A Murine Frailty Index Based on Clinical and Laboratory Measurements: Links Between Frailty and Pro-inflammatory Cytokines Differ in a Sex-Specific Manner

Abstract

A frailty index (FI) based on clinical deficit accumulation (FI-Clinical) quantifies frailty in aging mice. We aimed to develop a laboratory test-based murine FI tool (FI-Lab) and to investigate the effects of age and sex on FI-Lab scores, FI-Clinical scores, and the combination (FI-Combined), as well as to explore links between frailty and inflammation. Studies used older (17 and 23 months) C57BL/6 mice of both sexes. We developed an FI-Lab (blood pressure, blood chemistry, echocardiography) based on deviation from reference values in younger adults (12 months), which showed similar characteristics to a human FI-Lab tool. Interestingly, while FI-Clinical scores were higher in females, the opposite was true for FI-Lab scores and there was no sex difference in FI-Combined scores. All three FI tools revealed a positive correlation between pro-inflammatory cytokine levels and frailty in aging mice that differed between the sexes. Elevated levels of the pro-inflammatory cytokines interleukin (IL)-6, IL-9, and interferon-γ were associated with higher FI scores in aging females, while levels of IL-12p40 rose as FI scores increased in older males. Thus, an FI tool based on common laboratory tests can quantify frailty in mice; the positive correlation between inflammation and frailty scores in naturally aging mice differs between the sexes.

Keywords: Deficit accumulation; Deficit index; Inflammation; Pro-inflammatory cytokines; Sex differences.

Figure 1.

Impact of age and sex on FI-Clinical, FI-Lab, and FI-Combined. (A) Clinical frailty index (FI-Clinical) scores increased from 17 to 23 months of age in male and female mice. FI-Clinical scores for female mice were higher than male mice at 17 and 23 months of age. (B) Laboratory-based frailty index (FI-Lab) scores were higher in male than female mice at 17 and 23 months of age. (C) FI-Combined scores increased from 17 to 23 months in males and females, with no sex difference. The effect of age and sex was analyzed with two-way ANOVAs with Bonferroni post hoc tests (17-month males n = 34, females n = 37; 23-month males n = 13, females n = 13–17). *Indicates a significant difference p < .05.

Figure 2.

FI-Lab scores are higher than FI-Clinical scores at 17 and 23 months of age in mice. Mean and median scores for FI-Lab were higher than FI-Clinical scores in (A) 17-month-old females (FI-Lab median score 0.36, FI-Clinical median score 0.19), (B) 17-month-old males (FI-Lab median score 0.48, FI-Clinical median score 0.16), (C) 23-month-old females (FI-Lab median score 0.39, FI-Clinical median score 0.34), and (D) 23-month-old males (FI-Lab median score 0.55, FI-Clinical median score 0.27). Mean and median FI-Lab and FI-Clinical scores were compared with t-tests, and Mann–Whitney U tests (17-month males n = 34, females n = 37; 23-month males n = 13, females n = 13–17).

Figure 3.

Comparison of individual deficits from the FI-Lab and FI-Clinical in older male and female mice. Proportion of (A) 17-month-old and (B) 23-month-old male and female mice displaying deficits in each item that makes up the FI-Lab and FI-Clinical. Proportions of individual deficits observed in each sex, for each age group were compared with Chi-squared analysis. *Indicates significant difference between sexes, p < .05.

Figure 4.

Inflammatory cytokines are correlated with increasing FI-Combined scores in mice in a sex-specific manner. Correlation of FI-Combined values in older female mice with (A) interleukin (IL)-6 (r = 0.66), (B) IL-12p40 (NS), (C) interferon (IFN)-γ (r = 0.77), and (D) IL-9 (r = 0.75). Correlation of FI-Combined values in older male mice with (E) IL-6 (NS), (F) IL-12p40 (r = 0.67), (G) IFN-γ (NS), and (H) IL-9 (NS). Data analyzed using Spearman correlations and lines indicate significant correlations (p < .05). All cytokine data for 17- and 23-month-old mice included (males n = 18, females n = 13).