Abstract
Objectives:
Age-related loss in muscle and cognitive function is common in older adults. Numerous studies have suggested that inflammation contributes to the decline in physical performance and increased frailty in older adults. We sought to investigate the relationship of inflammatory markers, including CRP, IL-6, IL-10, TNF-α, TNFR1 and TNFR2, with muscle and cognitive function in frail early-aging and non-frail late-aging older adults.
Design:
Secondary analysis of a cross-sectional study.
Settings and Participants:
Two hundred community-dwelling older men and women were included. They had been recruited in two groups based on age and functional status: 100 early-agers (age 65-75, poor functional status, and more co-morbidities) and 100 late-agers (older than 75 years, who were healthier and had better functional status).
Measurements:
We assessed CRP, IL-6, IL-10, TNF-α, TNFR1, TNFR2, grip strength, Short Physical Performance Battery (SPPB) score, and cognitive function. We used correlation coefficients and partial correlations, and regression modeling adjusted for age, BMI, gender, and exercise frequency.
Results:
The mean age in the two groups were 70.4 and 83.2, respectively. In early-agers, there were significant associations between inflammatory markers and outcomes independent of covariates. Each mg/dl of CRP was associated with (regression coefficient ± standard error) −0.6±0.2 kg in grip strength (p=0.0023), as was each pg/mL of TNF-α with −1.4±0.7 (p=0.0454), each 500 pg/mL of TNFR1 with −1.9±0.6 (p=0.0008), and each 500 pg/mL of TNFR2 with −0.5±0.2 (p=0.0098). Each 500 pg/mL of TNFR1 was associated with −0.4±0.2 point in SPPB (p=0.0207) and each pg/mL if IL-6 with 0.2±0.1 point in MoCA (p=0.0475). In late-agers, no significant correlation was found between any of the inflammatory markers and functional outcomes.
Conclusion:
In early-agers with frailty and more co-morbidities, the inflammatory markers CRP, TNF-α, TNFR1, and TNFR2 were associated with grip strength, TNFR1 was correlated with physical performance, and IL-10 was correlated with cognitive function. However, in healthier late-agers, no relationship was found between inflammatory markers and muscle or cognitive function. Our findings suggest presence of a relationship between inflammation and loss of muscle and cognitive function in frailer and sicker individuals, regardless of their chronological age.
Keywords: Aging, Inflammatory Markers, Muscle function, Cognitive Function
INTRODUCTION:
Aging is a complex biological process associated with various physiological changes. Individuals of the same chronological age may exhibit divergent susceptibilities to stressors and different states of functional degradation [1]. This variation has led to classification of older adults as “early” and “late” agers. Early-agers are individuals who show signs of physiological aging at a relatively younger age, whereas late-agers maintain physical and cognitive functions well into their advanced senior years [1,2]. Studies, such as that conducted by Breitbach et al., have shown that phenotypically early-agers have worse clinical profiles than late-agers [3].
Sarcopenia is an age-related disorder characterized by progressive and generalized loss of skeletal muscle strength, mass, and function. Given that muscle mass comprises almost 60% of the total body mass, sarcopenia is associated with profound consequences such as frailty, functional impairment, prolonged hospitalization and even mortality in older adults [4,5]. The prevalence of sarcopenia varies between studies depending on the definition used, nonetheless, the global prevalence of sarcopenia ranges between 5 to 17 percent in adults who are 65 years or older [6].
Although age-related changes such as decline in number and size of skeletal muscle fibers with fibrous infiltration into cells driving sarcopenia [7], there is strong evidence that chronic inflammation and autoimmunity also play a major role in development of sarcopenia and muscle aging [8]. Previous studies have suggested a possible link between inflammatory markers with sarcopenia. Higher levels of C-reactive protein (CRP), Interleukin (IL)-6, tumor necrosis factor (TNF)-α, and TNF Receptors (−R) 1 and 2 have been associated with poor muscle strength, lower physical performance and reduced muscle mass [9–12]. However, the prior studies did not evaluate the potential different impact of inflammation on muscle function in early- and late-agers.
