Inflammatory biomarkers of frailty

Highlights

• Central role of inflammation and the cross-talk between frailty status and sarcopenia have led to a condition termed physical frailty, in which muscle atrophy is envisioned as the biological substratum of physical frailty.

• Different paradigms of ageing were recently discribed, including “inflamm-ageing”, “oxi-inflamm-ageing”, and “inflamm-inactivity” reveal inflammation as a common driver of age-related frailty.

• Frailty is seen as a multidimensional concept with various indicators such as weight loss, lack of physical activity, sarcopenia, and disability

• “Sarcopenia, i.e., reduced muscle mass, with limited mobility”, is defined as an individual with muscle loss whose speed of walking is equal to or less than 1 m/s or who cannot reach 400m of walk during a 6-minute walk, and who has a lean appendicular mass corrected for height squared of 2 standard deviations or more below the average of healthy individuals between 20 and 30 years of age of the same ethnic group.

• Ageing has been associated with an increase of inflammatory biomarkers. This age-related fluctuation of the inflammatory mediators is referred to as “inflamm-ageing”.

Abstract

Frailty is a functional term that describes a decline in physiological functions that leads to dependency, vulnerability to stressors, high risk for adverse health outcomes, increased risk of falls, and increased morbidity and mortality. The central role of inflammation and the cross-talk between frailty and sarcopenia have led to a condition termed physical frailty, in which muscle atrophy is viewed as the biological substratum of physical frailty. Different paradigms of ageing, including “inflamm-ageing”, “oxi-inflamm-ageing”, and “inflamm-inactivity” reveal inflammation as a common driver of age-related frailty. The key role of inflammation in frailty conditions have led to numerous studies screening for potential inflammatory biomarkers of frailty. This review summarizes the present knowledge of inflammatory biomarkers that are considered promising tools to evaluate frailty. Inflammatory biomarkers for different pathophysiological pathways have been identified, and can be divided into markers of inflammation, oxidative stress, muscle protein turnover and physical inactivity. Described candidate inflammatory biomarkers could support diagnosis, prognosis, and therapeutic decisions in frail elderly. Furthermore, exercise training and nutritional counselling could be implemented in the standard care of the elderly in order to prevent, delay, or ameliorate frailty and to reduce the levels of blood inflammatory biomarkers. Such tools and decision-making outcomes would improve selection and treatment of the elderly and contribute to the ultimate goal – healthy ageing.

Introduction

Healthy ageing and fostering independence in late-life health are two trends that have been extensively discussed, from both clinical and research perspectives. However, frailty status is very frequent in older adults. According to Collard et al., the prevalence of frailty in community-dwelling adults aged 65 years and older ranges enormously from 4% to 59% (Collard et al., 2012). In this context, it is important to understand that frailty is a functional term that describes a decline in physiological functions, which leads to dependency, vulnerability to stressors, high risk for adverse health outcomes, increased risk of falls as well as increased morbidity and mortality (Fried et al., 2005). It is important to emphasize that clinical and biological phenotypes of frailty are greatly dependent upon the operational definition chosen. In the absence of a gold standard, two different conceptual models have been suggested: The “Frailty phenotype” proposed by Fried et al. (2001) and the “Frailty index”, proposed by Rockwood and Mitnitski (2007). Fried's frailty phenotype – the most evaluated and most frequently used measure of frailty – represents a uni-dimensional construct that primarily focuses on physical frailty (Bouillon et al., 2013). Physical frailty recognizes the link between frailty status and sarcopenia, and views muscle atrophy as the biological substratum (Landi et al., 2015). As stated in Fried's diagnostic criteria (Fried et al., 2001), frailty is defined by the presence of at least three of the following elements: 1) Shrinking: unintentional weight loss of ≥4.5 kg in the previous 12 months or, at follow-up, loss of ≥5% of body weight in the previous year; 2) weakness: reduced grip strength in the lowest 20% at baseline, adjusted for gender and body mass index; 3) poor endurance and energy: as indicated by self-reported exhaustion and reduced peak oxygen uptake (peak VO₂); 4) slowness: based on the 4-meter gait speed test, adjusted for gender and height; 5) low physical activity level: a weighted score of kilocalories expended per week, adjusted for gender (Fried et al., 2001).

