Abstract
As life expectancy continues to rise worldwide, health concerns associated with advanced age are increasingly becoming prominent public health concerns. Among these concerns, nearly 30 years of discussion and research have yielded a wealth of information regarding the pathophysiology, biologic etiology, and clinical implications of age-related declines in skeletal muscle mass and function (i.e., sarcopenia). Recent years have yielded several debates surrounding both the definition and terminology of sarcopenia, yet many questions remain regarding interventions to treat the condition. Among major future challenges in the area will be to design and conduct high-quality clinical trials to ultimately provide new therapeutic strategies for the treatment of sarcopenia.
So we beat on, boats against the current, borne back ceaselessly into the past.
Commonly referenced estimates indicate that humans appear to experience a decrease in muscle mass at a rate of 1% to 2% per year after age 50 (Marcell 2003; Lauretani et al. 2003). These declines in muscle mass are largely due to the progressive atrophy and loss of type II muscle fibers and associated motor neurons (Tomlinson, Irving, and Rebeiz 1973; Larsson, Sjodin, and Karlsson 1978). Other morphological changes occurring during the atrophy process include increased variability in fiber size, accumulation of nongrouping and angulated fibers, expansion of extracellular space, and deposition of protein aggregates within the interstitial matrix (Brooks and Faulkner 1994; Faulkner et al. 2007; Rolland et al. 2008). These changes are well-documented to contribute to changes in locomotive ability, yet atrophy of skeletal muscle may also impair other physiological functions including glucose regulation, hormone production, and cellular communication. Skeletal muscle tissue also provides the body’s only major “reserve” of readily available amino acids. Thus, inadequate muscle mass prior to the onset of a disease condition may be dangerous in patients who need a large protein reservoir to recover including those facing surgical recovery (Rutan and Herndon 1990; Watters et al. 1993).
The term sarcopenia was formally coined nearly 30 years ago by Rosenberg (1989) who remarked that “No single feature of age-related decline (is) more striking than the decline in lean body mass (which) affects ambulation, mobility, energy intake, overall nutrient intake and status, independence, and breathing.” Since that time, academic interest in sarcopenia has increased exponentially as evidenced by the increase in publications on sarcopenia found in PubMed from just 2 in 1996 to 92 in 2006 to nearly 1,000 in 2016 (Figure 1). Literally translated from Greek as “poverty of flesh,” Rosenberg’s initial reference to sarcopenia referred specifically to declines in skeletal muscle size (atrophy) that can be observed with advanced age. Somewhere around the turn of the century, the loss of muscle strength that typically accompanies age-related muscle atrophy became commonly incorporated into the definition of sarcopenia (Visser et al. 2000; Roubenoff and Hughes 2000).
Number of publications in PubMed by year using the search term “sarcopenia.”
During these early days of sarcopenia research, much progress was made in identifying clinical characteristics associated with the condition as well as the underlying biologic processes that contribute to the loss of muscle mass and strength. These numerous processes include (but are not necessarily limited to) (1) declines in circulating concentrations of anabolic hormones and growth factors, (2) impaired neural transmission, (3) impaired myonuclear regeneration, (4) chronic tissue inflammation and fibrosis, (5) cumulative oxidative stress, (6) reduced protein synthesis and increased proteolysis, (7) altered apoptosis and autophagy, and (8) telomere shortening. Outstanding reviews regarding these aspects of sarcopenia can be found elsewhere (Short and Nair 2001; Bales and Ritchie 2002; Carmeli, Coleman, and Reznick 2002; Roubenoff 2003; Fulle et al. 2004).
More recently, however, understanding of the pathophysiology of sarcopenia has grown more complex. For instance, it is now recognized that advanced age is associated with not only muscle atrophy but also adipose tissue infiltration within skeletal muscle (Delmonico et al. 2009; Buford et al. 2012) and that this infiltration (i.e., myosteatosis) is associated with decreased muscle force production and physical function (Visser et al. 2002, 2005). Additionally, there has been discussion in the literature regarding the effects of chronic diseases in accelerating sarcopenia progression with mixed opinions whether disease directly contributes to sarcopenia per se (Buford et al. 2010; Hepple 2012; Dardevet et al. 2012). Similarly, significant discourse has taken place regarding the discordance between the degrees of atrophy and muscle force production. In this latter case, a new term specific for declining muscle force production—“dynapenia”—was coined (Clark and Manini 2008). Correctly, the originators of the term dynapenia highlighted the critical contributions of the nervous system to declining skeletal muscle strength and overall physical function. Still, some experts in the field expressed concerns at the time (noted via personal communications) that this delineation and coining of a new term could, despite scientific accuracy, blur the public health message surrounding sarcopenia and inhibit progress toward a standardized definition.
