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

Alice E Kane,Richard E Brown,Susan E Howlett,Natalia S Faustova,Sooyoun Shin,Emre Fertan,Aimee A Wong

doi:10.3389/fnagi.2018.00172

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.

Highlights

Alzheimer’s disease (AD) is the most common type of dementia and its prevalence is increasing as the population ages (Mielke et al, 2014; Scheltens et al, 2016)
Pairwise comparisons show that male 3xTg-AD mice have lower survival probability than male WTs (χ(21) = 24.01, p < 0.001), but there was no difference in survival probability between female 3xTg-AD mice and WT mice
Post hoc analyses showed the same trend as the Kaplan Meier (KM) curves, with male 3xTg-AD mice having a significantly lower mean lifespan than male WT, and female 3xTg-AD mice (p < 0.05; Table 1)

Summary

Introduction

Alzheimer’s disease (AD) is the most common type of dementia and its prevalence is increasing as the population ages (Mielke et al, 2014; Scheltens et al, 2016). There are sex differences in the lifespan of some AD mouse models, including 3xTg-AD mice, in which males have a shorter lifespan than females (Westmark et al, 2010; Rae and Brown, 2015). Males have longer lifespans than females (Pugh et al, 2007), or there is no sex difference (Rae and Brown, 2015; Brown et al, 2018) This makes it difficult to compare the lifespan and interventional data across different AD mouse models and between the sexes, as well as the translation of data from animal studies to the clinic. The consideration of healthspan, not just lifespan, in all longevity and aging studies is essential in the field of aging research (Howlett and Rockwood, 2014; Richardson et al, 2015; Huffman et al, 2016)

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