| |
Inflammation (lipodystrophy) Associated with Physical Performance Decline
|
| |
| |
"Individuals with lipodystrophy may be at increased risk for functional decline & aging".....inflammation associated with lipodystrophy and decline as measured by grip strength....."LIPO+ men had higher markers of inflammation compared to LIPO-"
Lipodystrophy and Inflammation Predict Grip Strength in HIV ...
Grip strength, a sensitive indicator of physical function, is associated with increased mortality in the general geriatric population, and declines with ...
www.natap.org/2010/IAS/IAS_46.htm
"Older age, lower mean body mass, increased systemic inflammation, and the presence of mixed lipodystrophy associated with grip strength, measured about 5 years later".....Grip strength, a sensitive indicator of physical function, is associated with increased mortality in the general geriatric population, and declines with lower lean body mass (LBM), increased systemic inflammation, and increased central fat distribution.
We used data from the MACS Body Composition substudy to determine whether lipodystrophy status, changes in regional adiposity, and markers of systemic inflammation assessed in 2001-2002 were associated with lower grip strength in 2007.
"Inflammation, measured as high levels of IL-6, CRP, and IL-1RA, is significantly associated with poor physical performance and muscle strength in older persons. These data also support the biological face validity of physical performance measures. The assessment of inflammatory markers may represent a useful screening test and perhaps a potential target of intervention."
The present study evaluated the relationship between inflammation and the results of objective tests of physical performance. Several previous studies have suggested an effect of inflammation on disability and muscular strength (7,8,14,16,26). In this study, we were able to test the simultaneous effect of a large number of cytokines, acute phase proteins, and soluble receptors. Our findings show that high CRP, IL-6, and IL-1RA levels are significantly and independently associated with poorer physical performance and muscle strength in elderly people. In our study, we included various inflammatory markers (e.g., IL-6sR, IL-10, IL-1ß, IL-1RA) that have not been examined in the context of physical performance in older persons.
Recently, Kuller discussed whether inflammatory markers or elevated acute-phase proteins are part of the pathway to the development of disability or just nonspecific markers of subclinical disease associated with inflammation and disability (6). However, the assessment of inflammatory markers may represent a useful screening test and perhaps a potential target of intervention. In the effort to better understand the physiopathological pathway leading to the onset of disability in elderly people, experimental clinical trials looking at physical decline are needed, especially among healthier older people with increased inflammatory markers.
In line with our findings, higher levels of IL-6 have been associated with lower muscle mass and lower muscle strength in elderly people (7,14,16,27), and increased IL-6 and CRP levels have been associated with increased mortality (7,8). Recently, a longitudinal study also showed that nondisabled persons with increased levels of IL-6 were more likely to develop disability in the next 4 years (16). The magnitude of the associations between IL-6 and CRP with physical performance and grip strength reported in the study by Taaffe was comparable to our associations (7).
Inflammatory markers and physical performance in older persons: the InCHIANTI study.
J Gerontol A Biol Sci Med Sci. 2004 Mar;59(3):242-8.
Cesari M, Penninx BW, Pahor M, Lauretani F, Corsi AM, Rhys Williams G, Guralnik JM, Ferrucci L.
Sticht Center on Aging, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. mcesari@wfubmc.edu
Abstract
BACKGROUND: Some studies have proposed chronic inflammation as an underlying biological mechanism responsible for physical function decline in elderly people. The aim of this study is to evaluate the relationship between several inflammatory markers and physical performance in an older population.
METHODS: This study is part of the "Invecchiare in Chianti" (InCHIANTI) study, a prospective population-based study of older people, aimed at identifying risk factors for late-life disability. The study sample consisted of 1020 participants aged 65 years and older living in the Chianti area of Italy. Physical performance was assessed using walking speed, the chair-stand test, and the standing balance test. Hand-grip strength was assessed using a hand-held dynamometer. Serum levels of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), IL-10, IL-1beta, IL-6sR, and IL-1RA were determined. Linear regression analyses were used to assess the multivariate relationship of inflammatory marker levels with physical performance, scored as a continuous variable from 0 to 3, and hand-grip strength after adjustment for demographics, chronic conditions, medication use, and other biological variables.
