ReviewLow muscle mass in older adults and mortality: A systematic review and meta-analysis
Introduction
Sarcopenia is a pathologic syndrome which comprises a concomitant loss of muscle mass and muscle function (Sanchez-Rodriguez et al., 2020). It affects predominantly older adults and its prevalence steadily increases after the age of 60 (Cruz-Jentoft et al., 2014). As the world population grows older and overall survival improves, it is expected for sarcopenia to have a greater impact on health systems (Ethgen et al., 2017). Hence, precise knowledge about sarcopenia pathogenesis, diagnosis and management is crucial for those health professionals who routinely care for older adults.
For the last three decades, definitions on sarcopenia have undergone substantial changes (Sanchez-Rodriguez et al., 2020). When first coined in 1989 by Rosenberg, the term was considered a mere synonymous of low muscle mass (LMM) (Rosenberg, 1997) and, for a long time, no particular emphasis was devoted to the muscle functional compromise, which usually accompanies and antedates loss of muscle mass (Larsson et al., 2019). It was only in 2010 that the European Working Group on Sarcopenia in Older People (EWGSOP) published the first consensus on sarcopenia that recognized muscle mass function as a mainstay of its diagnosis, gaining immediate international acceptance (Cruz-Jentoft et al., 2010).
Since then, much has been stressed over the importance of skeletal muscle function assessment for accurately determining sarcopenia. A couple of additional formal guidelines and societal official positions have followed similar recommendations after the EWGSOP's (Studenski et al., 2014; Chen et al., 2014; Chumlea et al., 2011). In addition, original observational studies have been published analyzing to which degree skeletal muscle function can predict hard outcomes, such as quality of life (QoL), falls, hospitalizations and, most importantly, overall mortality (Cesari et al., 2009; Gale et al., 2007; Legrand et al., 2014; Newman et al., 2006; Wickham et al., 1989). In those studies, skeletal muscle function has been routinely measured by either muscle strength or muscle performance. The first is usually assessed by handgrip strength and the latter by one of many different muscle performance tests available, among which Timed Up and Go (TUG) and Short Physical Performance Battery (SPPB) are likely the most common ones (Cruz-Jentoft et al., 2019).
Recent clinical research on sarcopenia has considerably focused on the undisputable role of skeletal muscle function on the higher morbidity and mortality in older adults (Chainani et al., 2016; Denk et al., 2018; García-Hermoso et al., 2018; Pavasini et al., 2016). Both decreased skeletal muscle strength and muscle performance have been shown to independently predict higher morbidity and mortality, even after appropriate adjustment for LMM (Cesari et al., 2009; Gale et al., 2007; Legrand et al., 2014; Newman et al., 2006; Wickham et al., 1989). Moreover, it has been hypothesized that the association between LMM and higher mortality in older adults is primarily driven by low skeletal muscle function (LMF), whether by low skeletal muscle strength (LMS) or low skeletal muscle performance (LMP) (Li et al., 2018). Consistent with that, Newman et al. found that a reduced skeletal muscle strength as assessed by handgrip dynamometry or knee extension was independently associated with a higher mortality in individuals aged between 70 and 79 years, while no association for LMM assessed by DXA or CT was found (Newman et al., 2006).
Several systematic reviews with meta-analysis have assessed the association between sarcopenia, comprising the combination of LMM and LMF, and mortality (Beaudart et al., 2017; Liu et al., 2017a; Chang and Lin, 2016; Zhang et al., 2018). All of these studies found an association between the presence of sarcopenia and mortality. They have in common the use of operational definitions of sarcopenia and predefined cut-off points. Although these meta-analyses provide consistent answers about the ability of the operational definitions of sarcopenia to predict mortality, they did not assess the question of whether muscle mass itself would be associated with this outcome. Besides, none of these meta-analyses performed meta-regression, including data on muscle mass and muscle strength measurements.
Although it is now clear that the association between LMM and a higher mortality in older adults can be partly explained by confounding due to compromised muscle strength and performance, caution must be exercised to not overlook its genuine importance. For instance, lack of statistical significance for this association might simply be a result of underpowered studies. In this issue, meta-analytical approaches could be helpful in increasing one's power to detect such an association. Systematic reviews and meta-analysis to date, however, have mostly focused on the combined definition of sarcopenia (LMM + LMF) as the primary exposure, hampering their ability to conclude on isolated LMM as independent risk factor for mortality (Chang and Lin, 2016; Liu et al., 2017b; Yeung et al., 2019).
In this study, we conducted a systematic review and subsequent meta-analysis in the current literature to test whether LMM assessed by different methods is independently associated with increased mortality in community-dwelling, non-frail older adults. This meta-analysis complied with the recommended steps in the checklist from the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) (Moher et al., 2016) and was previously registered in the PROSPERO database (registration number CRD42019146511).
Section snippets
Published literature search and selection
From February 2019 to August 2020 (last search August 10th,2020), we systematically searched the medical literature in two databases [the National Library of Medicine (PudMed®) and the Excerpta Medica database (Embase®)] for articles on the association between LMM and mortality in older adults. Inclusion criteria consisted of cohort or case-control studies reporting on the association of muscle mass and mortality and enrolling community-dwelling older adults aged 65 years or more.
Results
A total of 6722 and 3841 results were initially retrieved from Pubmed® and Embase®, respectively. Following the stepwise process of selection, nine articles were considered eligible for the study and were then included for analysis (Bianchi et al., 2016; De Buyser et al., 2016; de Santana et al., 2019; Kruse et al., 2018; Moon et al., 2016; Nakamura et al., 2020; Seino et al., 2020; von Berens et al., 2020; Woo and Leung, 2018) (Table 1). These comprised a pooled sample of 10,028 older adults.
Discussion
The present meta-analysis uncovered a significant pooled difference in appendicular skeletal muscle mass, as measured by ASMI, between older adults who died as compared to those who survived across follow-up cohort studies. This difference was just partly attenuated by known mortality risk factors after meta-regressing them. Noteworthy, handgrip strength differences between groups were unable to explain the higher mortality found in lower ASMI individuals as compared to those with higher ASMI.
Conclusions
In summary, we found that appendicular skeletal muscle mass adjusted for height, as assessed by ASMI, is inversely associated with mortality in older adults. This association cannot be completely explained by differences in muscle strength, as assessed by handgrip strength, or other known clinical and demographic factors. It appears, however, that the intensity of the association between ASMI and mortality does modify according to such factors. For instance, in overweight and obese individuals
Funding
This research did not receive any specific direct grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Felipe M de Santana (FMS): Conceptualization; Methodology; Formal analysis; Investigation; Resources; Writing - Original Draft; Writing - Review & Editing; Visualization; Project administration.
Melissa O Premaor (MOP), Ph.D MD, Professor: Conceptualization; Methodology; Formal analysis; Writing - Original Draft; Writing - Review & Editing.
Nicolas Y Tanigava (NYT), Acad Med: Investigation; Resources; Writing - Original Draft; Writing - Review & Editing.
Rosa MR Pereira (RMRP), Ph.D MD, Professor:
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We acknowledge the contribution of all the authors of the included studies who kindly supplied us with the data of interest when requested. We particularly acknowledge the MrOs project team contribution. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for
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