In the present study, our primary goal was to investigate the association of the inflammatory markers such as IL-6, IL-10, TNF-α, TNFR1 and TNFR2 with gait speed and the Short Physical Performance Battery (SPPB) as surrogates for muscle strength and physical performance in early- and late-aging community-dwelling older adults. As a secondary goal, we investigated correlation between inflammatory markers and cognitive function in the two groups. We postulated that elevated levels of inflammatory markers might be associated with poorer muscle function, and that this relationship may be more pronounced in early-agers with the view that our findings may provide valuable insight into impact of inflammation on biological mechanisms of sarcopenia and aging.
MATERIAL and METHODS:
Study Design:
We analyzed the data from 200 participants of a parent study assessing the genetic determinants of early and late aging. The study was conducted at the University of Pittsburgh Claude D. Pepper Older Americans Independence Center. Participants were recruited from a registry of community-dwelling older adults residing in the greater Pittsburgh, PA metropolitan area. The study was reviewed and approved by the institutional review board.
Participants:
The study participants included 200 community-dwelling men and women aged 65 years and older. Participants were recruited as two cohorts: 100 early-agers and 100 late-agers. Early-agers, aged between 65 and 75 years, were unable to walk for 15 minutes without resting or climb a flight of stairs. Late-agers, aged over 75 years, could walk for 15 minutes without resting and climb a flight of stairs. Participants with a history of a major cancer were excluded from the study. The specific recruitment strategy had been employed to maximize the signal for the parent study examining genetic differences.
Measures:
Inflammatory Markers:
We obtained common inflammatory biomarkers of aging and frailty, including IL-6, IL-10, CRP, TNF-α, TNFR1, and TNFR2. IL-6 is produced by T cells and macrophages, has both pro-inflammatory and anti-inflammatory properties, and has been associated with age-related morbidity and poor health outcomes [13,14]. IL-10 is a cytokine with anti-inflammatory effects, with low levels associated with decreased inflammation [15]. CRP is an acute phase inflammatory cytokine produced in the liver that rises with inflammation and is involved in pathogenesis of many age-related disorders, such as cardiovascular disease and frailty [16, 17]. TNF-α is an inflammatory cytokine produced primarily by monocytes, macrophages, and T cells, mediating the signaling pathways leading to cell necrosis and apoptosis. TNF-α exerts many of its function via two signaling mediators, TNFR1, and TNFR2 [13].
Short Physical Performance Battery (SPPB):
The SPPB comprises of balance, gait speed, and chair stand components. The balance component required participant to maintain a tandem, semi-tandem, and side-by-side stance for ten seconds. Gait speed was the average walking speed over a four-meter distance from two trials. The chair stand test required participants to rise from a chair five times with their arms across their chest. The total sum of the components comprised the final SPPB score, ranging from 0 to 12 (a higher score indicates better functioning). A low SPPB score correlates with adverse health outcomes and mobility disability [18–20].
Grip Strength (kg):
Grip strength, an index for upper extremity muscle strength, was measured in the non-dominant hand in 3 trials using a standard dynamometer (JAMAR Technologies, Hatfield, PA) [21] and averaged.
Frailty Score:
Fried frailty index, a five-item screening tool to assess physical frailty, was used to assess physical frailty. The components of the Fried frailty model are unintended weight loss, self-reported exhaustion, weakness, slow walking speed, and low physical activity. Higher scores indicate frailty [22].
Montreal Cognitive Assessment (MoCA)
MoCA, a standard screening tool, was used to assess cognitive function. Higher scores indicate better cognitive function [23].
Co-morbidity Index:
The comorbid burden was assessed using a self-reported questionnaire. The questionnaire encompasses 18 common conditions across 8 separate domains (cardiovascular, respiratory, musculoskeletal, neurological, cancer, diabetes, visual/hearing and pain/mood/sleep), all of which are known to significantly impact on physical performance. A higher co-morbidity index score is indicative of poorer health [24].
Physical Activity:
The Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire was used to assess physical activity. CHAMPS is a self-report questionnaire, designed to evaluate the weekly frequency and duration of various physical activities from light to vigorous intensity [25]. We used frequency of all exercise-related activities in our analysis.