RESULTS: CRP, IL-6, and IL1RA were significantly correlated with physical performance (r=-0.162, r=-0.251, and r=-0.127, respectively). Significant correlations with hand-grip strength were found for CRP and IL-6 (r=-0.081 and r=-0.089, respectively). After adjustment for covariates, high levels of IL-6 and IL-1RA continued to be strongly associated with worse physical performance (p<.001 and p=0.004, respectively). High levels of CRP (p<.001) and IL-6 (p<.001) were associated with low hand-grip strength. Mean adjusted physical performance scores ranged from 2.21 in the CRP<0.59 mg/dl group to 2.07 in the CRP>0.60 mg/dl group (p for trend=.004), and from 2.25 in the lowest IL-6 quartile to 2.08 in the highest IL-6 quartile (p for trend<.001). This trend was also reflected in mean adjusted hand-grip strength, with a range from 28.8 kg for the CRP<0.59 mg/dl group to 26.0 kg for the CRP>0.60 mg/dl group (p for trend=.001), and from 27.4 kg for the lowest IL-6 quartile to 25.1 kg for the highest IL-6 quartile (p for trend=.001).
CONCLUSIONS: Inflammation, measured as high levels of IL-6, CRP, and IL-1RA, is significantly associated with poor physical performance and muscle strength in older persons. These data also support the biological face validity of physical performance measures. The assessment of inflammatory markers may represent a useful screening test and perhaps a potential target of intervention.
AGING is associated with a decline in physical function and performance that negatively impacts quality of life and may compromise independence (1,2). The assessment of physical function is a critical component of the assessment of older persons and some performance measures, such as the summary performance score and hand-grip strength, have been shown to be useful in the prediction of institutionalization, disability, and mortality (3-5). A biological mechanism recently proposed to underlie the decline in physical function is chronic inflammation (6,7). Inflammation is the body's integrated reaction and defense against disturbances of homeostasis, particularly infections and injuries. This response is initially characterized by a local release of cytokines, soluble polypeptides responsible for the amplification and regulation of the inflammatory cascade (8). Cytokines are also involved in numerous physiological functions, such as muscle and bone tissues turnover, immunoregulation, and hematopoiesis (9,10), and their circulating levels have been related to several disease processes, primarily atherosclerosis and cardiovascular disease (11-13).
Inflammation has been associated with increased morbidity and mortality in elderly persons (14,15). Moreover, it has been proposed that a chronic inflammatory state may be detrimental by accelerating the progression of medical conditions that result in functional decline and disability (7,16). Finally, a direct role of inflammation in the development of disability can be hypothesized based on the catabolic effects that proinflammatory cytokines may have on muscles. In fact, an accelerated decline of muscle mass and strength with aging is probably one of the major causes of disability in late life (3,14).
Even though some inflammatory markers, such as C-reactive protein (CRP) and interleukin (IL)-6, have been studied before (7,16-18), there is still a lack of knowledge about many others. Tumor necrosis factor-alpha (TNF-α) is a first-line factor in promoting and developing the inflammation pathway (19). IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to inhibit the production of proinflammatory cytokines by monocytes (20). IL-1ß is one of two forms of IL-1, and its main biological activity consists of the stimulation of T-helper cells, which are induced to secrete IL-2, a cytokine able to promote inflammatory cells proliferation (21). IL-6sR is critically involved in the transition between the acute and sustained state of inflammation and in the perpetuation of chronic inflammatory diseases (22). If inflammation is part of the pathway to physical decline and disability, it will be interesting to expand research to new inflammatory markers in order to better understand mechanisms underlying age-related physical performance and strength loss.
The aim of our study was to evaluate the potential association between inflammation and physical performance. In our study, we explored the relationship between blood levels of several inflammatory markers (such as CRP, IL-6, IL-10, TNF-α, and IL-1ß), and cytokine-soluble receptors (such as IL-6sR and IL-1RA) with physical performance (assessed through measures of lower extremity performance and hand-grip strength), in an elderly community-dwelling population.
