Physical Interventions Restore Physical Frailty and the Expression of CXCL-10 and IL-1β Inflammatory Biomarkers in Old Individuals and Mice

Abstract

Background: Frailty is a geriatric syndrome associated with negative health outcomes that represents a dynamic condition with a potential of reversibility after physical exercise interventions. Typically, inflammatory and senescence markers are increased in frail individuals. However, the impact that physical exercise exerts on inflammatory and senescence biomarkers remains unknown. We assessed the effect of physical intervention in old individuals and mice and determined the expression of inflammatory and senescence markers.

Methods: Twelve elderly individuals were enrolled from a primary care setting to a 3-month intervention. Frailty was measured by SPPB and the expression of biomarkers by cytokine array and RT-qPCR. In addition, 12 aged C57BL/6 mice completed an intervention, and inflammation and senescence markers were studied.

Results: The physical intervention improved the SPPB score, reducing frail and pre-frail individuals. This was correlated with a reduction in several pro-inflammatory biomarkers such as IL-6, CXCL-1, CXCL-10, IL-1β, IL-7, GM-CSF as well as p16^INK4a and p21^CIP1 senescence markers. Otherwise, the levels of anti-inflammatory biomarker IL-4 were significantly increased. Moreover, the physical intervention in mice also improved their functional capacity and restored the expression of inflammatory (Il-1β, Cxcl-10, Il-6, and Cxcl-1) and senescence (p21^Cip1) markers. Additionally, PLSDA and ROC curve analysis revealed CXCL-10 and IL-1β to be the biomarkers of functional improvement in both cohorts.

Conclusions: Our results showed that a physical intervention improves physical frailty, and reverses inflammation and senescence biomarkers comprising CXCL-10 and IL-1β.

Keywords: frailty; inflammation; physical intervention; senescence.

Figure 1

Analysis of clinical data and inflammatory and senescence markers in community dwelling individuals enrolled in primary care setting. (A) Description of participants (n = 12) before and after 12-week exercise training intervention. (B) Changes of percentage of individuals in each frailty category before and after physical intervention based on SPPB score. (C) Levels of plasma circulating inflammatory genes differentially expressed in basal condition (pre) and after exercise training (post). (D) Data as mean ± standard error of mean (SEM), and p-values of inflammatory mediators. (E) PBMCs mRNA expression levels of senescence markers. (F) Data as mean ± SEM, and p-values of senescence markers. ^a paired t-test, ^b Wilcoxon test. Bold numbers represent statistical significance (p < 0.05), and italic numbers represent tendency (p < 0.1). * p < 0.05; ≠ p < 0.1.

Figure 2

PLSDA analysis and ROC curves of primary care setting cohort. (A) PLSDA model classifying participants based on inflammatory and senescence measurements. (B) VIP score rank of markers’ importance implicated in PLSDA classification. (C–E) IL-β, p21^CIP1, and CXCL-10 ROC curves, respectively.

Figure 3

Analysis of functional parameters and mRNA levels of inflammatory and senescence markers in mice cohort. (A) Description of 23-month male C57BL/6 mice cohort, rested group (n = 8), and trained group (n = 12) before and after 10-week physical intervention. (B) ANCOVA analysis of clinical data. (C) mRNA expression levels of inflammatory mediators. (D) Data as mean ± standard error of mean (SEM), and p-values of inflammatory mediators. (E) mRNA expression levels of senescence markers. (F) Data as mean ± SEM, and p-values of senescence markers. ^a t-test, ^b U-Mann–Whitney test. Bold numbers represent statistical significance (p < 0.05), and italic numbers represent tendency (p < 0.1). *** p < 0.001; ** p < 0.01; * p < 0.05; ≠ p < 0.1.

Figure 3

Analysis of functional parameters and mRNA levels of inflammatory and senescence markers in mice cohort. (A) Description of 23-month male C57BL/6 mice cohort, rested group (n = 8), and trained group (n = 12) before and after 10-week physical intervention. (B) ANCOVA analysis of clinical data. (C) mRNA expression levels of inflammatory mediators. (D) Data as mean ± standard error of mean (SEM), and p-values of inflammatory mediators. (E) mRNA expression levels of senescence markers. (F) Data as mean ± SEM, and p-values of senescence markers. ^a t-test, ^b U-Mann–Whitney test. Bold numbers represent statistical significance (p < 0.05), and italic numbers represent tendency (p < 0.1). *** p < 0.001; ** p < 0.01; * p < 0.05; ≠ p < 0.1.

Figure 4

PLSDA analysis and ROC curves of mice cohort. (A) PLSDA model classifying mice based on inflammatory, senescence, and clinical measurements. (B) VIP score rank of variable importance implicated in PLSDA classification. (C,D) Cxcl-10 and Il-1β ROC curves, respectively.