Statistical Analysis:
We employed appropriate descriptive statistics to summarize the characteristics of participants in the two cohorts separately and compared them using independent samples t- and chi-square tests. We fitted a series of linear models with each measure of function as the dependent variable; participant group, each inflammatory marker, and their interaction as independent variables; and age as a covariate. Upon observing significant interaction effects, subsequent analyses were stratified by participant group. Regression coefficients were re-scaled for a more intuitive interpretation without altering statistical significance. Pearson product-moment correlation coefficients were used to evaluate the associations of serum inflammatory marker levels (CRP, IL-6, IL-10, TNF-α, TNFR1, and TNFR2) with grip strength, SPPB, and MoCA scores. To quantify the strengths of the associations independent of age, we used partial correlation coefficients and also adjusted for age, BMI, gender, and physical activity. All analyses were conducted using the SAS® 9.4 software (SAS Institute, Inc., Cary, North Carolina).
RESULTS:
Early-agers had a mean ± standard deviation age of 70.4 ± 3.0 years and a BMI of 33.5 ± 8.3 kg/m2; and the late-agers had an age of 83.2 ± 5.4 years and a BMI of 27.3 ± 4.6 kg/m2 (Table 1; p<0.0001). Among the early-agers and late-agers 63% and 56% were women, respectively (p=0.3133). The mean co-morbidity index was 4.4 and frailty score 2.6 in early agers while the mean co-morbidity index was 2.6 and frailty score 0.6 in later agers (both p<0.0001). We found a statistical trend towards a difference in CRP (4.95±3.94 vs 4.02±3.13 mg/dl; p=0.0669) and IL-10 (1.09±3.33 vs 0.47±0.37 pg/mL; p=0.0692) between early- and late-agers.
Table 1:
Participant Characteristics: Mean ± Standard Deviation or N (%)
| Characteristics | Early ager 65-75 (N = 100) |
Late ager > 75 (N = 100) |
p-Value |
|---|---|---|---|
|
| |||
| Age (years) | 70.4 ± 3.0 | 83.2 ± 5.4 | N/A |
|
| |||
| Females | 63 (63.0) | 56 (56.0) | 0.3133 |
|
| |||
| BMI (kg/m2) | 33.5 ± 8.3 | 27.2 ± 4.6 | <0.0001 |
|
| |||
| Grip strength (kg) * | 23.4 ± 10.0 | 23.8 ± 8.9 | 0.7871 |
|
| |||
| SPPB total score (0-12) * | 9.1 ± 2.5 | 10.2 ± 1.8 | 0.0005 |
|
| |||
| Comorbidity index (0-8) ** | 4.4 ± 1.8 | 2.5 ± 1.6 | <0.0001 |
|
| |||
| CHAMPS exercise frequency | 14.3 ± 9.7 | 19.9 ± 10.3 | 0.0001 |
|
| |||
| Frail scale (0-5) ** | 2.6 ± 1.3 | 0.6 ± 0.9 | <0.0001 |
|
| |||
| MoCA (0-30) * | 25.6 ± 2.8 | 24.5 ± 3.4 | 0.0156 |
|
| |||
| Inflammatory markers | |||
| CRP (mg/dl) | 4.95 ± 3.94 | 4.02 ± 3.13 | 0.0669 |
| TNF-α (pg/mL) | 2.72 ± 1.08 | 2.51 ± 0.78 | 0.1228 |
| TNFR1 (pg/mL) | 1720.69 ± 654.16 | 1689.83 ± 731.94 | 0.7548 |
| TNFR2 (pg/mL) | 4986.64 ± 2065.03 | 4827.83 ± 1853.75 | 0.5697 |
| IL-6 (pg/mL) | 2.16 ± 2.26 | 3.72 ± 19.61 | 0.4336 |
| IL-10 (pg/mL) | 1.09 ± 3.33 | 0.47 ± 0.37 | 0.0692 |
N/A = Not applicable due to difference by design, BMI = Body Mass Index, SPPB = Short Physical Performance Battery, MoCA = Montreal Cognitive Assessment, CRP = C-reactive protein, IL = Interleukin, TNF = Tumor Necrosis Factor, CHAMPS = Community Healthy Activities Model Program for Seniors physical activity questionnaire
Higher score is better.
Lower score is better.