Next to reduced exercise capacity, sarcopenia is considered an important parameter of physical frailty by Fried and colleagues. Skeletal muscle loss commences in the 4th and 5th decade of life and accelerates from the 6th decade onwards with per annum losses in the order of 1–2% (Janssen et al., 2000; Frontera et al., 2000). Age-related decline in muscle strength is even higher, amounting to 3% annually after the age of 60 (von Haehling et al., 2010; Ramírez-Vélez et al., 2019). A concept of sarcopenia was proposed in 1988, to describe age-related muscle wasting (Rosenberg, 1997). The term originates from two Greek words: sarx for flesh and penia for deficiency and can be divided into primary (age-mediated) and secondary (disease-related) sarcopenia (Bauer et al., 2019), even though this differentiation is being hotly debated at international symposia and in the literature. Sarcopenia is defined as an appendicular skeletal muscle mass (ASM, kg) per height in meters squared (m²) two standard deviations below the mean of a young healthy reference group, as measured by dual-energy X-ray absorptiometry (DEXA) (Baumgartner et al., 1998; Buckinx et al., 2018). The definition has been updated, upon a consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders, where Morley et al. stated that, “Sarcopenia, i.e., reduced muscle mass, with limited mobility”, is defined as an individual with muscle loss whose speed of walking is equal to or <1 m/s or who cannot reach 400 m of walk during a 6-minute walk, and who has an ASM corrected for height squared of 2 standard deviations or more below the average of healthy individuals between 20 and 30 years of age of the same ethnic group (Morley et al., 2011). Following multiple operational definitions of physical frailty and sarcopenia, another definition with wide acceptance is the European consensus that has been updated in 2019 by the European Working Group on Sarcopenia in Older People (EWGSOP). The authors of the revised European consensus used the term sarcopenia to refer to a muscle failure, rooted in detrimental muscle changes that occur over the lifetime (Cruz-Jentoft et al., 2019). In this updated sarcopenia operational definition, the Working Group uses the SARC-F questionnaire and low muscle strength as the primary identifying parameters of sarcopenia (Cruz-Jentoft et al., 2019). Upon identifying low muscle strength, a diagnosis of sarcopenia is confirmed by the existence of low muscle quantity or quality (Cruz-Jentoft et al., 2019). The updated consensus paper provides clear cut-off points for diagnostic variables of sarcopenia: ASM/height² < 7.0 kg/m² for men and ASM/height² < 5.5 kg/m² for women (Cruz-Jentoft et al., 2019; Gould et al., 2014). In contrast to Fried's frailty phenotype, Rockwood's frailty index is a multi-dimensional construct involving more domains of health status (physical, mental, nutritional, and socioeconomic frailty) (Rockwood and Mitnitski, 2007). Both conceptual models have resulted in a large number of instruments, tools, and biomarkers used to assess frailty. While frailty index and phenotype have a long history, there has been a recent bloom of interest in a new functional classification based on frailty and disability. This innovative classification, composed of basic (BADL) and instrumental activities of daily living (IADL) and frailty, has been proven to be an effective tool for stratifying the mortality risk in older adults (Hoogendijk et al., 2019). The full pathway from robustness to severe disability and its prognostic relevance emphasizes the function, as the cornerstone of the geriatric medicine (Hoogendijk et al., 2019; Abizanda and Rodríguez-Mañas, 2017). These findings highlight the major importance of maintaining functional independence in older adults in order to prevent adverse outcomes. Statistics suggest that increasing longevity, along with the consequent acceleration of population ageing worldwide, will result in a tripling of the global population aged older than 65 years from 600 million in the year 2000 to >2 billion people by 2050 (Sander et al., 2015). Flatt (Flatt, 2012) citing Rose (Rose et al., 2007) defined ageing as a time-dependent decline of adaptation, and weakening of the vigorous components of an organism. Landi et al. suggested that sarcopenia and physical frailty should be studied in parallel, since both conditions represent hallmarks of the ageing process (Landi et al., 2015). The important question, which remains unresolved, is: What is the difference, if any, between frailty and ageing (Bergman et al., 2007)? The proposed answer is that frailty encompasses a group of older adults who appear weaker and more vulnerable compared to their age-matched counterparts, despite having similar demographic characteristics, co-morbidities and gender (Bergman et al., 2007).