Discussion
The present study evaluated the relationship between inflammation and the results of objective tests of physical performance. Several previous studies have suggested an effect of inflammation on disability and muscular strength (7,8,14,16,26). In this study, we were able to test the simultaneous effect of a large number of cytokines, acute phase proteins, and soluble receptors. Our findings show that high CRP, IL-6, and IL-1RA levels are significantly and independently associated with poorer physical performance and muscle strength in elderly people. In our study, we included various inflammatory markers (e.g., IL-6sR, IL-10, IL-1ß, IL-1RA) that have not been examined in the context of physical performance in older persons.
In line with our findings, higher levels of IL-6 have been associated with lower muscle mass and lower muscle strength in elderly people (7,14,16,27), and increased IL-6 and CRP levels have been associated with increased mortality (7,8). Recently, a longitudinal study also showed that nondisabled persons with increased levels of IL-6 were more likely to develop disability in the next 4 years (16). The magnitude of the associations between IL-6 and CRP with physical performance and grip strength reported in the study by Taaffe was comparable to our associations (7).
A unique finding of this study was the strong, independent association between IL-1RA and physical performance. The IL-1RA is a pure antagonist of the proinflammatory cytokines IL-1α and IL-1ß, and, as such, plays an important role in regulating the inflammatory process (28-30). In fact, IL-1ß is an early-acting inducer of the inflammation cascade, and its influence on systemic levels of inflammatory markers, such as CRP, has been demonstrated (31). IL1-RA acts as an antiinflammatory substance and its inhibition activities on inflammation has been demonstrated in several diseases, such as rheumatoid arthritis (32) and hemorrhagic shock (33). IL-1RA levels, as those of other cytokine receptors, are increased in the presence of inflammation and tend to remain at higher levels even longer than cytokines (34,35).
Several possible mechanisms may explain the inverse association between inflammatory marker levels and physical performance. In fact, cytokines have such a wide spectrum of activities in the context of immunoregulation, tissue homeostasis, hematopoiesis, and the inflammatory cascade (9,10) that is difficult to indicate a single possible mechanism that is able to explain their potential effects on physical performance. More likely, inflammation influences performance by its effect on body composition, namely by accelerating changes that are typical of the aging process (16). Higher levels of CRP have been associated with obesity and insulin resistance (36-39). These findings could be explained through the inverse association found between physical activity and markers of inflammation (26). A direct influence of cytokine levels on muscle mass has also been demonstrated in humans (40) as well as in animal models (41-43). Some studies suggest that chronic inflammation can lead to hypermetabolism and relative anorexia (44). Moreover, reduced lean tissue mass has been associated with IL-6 and TNF-α levels in patients with congestive heart failure or COPD (40,45), as well as in healthy older adults (14). Furthermore, it has been shown that some treatments, such as short-term thalidomide in patients infected with the human immunodeficiency virus, inhibit cytokine production, leading to weight gain and lean tissue anabolism (19).
Our study has several limitations. The cross-sectional design does not allow us to evaluate the cause-effect association between inflammation and physical decline. Further investigation aimed at assessing the predictive value of inflammatory marker levels on strength and physical decline are needed. Another limitation may be found in the circadian variability characteristic of cytokines. However, most of the blood sampling was done at the same time in the morning, limiting this potential source of bias. The cytokine circadian variability during the day could be an explanation to the lack of findings in our study for TNF-α, IL-10, IL-1ß, and IL6-sR. Further studies aimed at assessing the role of these inflammatory markers are needed.
Our findings support the idea that inflammatory markers and, in this particular study, IL-6, CRP, and IL-1RA, are inversely associated with physical performance. Furthermore, our data provide biological face validity for the use of physical performance measures, increasingly applied in research and clinical geriatric assessment settings. Recently, Kuller discussed whether inflammatory markers or elevated acute-phase proteins are part of the pathway to the development of disability or just nonspecific markers of subclinical disease associated with inflammation and disability (6). However, the assessment of inflammatory markers may represent a useful screening test and perhaps a potential target of intervention. In the effort to better understand the physiopathological pathway leading to the onset of disability in elderly people, experimental clinical trials looking at physical decline are needed, especially among healthier older people with increased inflammatory markers.
| |
| |
| |
|
|
|