TNFR1 and CRP were differentially associated with grip strength in early- and late-agers (interaction p-value=0.0366; Table 3). Each mg/dl of CRP was associated with (regression coefficient ± standard error) −0.6±0.2 kg in grip strength (p=0.0023), as was each pg/mL of TNF-α with −1.4±0.7 (p=0.0454), each 500 pg/mL of TNFR1 with −1.9±0.6 (p=0.0008), and each 500 pg/mL of TNFR2 with −0.5±0.2 (p=0.0098) independent of the covariates. IL-6 and IL-10 did not exhibit a significant independent association with grip strength.
Table 3:
Regression modeling of function with age group and inflammatory markers adjusted for age, BMI, gender and exercise frequency
| Inflammatory Marker (Unit) | Group/Effect | Grip Strength | SPPB | MoCA | |||
|---|---|---|---|---|---|---|---|
| β ± SE | p-Value | β ± SE | p-Value | β ± SE | p-Value | ||
| CRP (mg/dl) | Interaction | 0.0366 | 0.7767 | 0.4598 | |||
| Early agers | −0.606±0.196 | 0.0023 | −0.032±0.056 | 0.5649 | 0.005±0.083 | 0.9541 | |
| Late agers | 0.022±0.232 | 0.9241 | −0.008±0.066 | 0.9012 | −0.089±0.098 | 0.3661 | |
| TNF-α (pg/mL) | Interaction | 0.9306 | 0.3870 | 0.2991 | |||
| Early agers | −1.354±0.672 | 0.0454 | −0.098±0.189 | 0.6046 | −0.022±0.282 | 0.9379 | |
| Late agers | −1.250±0.978 | 0.2030 | −0.388±0.276 | 0.1605 | −0.541±0.411 | 0.1892 | |
| TNF-R1 (pg/mL) | Interaction | 0.0276 | 0.5214 | 0.3157 | |||
| Early agers | −1.884±0.550 | 0.0008 | −0.362±0.155 | 0.0207 | 0.253±0.235 | 0.2835 | |
| Late agers | −0.219±0.515 | 0.6703 | −0.226±0.145 | 0.1198 | −0.069±0.219 | 0.7525 | |
| TNF-R2 (pg/mL) | Interaction | 0.1754 | 0.8992 | 0.7076 | |||
| Early agers | −0.462±0.177 | 0.0098 | −0.056±0.050 | 0.2671 | 0.057±0.075 | 0.4493 | |
| Late agers | −0.096±0.201 | 0.6326 | −0.046±0.057 | 0.4191 | 0.014±0.085 | 0.8691 | |
| IL-6 (pg/mL) | Interaction | 0.1734 | 0.2148 | 0.3124 | |||
| Early agers | −0.460±0.328 | 0.1625 | −0.117±0.092 | 0.2007 | 0.129±0.136 | 0.3452 | |
| Late agers | −0.009±0.037 | 0.8197 | −0.003±0.010 | 0.7897 | −0.010±0.016 | 0.5188 | |
| IL-10 (pg/mL) | Interaction | 0.2200 | 0.7045 | 0.7088 | |||
| Early agers | −0.141±0.219 | 0.5206 | −0.014±0.062 | 0.8206 | 0.181±0.091 | 0.0475 | |
| Late agers | −2.623±2.003 | 0.1920 | 0.201±0.562 | 0.7212 | −0.131±0.828 | 0.8747 | |
β = Regression coefficient, SE = Standard error, SPPB = Short Physical Performance Battery, MoCA = Montreal Cognitive Assessment, CRP = C-reactive protein, IL = Interleukin, TNF = Tumor Necrosis Factor
In early-agers, each 500 pg/mL of TNFR1 was associated with −0.4±0.2 point in SPPB (p=0.0207) independent of the covariates (Table 3). Other inflammatory markers did not show a significant independent association with SPPB. Among all inflammatory markers, only IL-10 had an independent association with MoCA where each pg/mL was associated with 0.2±0.1 (p=0.0475).
In late-agers, there was no significant association between any of the inflammatory markers (CRP, IL-6, IL-10, TNF-α, TNFR1, and TNFR2) and grip strength, SPPB score, or MoCA (Table 3).
