Construction and evaluation of clinical, blood-derived and combined frailty models in sheep

Frailty is correlated with but not inevitable in advanced age. Higher frailty is associated with longer hospital stays and worse risks of infection and postoperative complications (Partridge et al, 2012). The ageing population in western nations has lead to a rise in the frail population, but there is no consensus on assessment methods for frailty, many of which are time-consuming and involved. Furthermore, while murine models are key to our understanding of frailty there is a need to develop a Frailty Index (FI) in a large animal model for future translation to clinical practice. We have designed and evaluated clinical (FIClinical) and blood-derived (FILab) deficit-accumulation Frailty Indices (see Mitniski et al, 2001) in sheep, and observe the effects of ageing on the FI and cardiac function as measured by fractional shortening. Old (>8 years, n=4) and young (~18 months, n=7) female welsh mountain sheep were monitored for blood biochemistry parameters and echocardiographic lfractional shortening. The FIClinical was determined using a 49-item questionnaire, refined over the course of the study be removing consistently non-scoring elements. All measures were repeated weekly. Control young sheep (n= 19) were used to calculate the normal range (±1.5 standard deviations from the mean) for each parameter of a standard metabolic blood panel. For the FILab, blood values within the normal range scored 0 and outside the normal range scored 1. The average of these scores is the FILab. Data is presented as mean ± SEM. Statistical analysis was performed using a Student’s t-test or two-way ANOVA. FIClinical increased with age in sheep (0.06 ± 0.02 young vs. 0.15 ± 0.03 old, n=4-7, p<0.05). FILab also increased with age (0.07 ± 0.02 young vs. 0.45 ± 0.03 old, n=4-7, p<0.001). An increase in FIClinical was associated with a loss of fractional shortening (p<0.05; Figure 1). Mean FILab score was higher than the FIClinical score, possibly reflecting earlier visibility of the effects of ageing on the biochemical (FILab) level before the phenotype (FIClincal) level. [Figure 1] Figure 1 – A, scores of FILab and FIClinical increase with ageing in female welsh mountain sheep. B, an increase in FIClinical is associated with decreased fractional shortening. The FIClinical allows quantification of frailty in sheep. It increases with age and is associated with loss of fractional shortening. The FILab presents an attractive alternate FI, easily integrated into existing clinical practise, minimally invasive and based solely on objective measurements. Sheep are suitable as a large mammal model of frailty.