Although it is both impossible and impractical to directly attribute such developments to the coining of a new, technically accurate term, subsequent years have in fact revealed such difficulty in establishing an accepted definition of sarcopenia. For instance, since 2010 multiple expert consensus statements have been released attempting to define sarcopenia (Cruz-Jentoft et al. 2010; Fielding et al. 2011; Morley et al. 2011; Chen et al. 2014) detracting from clarity regarding the “proper” definition for scientists and clinicians to target. Indeed, a litany of articles can be found in the literature applying each of these definitions to a variety of cohorts—with dramatically different results in sarcopenia prevalence and/or ability to predict health outcomes depending on the definition chosen. More recently, results were published from a U.S. National Institutes of Health Working Group, which culminated in yet another definition for sarcopenia and redefining with another new term: “skeletal muscle function deficit” (Correa-de-Araujo and Hadley 2014; Cawthon et al. 2014; McLean et al. 2014). This project notably applied a classification and regression tree analysis to epidemiologic and clinical trial data to identify criteria for clinically relevant muscle weakness and low lean mass (resultant definition shown in Table 1).
Recommendations for Cut Points for Weakness and Low Lean Mass.a
Impressively, the “Foundation for the National Institutes of Health Sarcopenia Project” (as this latter effort was known) capitalized on substantial intellectual and data resources to develop this updated definition and terminology. Still, questions remain regarding the likely outcomes from this effort. For instance, will this be yet another “consensus definition” from which scientists and clinicians will have to choose? A major issue facing the sarcopenia field is that, despite nearly 30 years and dramatic increases in thought, discourse, and acquired knowledge surrounding sarcopenia, there is still no Food and Drug Administration (FDA)-approved definition on which promising drug treatments might be approved. Indeed, questions remain which of the consensus definitions might be FDA approvable, and if persons matching those characteristics will be willing/capable of participating in clinical trials. Secondly, it remains to be seen whether definitions requiring objective performance tests will be acceptable for use within clinical settings due to the time required to perform the tests. To this end, recent efforts to create questionnaires validated against performance tests which can efficiently make a sarcopenia diagnosis may represent an important advance in this area (Cao and Morley 2016). Finally, it is unclear what effect the creation of another new terminology will have on communication of the sarcopenia public health message. It took over 25 years of raising awareness to (finally) establish a code for sarcopenia in the Statistical Classification of Diseases and Related Health Problems (Cao and Morley 2016). And yet, despite this progress, at least some are calling for the complete abandonment of the term sarcopenia (Menant et al. 2017). It seems that this approach might be counterproductive to the progress that it has taken so long to achieve. The simple elegance of a one-word term with an established history (similar to osteoporosis) likely has importance for communicating to the public—even as discussion continues regarding the optimal, formal definition to be associated with the term.
And so, as we move toward another decade of sarcopenia research, perhaps our challenge is to avoid the trap outlined in the final line of The Great Gatsby of continuing to circle around themes and discussions that have dominated the past. That’s not to say that these areas weren’t valuable—quite the contrary—however, continued progress will be made by capitalizing on this past knowledge to ultimately progress testing and implementation of novel therapeutic strategies to slow (or even prevent?) sarcopenia progression. To date, a number of therapeutic strategies have been proposed—including physical exercise, dietary restriction, protein supplementation, vitamin D, myostatin inhibitors, sex hormone administration (i.e., testosterone/ estrogen), and renin–angiotensin system inhibitors (Buford et al. 2010; Pillard et al. 2011; Carter et al. 2012; Cesari 2013; Fragala et al. 2015; Anton et al. 2016)—but definitive trials are lacking. To achieve the needed progress in this area, we must (1) quickly solidify a sarcopenia definition that applies to a broad enough population who are able/willing to participate in clinical trials, (2) push forward toward FDA approval of this definition for large-scale testing of interventions to treat sarcopenia, (3) identify methods to facilitate rapid assessment of sarcopenia in clinical settings, (4) conduct rigorous clinical trials to identify novel treatments, and (5) present a consistent message to the public regarding implications of sarcopenia and potential therapeutic options. We must avoid becoming entangled in the “what” of the innumerous academic issues surrounding sarcopenia (i.e., the trees) at the expense of the “why” we choose to investigate and discuss these issues in the first place (i.e., the forest). I look forward to seeing this progress in the coming years to ultimately identify a variety of therapeutic options to improve the health and quality of life among older adults with sarcopenia.
Footnotes
Author Contribution
The author (TB) contributed to conception or design, data acquisition, analysis, or interpretation; drafted the manuscript; and critically revised the manuscript. The author gave final approval and agreed to be accountable for all aspects of work in ensuring that questions relating to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.