DISCUSSION:
In early-agers, we found a modest but statistically significant association of CRP, TNF-α , TNFR1, and TNFR2 with grip strength, a surrogate for overall muscle strength. Additionally, a significant association was found between TNFR1 level and SPPB score, a surrogate for physical performance. However, in late-agers, we did not find a significant association between the inflammatory markers and the SPPB score or grip strength. The lack of an association between inflammation and function in late-agers could be attributed to lower burden of comorbidities, more regulated immune response to inflammation, or better compensatory mechanisms to maintain functionality in the face inflammation in this group. Furthermore, in early-agers, we noted an association between the IL-10 level and cognitive function, as measured by MoCA. As anticipated, a statistical trend was observed where inflammatory markers were higher in early-agers who were frailer and had a higher co-morbid burden, compared to healthier, less-frail late-agers. As the measures of dispersion in late agers were not substantially or uniformly smaller, we do not feel their weaker correlation is due to participant homogeneity. The lack of stronger associations, may be due to influence of other factors on physical strength and performance apart from inflammation.
Inflammation is associated with adverse health outcomes in older adults [26]. Previous studies have shown that inflammatory markers, including CRP, IL-6, TNF-α, TNFR1, and TNFR2, correlate with sarcopenia and frailty [13, 27–29]. However, despite substantial amount of prior research, the extent of their association with muscle function in the context of early and late-aging remained hitherto unknown. In a study by Schaap et al., in 986 older men and women with a median age of 74.6 years, higher levels of CRP were associated with poor muscle strength, similar to our findings [30]. A metanalysis by Tuttle and colleagues found a significant association of CRP, IL-6, and TNF-α levels with grip strength. In contrast, we did not find a significant correlation between IL-6 with muscle strength [27]. A study by Cesari et al., in 1200 older adults in Italy found a correlation between grip strength with CRP and IL-6 but not with TNF-α or IL-10, similar to our findings [11].
Regarding the association between inflammatory markers and the SPPB score as an index for physical performance, a study by Manrique-Espinoza et al., involving 307 community-dwelling older men and women with an average age of 80.6 years, found a significant association between physical performance and higher CRP levels, but not with IL-10 and TNF-α. Their findings are partially consistent with our observations in late-agers, where none of the inflammatory markers had a significant relationship with SPPB score [31]. In a separate study by Hsu et al. in 1269 participants with a mean age of 73 years, a relationship was reported between SPPB with TNF-α, TNFR1 and TNFR2, but not with CRP or IL-6 [16]. Their findings are also partially consistent with our findings in early-agers, where only TNFR1 correlated with the SPPB score.
With respect to the association between inflammatory markers and cognitive function, our findings partially align with previous studies. In a study by Roberts et al., among 1969 subjects with a median age of 80 year, among CRP, IL-6, and TNF-α, only plasma CRP level was found to be associated with cognitive function [32]. Notably, IL-10 had not been collected, participants had a higher comorbid burden, and other neurological assessment tools besides MoCA were used to examine the cognitive function. In a study by Wennberg et al., which involved 1,602 community-dwelling older adults with a median age of 72.8 years, it was found that a higher plasma IL-10 level was associated with greater odds of cognitive impairment [33]. These results are in contrast to our findings, where a higher IL-10 level correlated with a better MoCA score. However, it is important to note that in the study by Wennberg et al., participants had fewer co-morbidities compared to the early-agers in our study and their cognitive function was assessed by a comprehensive neuropsychological evaluation. In summary, the data regarding the association between inflammatory markers and muscle as well as cognitive function is mixed. This variability may be explained by the impact of factors other than inflammation on muscle and cognitive function, as well as the heterogeneity among different study populations, which may encompass various comorbid conditions. [31].
The main strength of our study lies in being, to the best of our knowledge, the first to assess the relationship between inflammatory markers with muscle function in the context of early and late-aging. Additionally, we adjusted our findings for age to mitigate its potential residual confounding effect within age group on our results. However, our study also has several limitations. First, given that this is a cross-sectional correlation study, we are unable to establish a cause and effect relationship due to the inability to account for all potential confounding factors. Therefore, a longitudinal follow-up may be necessary to draw more compelling conclusions. Second, we included only a limited number of inflammatory markers, which may limit the comprehensiveness of our findings. Third, we did not adjust for comorbid burden as it may plausibly lie in the causal pathway from inflammation to outcomes. Further study with a larger sample size is warranted to assess a potential mediating role of comorbidities. Lastly, our study participants may not represent the general population as all participants were local and predominantly white.
