Life-long endurance exercise in humans: Circulating levels of inflammatory markers and leg muscle size
Introduction
Aging of the human body is associated with a gradual loss of muscle mass (sarcopenia). In some cases, a critically low muscle mass, together with reduced muscle function, will result in frailty, which is a powerful predictor of mortality (Fried et al., 2001). Part of the loss of muscle mass is clearly associated with reduced levels of physical activity and muscle disuse. However, individuals who maintain a high level of physical activity throughout life do experience some loss of skeletal muscle mass, indicating that exercise cannot completely prevent the age-related decline in muscle mass (Faulkner et al., 2008). The explanation for this remains unknown, but factors like neuro-muscular impairment, cell membrane changes or altered intracellular signaling have been demonstrated to play a role in animal models (Andersson et al., 2011, Burks et al., 2011, Narici and Maffulli, 2010). However, a comprehensive explanation for sarcopenia in humans is still lacking. A decline in adaptive immunity, or the development of low-grade inflammation with elevated levels of inflammatory markers, possibly derived from adipose tissue, may play a role (Lutz and Quinn, 2012). With regard to systemic inflammation, elevated circulating levels of the acute phase protein C-reactive protein (CRP) and cytokines, such as tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6), have been found in elderly individuals (Bruunsgaard et al., 2000) and these factors have been reported to be related to mortality (Harris et al., 1999). Similarly, the soluble urokinase plasminogen activator receptor (suPAR), which is also a marker of systemic low-grade inflammation, has been found to be associated with age, chronic diseases, cancer and mortality (Eugen-Olsen et al., 2010, Langkilde et al., 2011).
Inflammation is considered to play a role in disease development and prognosis (Toth et al., 2006, Visser et al., 2002), and high levels of inflammatory markers are associated with an increased risk of development of cardiovascular disease and cancer (Allin et al., 2010, Wensley et al., 2011). In addition, obesity and visceral adiposity are positively associated with elevated cytokine levels (TNFα and IL-6) and CRP (Park et al., 2005). A reduction in trunk fat induced by 10 months of cardiovascular exercise training was significantly related to a drop in circulating CRP levels (Vieira et al., 2009). SuPAR in the general population is not uniformly related to obesity and visceral adiposity but is associated with an increased risk of cardiovascular disease (Lyngbaek et al., 2013a).
Several large cohort studies have found a relationship between self-reported physical activity levels and systemic markers of inflammation: higher levels of physical activity are coupled to lower levels of circulating inflammatory markers in elderly individuals (Taaffe et al., 2000, Geffken et al., 2001, Wannamethee et al., 2002, Reuben et al., 2003, Colbert et al., 2004, Albert et al., 2004, Rahimi et al., 2005, Yu et al., 2009, Valentine et al., 2009, Elosua et al., 2005). This coupling was also evident after adjustment for other risk factors and persisted even with relatively low levels of physical activity (Elosua et al., 2005). Aerobic fitness was inversely associated with inflammatory biomarkers in persons above 60 years (Taaffe et al., 2000, Valentine et al., 2009, Rahimi et al., 2005). Intervention studies have shown that physical training over several months reduces circulating levels of CRP and IL-6 in some (Kohut et al., 2006, Vieira et al., 2009, Campbell et al., 2009) but not all studies (Nicklas et al., 2005, Nicklas et al., 2008, Hammett et al., 2004, Lund et al., 2011). It is important to note that these intervention studies were performed in patient groups or in persons that had several risk factors, and thus all had relatively high levels of inflammatory markers to begin with. Most of the studies demonstrated that training induced a reduction in chronic inflammation and weight loss, but one study (Nicklas et al., 2008) showed that regular aerobic exercise training was efficient in lowering IL-6 levels even without weight loss.
The aim of the present study was to investigate the influence of life-long endurance exercise on the levels of inflammatory markers and muscle size in healthy, normal-weight young and elderly males. We used endurance trained individuals (long-distance runners) as the active group of subjects, either young endurance athletes or elderly master athletes in order to obtain data from individuals who were healthy and had performed regular training for most of their life. As healthy control individuals we used untrained, weight-matched males for the respective age groups.
We hypothesized that age and life-long endurance training would affect systemic inflammatory levels and muscle size, and that small differences in circulatory inflammatory markers would be inversely related to muscle size. Inflammatory biomarkers were determined from circulating blood, and muscle size and function were measured. In addition, blood lipid profile, glucose homeostasis and body composition were determined to evaluate any potential coupling of these parameters to aging and endurance training.
Section snippets
Subjects
We recruited a total of 49 males: 15 male endurance runners (master athletes, old trained, O-Tr; running distance of 49 ± 3 km/wk (4–6 training days/wk) over the last 28 ± 2 years (mean ± SE)), 12 old untrained weight matched healthy controls (O-Un), and 10 young males matched for current running distance to the old trained (young trained, Y-Tr; 43 ± 5 km/wk (4–6 training days/wk), endurance runners during the last 6 ± 1 years) and 12 young untrained weight matched controls (Y-Un). The untrained subjects
Subject characteristics (Table 1)
Anthropometric data for the subjects revealed 4 groups of normal weight, non-obese individuals. BMI was slightly higher in O-Un than in O-Tr (Table 1). Waist circumference was higher in (O-Un) than both O-Tr (*) and Y-Un (§) (Table 1).
Physical activity (Table 1)
Habitual running distance per week (mileage in km) was similar in the O-Tr (49 ± 3 km/wk) and Y-Tr (43 ± 5 km/wk NS) groups (Table 1). Likewise, running distance during the last week prior to the study was similar between these groups (O-Tr 43 ± 5; Y-Tr 48 ± 7 km/wk, NS).
Discussion
To the best of our knowledge, this is the first study to investigate the interaction between the influence of aging and physical activity on inflammatory biomarkers and skeletal muscle mass in elderly master athletes. One of the major findings of the present study was that life-long endurance exercise was associated with a larger muscle size than O-Un and an attenuation of the age-related increase in inflammatory markers. Moreover, endurance training was associated with improved insulin
Conclusion
In non-obese healthy males, endurance training was associated with improved insulin sensitivity and lower triglyceride levels, which was independent of age. Furthermore, age-related changes in waist circumference, VO2 peak, cholesterol, LDL, leg muscle size, CRP and IL-6 were counteracted by the effects of physical activity level in the old (and young) groups. Finally, life-long endurance exercise was associated with attenuation in both the age-related elevation of some inflammatory markers
Acknowledgements
Ann-Christina Reimann is acknowledged for expert technical assistance, and the technical staff at the Department of Radiology, Bispebjerg Hospital for help in obtaining the MRI images. The study was supported by grants from The Danish Medical Research Council (no. 10-09402), The Nordea Foundation (Healthy Ageing grant), EU 7th framework grant “Myoage” (no. 223576), The Danish Rheumatism Association (R92-A1592) and The Danish Agency for Culture.
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These authors contributed equally to this work.