Sex Differences in Healthspan Predict Lifespan in the 3xTg-AD Mouse Model of Alzheimer's Disease

Abstract

Mouse models of Alzheimer's disease (AD) exhibit marked differences in life expectancy depending on their genotype and sex. The assessment of frailty could provide a measure of healthspan to facilitate comparisons between different AD models. We used a validated mouse frailty index (FI) assessment tool to explore genotype and sex differences in lifespan and healthspan of 3xTg-AD mice and their B6129F2 wild-type (WT) controls. This tool is based on an approach commonly used in people and quantifies frailty by counting the accumulation of age-related health deficits. The number of deficits in an individual divided by the total number measured yields an FI score theoretically between 0 and 1, with higher scores denoting more frailty. Male 3xTg-AD mice aged 300-600 days had higher FI scores (Mean FI = 0.21 ± 0.03) than either male WT (Mean FI = 0.15 ± 0.01) or female 3xTg-AD mice (Mean FI = 0.10 ± 0.01), and the elevated frailty scores were accompanied by parallel increases in mortality. Frailty increased exponentially with age, and higher rates of deficit accumulation elevated mortality risk in all groups of mice. When mice were stratified by FI score, frailty predicted mortality, at least in females. Therefore, the mouse clinical FI provides a valuable tool for evaluating healthspan in mouse models of AD with different lifespans.

Keywords: deficit accumulation; deficit index; frailty; frailty index; sex differences.

Figure 1

Kaplan-Meier survival curves for male and female 3xTg-AD and wild-type (WT) mice. Log rank analyses were used to compare survival curves (p < 0.001). Pairwise analyses show that male 3xTG-AD mice (n = 33) were significantly shorter lived than both male WT mice (n = 76), and female 3xTG-AD mice (n = 54; p < 0.001). By contrast, there was no significant difference in survival between the female WT (n = 84) and 3xTg-AD mice. *p < 0.05 compared to corresponding female group, ^#p < 0.05 compared to corresponding WT group.

Figure 2

Natural log frailty index (FI) scores increase with age in male and female 3xTg-AD and WT mice. Ln FI Score was correlated with age for (A) WT males (n = 84, r = 0.681, p < 0.0001), (B) 3xTg-AD males (n = 35, r = 0.677, p < 0.0001), (C) WT females (n = 91, r = 0.608, p < 0.0001) and (D) 3xTg-AD females (n = 62, r = 0.755, p < 0.0001). The slope of the linear regression line (m, shown on each graph) is equivalent to the rate of deficit accumulation and is 0.023, 0.035, 0.020 and 0.031 for male WT, male 3xTg-AD, female WT and female 3xTg-AD respectively. A larger slope indicates a faster accumulation of deficits.

Figure 3

Sex and genotype differences in mean FI scores over the lifespan. Mean FI scores were plotted for each sex and genotype group at three different ages (0–300 days, 300–600 days and 600+ days). Analysis was completed with 3-way and 2-way analyses of variances (ANOVAs) with Bonferroni post hoc testing. Three-way ANOVA showed a significant effect of age and sex, and 2-way ANOVA showed a significant effect of genotype for males only. Two-way ANOVAs of age group and either sex or genotype showed that for all groups, mean FI scores increased with increasing age (statistics not shown on graph). *p < 0.05 between sexes. 0–300 days Male WT n = 23, Male 3xTg-AD n = 26, Female WT n = 22, Female 3xTg-AD n = 19; 300–600 days Male WT n = 47, Male 3xTg-AD n = 9, Female WT n = 41, Female 3xTg-AD n = 25; 900 + days Male WT n = 17, Male 3xTg-AD n = 0, Female WT n = 29, Female 3xTg-AD n = 17.

Figure 4

Kaplan-Meier survival curves for male and female 3xTg-AD and WT mice with low and high FI scores. Survival curves for (A) male WT, (B) male 3xTg-AD, (C) female WT and (D) female 3xTg-AD mice split into those with low (<0.21) and high (≥0.21) FI scores. Survival (days) post FI score was plotted. Log rank analysis was used to compare curves and showed that, for female mice of both groups, higher FI scores were associated with shorter survival times (p < 0.01). A similar trend was also seen for males but this was not statistically significant. *p < 0.05 compared to corresponding low FI group. Male WT low FI n = 66, high FI n = 10; Male 3xTg-AD low FI n = 30, high FI n = 3; Female WT low FI n = 74, high FI n = 10; Female 3xTg-AD low FI n = 48, high FI n = 6.