CONCLUSION:
In early-agers who were frailer and had more co-morbidities, inflammatory markers CRP, TNF-α, TNFR1, and TNFR2 were found to be associated with grip strength, with TNFR1 also correlating with physical performance. Additionally, IL-10 was correlated with cognitive function. However, in less-frail, healthier late-agers, there was no association between these inflammatory markers and muscle and cognitive functions. The modest magnitudes of the associations may indicate the presence of other influencing factors. Further longitudinal studies are required to confirm and extend our findings.
Table 2:
Unadjusted regression modeling of function with age group and inflammatory markers
| Inflammatory Marker (Unit) | Group/Effect | Grip Strength | SPPB | MoCA | |||
|---|---|---|---|---|---|---|---|
| β ± SE | p-Value | β ± SE | p-Value | β ± SE | p-Value | ||
| CRP (mg/dl) | Interaction | 0.0767 | 0.3677 | 0.4837 | |||
| Early agers | −0.632±0.241 | 0.0093 | −0.096±0.057 | 0.0903 | 0.027±0.080 | 0.7384 | |
| Late agers | 0.058±0.304 | 0.8492 | −0.014±0.071 | 0.8416 | −0.063±0.100 | 0.5290 | |
| TNF-α (pg/mL) | Interaction | 0.4705 | 0.7958 | 0.1579 | |||
| Early agers | −1.132±0.885 | 0.2021 | −0.194±0.206 | 0.3475 | −0.099±0.286 | 0.7284 | |
| Late agers | −0.038±1.228 | 0.9753 | −0.286±0.286 | 0.3192 | −0.793±0.400 | 0.0471 | |
| TNF-R1 (pg/mL) | Interaction | 0.0270 | 0.2241 | 0.2140 | |||
| Early agers | −1.705±0.725 | 0.0197 | −0.434±0.168 | 0.0106 | 0.236±0.239 | 0.3240 | |
| Late agers | 0.464±0.649 | 0.4755 | −0.159±0.150 | 0.2922 | −0.163±0.213 | 0.4454 | |
| TNF-R2 (pg/mL) | Interaction | 0.0642 | 0.2562 | 0.5432 | |||
| Early agers | −0.574±0.230 | 0.0131 | −0.114±0.054 | 0.0348 | 0.047±0.076 | 0.5352 | |
| Late agers | 0.065±0.256 | 0.7995 | −0.023±0.060 | 0.7061 | −0.022±0.084 | 0.7944 | |
| IL-6 (pg/mL) | Interaction | 0.0314 | 0.0836 | 0.2297 | |||
| Early agers | −0.960±0.420 | 0.0233 | −0.175±0.099 | 0.0778 | 0.158±0.138 | 0.2551 | |
| Late agers | −0.044±0.048 | 0.3668 | −0.002±0.011 | 0.8435 | −0.010±0.016 | 0.5365 | |
| IL-10 (pg/mL) | Interaction | 0.5792 | 0.2974 | 0.9494 | |||
| Early agers | −0.159±0.289 | 0.5824 | −0.017±0.067 | 0.7965 | 0.177±0.093 | 0.0597 | |
| Late agers | −1.625±2.623 | 0.5363 | 0.625±0.611 | 0.3078 | 0.123±0.846 | 0.8849 | |
β = Regression coefficient, SE = Standard error, SPPB = Short Physical Performance Battery, MoCA = Montreal Cognitive Assessment, CRP = C-reactive protein, IL = Interleukin, TNF = Tumor Necrosis Factor
Funding:
This work was supported by following grants: National Institutes of Health (Grant T32AG021885), and Pepper Older Americans Independence Centers (Grant P30AG024827).
Footnotes
STATEMENTS and DECLARATIONS:
Nami Safai Haeri, Subashan Perera, Neelesh K. Nadkarni, and Susan L. Greenspan report no conflicts of interest in the subject matter or materials discussed in this manuscript.
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