Recognizing that ageing is related to functional decline and frailty, Rowe and Khan created the concept of healthy ageing (Rowe and Kahn, 1997). Their multi-dimensional concept of healthy ageing is based on the balance between the three components: 1) absence of disease and disability; 2) high exercise and functional capacity; 3) active engagement with life (Rowe and Kahn, 1997). Representing the opposite side of the same coin (Woo et al., 2016), frailty encompasses a detrimental age-associated condition at the patient level, and an important public health challenge as well as an economic problem of health care (Buckinx et al., 2015). Improving our understanding of the biological basis of ageing, identifying and broadly implementing potential diagnostic and prognostic biomarkers would allow development of preventive interventions that would increase quality of life for the geriatric population and decrease the enormous health care cost. Accordingly, candidate biomarkers of ageing, with emphasis on immune response, inflammation, epigenetics, cellular senescence, muscle protein turnover, circadian rhythms and physical inactivity started to get published in the literature (Ferrucci et al., 2002). Additionally, the International Working group on Sarcopenia (Cesari et al., 2012) specified that different biological, functional and imaging parameters could be used as biomarkers for physical frailty and sarcopenia (Calvani et al., 2017). These geriatric syndromes are likely to occur as a response to alterations in circulatory inflammatory factors (Hubbard et al., 2009). The possible sources of these inflammatory mediators are, however, still under debate.

Although it is clear that the process of ageing has a strong inflammatory and genetic component, much work remains to be elucidated on how the immunological and inflammatory mechanisms regulate ageing. Ageing has been associated with an increase in the serum levels of inflammatory biomarkers, for instance pro-inflammatory cytokines like tumour necrosis factor (TNF), interleukin (IL)-6, IL-1, and C-reactive protein (CRP) (Saedi et al., 2019). This age-related fluctuation of the inflammatory mediators is referred to as “inflamm-ageing” (Franceschi et al., 2000). Moreover, postulated with the dynamic interaction among inflammation, ageing and oxidative stress, the “oxi-inflamm-ageing” theory of ageing has been suggested (De la Fuente and Miquel, 2009). This phenomenon, which is referred to as the state of chronic, age-related, low-grade inflammation, resulted in the proposal of inflammatory and oxidative biomarkers of frailty. Notably, as the pathophysiology of both frailty and sarcopenia has an inflammatory component (Dalle et al., 2017), and there is a cross-talk between the underlying mechanisms of these geriatric syndromes (Landi et al., 2015), the groups of muscle protein turnover (Nedergaard et al., 2013; Bhasin et al., 2009) and physical inactivity biomarkers (Liguori et al., 2018; Watanabe et al., 2015; Penninx et al., 2004; Schalk et al., 2005; Lauretani et al., 2007; Dominguez et al., 2009) emerged in the literature and describe the most recent advances in the field. Finally, a novel “inflamm-inactivity” paradigm reveals the crucial role of physical activity as a potent counter-measure to age-related frailty (Flynn et al., 2019). Consequently, the aim of this review is to summarize the present state of knowledge about inflammatory biomarkers that are considered promising tools to evaluate frailty.