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.

Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer’s disease

“…We determined that the AD cortex was 6.7 months older (median difference) compared to their chronological age, while the hippocampus was 0.7 months younger ( Figure 2C , 2D ). As the mean lifespan of female AD mice is 17 months [ 42 ], we indicated for the cortex a 39.4% acceleration of their lifespan and for the hippocampus a 4.1% deceleration. Compared to their chronological age, the B6 cortex was 2.4 months older, while the hippocampus was 2.1 months younger ( Figure 2C , 2D ).…”

Sex-specific components of frailty in C57BL/6 mice

“…After determining the prevalence of frailty and overall mortality risk did not appear to have prominent sex differences, we turned to examining sex-specific characteristics used in the frailty assessment tool. Kane et al [29] recently articulated the concept that, “there are different ways to become frail and each of them is valid for the person or mouse who becomes frail in that way,” a concept we explored further and assessed whether it was also sex-specific. Our results indicate that although some frailty markers were similar between sex, others appeared to be dependent on being male or female.…”

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

“…No studies have yet explored sex differences in whisker movement in different strains of mice or rats and these needs to be completed before whisker measurements become a standard behavioural test for exploration and object recognition. There are significant sex differences in mouse models, in general, and in AD model mice specifically, in terms of disease pathology, lifespan and healthspan and behaviour …”