The Effect of Age, Sex, Polypharmacy, and the Drug Burden Index on the Gut Microbiome, Physical and Cognitive Function in Mice.

Abstract

People aged 65 and over are a growing population with increasing morbidity and polypharmacy use, increasing their risk of adverse outcomes related to drug classes and doses. The Drug Burden Index (DBI) is a clinical risk assessment tool that quantifies anticholinergic and sedative medication exposure. Using data from experiments on mouse models of polypharmacy with medications commonly prescribed in Australian older adults, this thesis demarcates the effects of age, sex, and polypharmacy, in examining relationships between physical function, cognitive function, and the microbiome.

Chapter 1 reviews the literature on ageing, related changes in cognitive and physical function, the role of the microbiome, and polypharmacy. Complexity and overlap between geriatric syndromes convey the importance of preclinical mouse models in elucidating mechanisms.

Chapter 2 is a longitudinal study in young and old, male, and female mice, assessing different types of physical function, before and after randomisation to high DBI polypharmacy or control. Only old female polypharmacy mice decline on all tests, other polypharmacy mice decline in grip strength, and considerable individual differences exist within highly controlled groups. Findings inform future study designs and confirm polypharmacy can independently reduce physical function.

Chapter 3 entails the first randomised-controlled study to assess polypharmacy and ageing effects on the gut microbiome. From middle age, the study shows polypharmacy effects on the microbiome outweighed ageing effects, deprescribing reverses some changes, and the microbiome is associated with frailty and function.

Chapter 4 investigates changes in cognitive function using the Barnes maze in mice, and gut microbiome associations. Results show an inconsistent relation between polypharmacy DBI status and Barnes maze performance, no difference between higher and lower performance quartiles in microbiome diversity, but differences in microbial features.