysis of observational studies, we begin with 2 points and add one or two points
according to effect size, dose-response gradient, and positive influence of confounding
factors. It will lead to a quality of evidence that ranges from very low (≤1) to high (4).

3 RESULTS
       From 198 records initially identified, 5 studies leading to 18 subgroups comparing
the baseline metabolism in KJ/min or KJ/day between young and older adults were
included in the meta-analysis. Details of the selection of studies can be seen on Figure 1.

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          Figure 1. Flow diagram of studies selection. Legend: RMR: resting metabolic rate.

       The studies included very different sample sizes in each group; with age
differences varying from right next year to 40 years difference; men, women and mixed
samples (Table 1). Table 2 shows the exact body mass difference between older and
younger ones in each study subgroup, that varied from around 2kg to near 10kg and were
clustered for analysis. The differences in other body composition components between
older and young adults were not clustered in categorical variables, but since they were
tested in regression analysis, their continuous differences used for analysis are detailed
on table 2.
       All studies assessed RMR by indirect calorimetry, using open-circuit which is a
                                                         13,14
widely accepted method of measuring RMR                          . The assessments lasted from 25 to 45
min, in thermoneutral environments and, despite many studies did not describe their
orientation for participants fasting and refraining from physical activity, it is expected
that they recommended it as part of the RMR protocols. Usually, the first minutes of data
are discarded, and the remaining ones must be averaged to the final value of resting
                                    19
metabolic rate. Weir formula             was used to determine the energy equivalent of oxygen
volume in all studies.

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     Table 1. General characteristics of the studies included. Legend: B: Both sexes; M: Men; NR: not reported; W: women; diff: mean difference category between groups.
 First author, year Subgroups                                   Older                               Younger                                   Age (y)                    Sex
                                               Mean            SD RMR        n         Mean          SD RMR         n         Older           Younger        diff
                                               RMR             (KJ/d)                  RMR           (KJ/d)
                                               (KJ/d)                                  (KJ/d)
Krems, 2005           Men                      6720            686           84        7867          936            67        68.9 (5.1)      26.8 (3.4)     >40       M
Krems, 2005           Women                    5455            685           132       5809          680            159       69.9 (5.5)      24.8 (3.0)     >40       W
Luhrmann, 2010        Men                      6517            677           55        6809          704            55        76.3 (5.2)      66.3 (5.2)     Right     M
                                                                                                                                                             next
Luhrmann, 2010        Women                    5476            697           107       5566          599            107       76.3 (5.2)      66.3 (5.2)     Right     W
                                                                                                                                                             next
Krems, 2004           Men                      6353            725           107       7371          945            67        66.9 (5.1)      26.8 (3.4)     >40       M
Krems, 2004           Women                    5118            609           178       5374          560            154       67.8 (5.7)      24.8 (3.0)     >40       W
Lührmann, 2002        Men (65-69yrs)           6762            881           38        6978          746            40        65-69           75
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                               Table 2. Body composition of the studies included. Legend: NR: not reported; diff: mean difference between groups.
First author, year      Subgroups                    Body mass (kg)                      BMI (kg/m2)                       fat mass (kg)                Fat free mass (kg)
                                              Older     Younger        diff      Older     Younger       diff     Older      Younger      diff    Older   Younger       diff

Krems, 2005             Men                          77.7        77 (9.6)
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Alfonzo-González,      Both (40-49.9yrs)            79.0        71.2 (19.6)
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        The 18 groups of comparison led to significant reduction of RMR in older adults
compared to younger ones (Figure 2). It was significantly heterogeneous (p
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Table 3. Subgroup analysis. Legend: k= number of study groups; RMD=raw mean difference (KJ/day); p-
value = p-value for significance (P
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the statistically significant and progressively higher magnitude of RMR reduction with
higher age differences between groups.
        Despite changes in body mass account for some RMR reduction, the main reason
                                                              20
for this reduction might be the muscle mass loss                   . In fact, there is a strong correlation
between RMR and muscle mass, which is the main variable used to indirectly predict
RMR 20. The influence of muscle mass on RMR was also confirmed by our regression
analysis. While body mass, BMI, fat mass and even the age difference per se did not
explain the RMR difference between older and younger ones, muscle mass difference
significantly predicted it. Additionally, despite both men and women undergo muscle loss
along aging, men have greater relative and absolute muscle mass than women, and thus
it makes sense that men undergo a more prominent reduction (slope 0.18; women slope:
0.08) across lifespan 20,21.
        Muscle loss becomes more evident after the 40th decade, mediated by mechanics
involving: (1) reduced number of satellite cells and its capability to proliferate; (2) loss
of balance between protein synthesis and degradation and responsiveness of anabolic
stimulus from nutrients; (3) infiltration of fat and connective tissue, reducing quality of
muscle and increasing stiffness; (4) changes in motor units axions and fiber type; (5)
increased production of reactive oxygen species and blunted antioxidant system; (6) and
inflammation in aging muscle, via production of cytokines which also increases ROS 22.
In this way, even among individuals who maintain exercise across the whole life span,
reduction in muscle mass is inevitable.
        The maintenance of physical activity along the life span could be another factor
mediating age-induced reduction. The lower level of physical activity among older adults
is well known 23, Given the importance of muscle mass within this scenario, American
college of sports medicine have highlighted that not just the general physical activity
maintenance is important for older adults, but resistance training would be fundamental
                     24
to regulate RMR           . They state that, although the energy expenditure associated with
resistance training is not large, increased muscle mass through resistance training is
                                         24
determinant to increase RMR                   . The benefits of physical activity on RMR are
incompletely understood, nevertheless, exercise may prevent or at least attenuate
important age alterations such as increased oxidative stress, shifting of energetic needs
for other homeostatic mechanisms, rising catabolic state associated with weight loss, and
chronic fatigue 5.

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       Despite higher body mass might suggest higher muscle mass, it is very common
                                                                                        25
that obese individuals have also lower muscle mass than they pairs                           . The age-related
                                                                                                                 26
shifts in body composition that induce sarcopenia favor the development of obesity                                    ,
which might explain the higher frequency of sarcopenic obesity among older adults. In
this way, we believe the association we found between larger body mass and lower RMR
in subgroup analysis is due to the lower muscle mass in heavier individuals. Furthermore,
since our regression analyses did not show association with body mass, or fat mass, but a
significant positive association with fat free mass difference between older and young
adults and their RMR difference (r2=0.55), it reinforces that muscle mass plays a
considerable role on aging RMR changes. Indirectly, our results suggest that therapies
designed to increase muscle mass such as exercise training, protein or other types of
supplementations could attenuate the reduction of RMR with age27,28.
       A limitation of our analysis was the sample overlapping in some control groups,
                                                   11
such as in the studies of Lührmann et al.               and Alfonzo-González et al. 29. It led to an
impression of larger sample number in younger control groups, but the number of older
and young adults in each group were in fact very well balanced.

5 CONCLUSION
       RMR is progressively lower in older compared to younger adults, with a more
prominent reduction in men than women. The main player in this process is the age-
induced muscle loss. Future studies should investigate how much of this reduction can
account for poor health conditions in older adults and whether interventions for increase
muscle mass, such as resistance exercise could be a good strategy to oppose the natural
changes.

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