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bioRxiv · 10.64898/2025.12.22.696115

Frailty, polypharmacy, deprescribing and 23-hour activity: insights from a mouse model

Mach, J.·Winardi, K.·Hilmer, S. N.
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Abstract

Management of older people with frailty commonly includes polypharmacy and deprescribing. The impacts of frailty on the outcomes of medication use and deprescribing are poorly understood; as are the effects of medication use and deprescribing on frailty and function. Here, using aged C57BL/6J (B6) male mice, we explore the effects of different chronic drug regimens (polypharmacy and monotherapy) and deprescribing on daily activities using an automated behavioral recognition cage, and explore the relationship with frailty and trajectories. At 12 months, male C57BL/6 mice were chronically administered control diet, one of 5 monotherapy diets or one of 3 polypharmacy diets with an increasing Drug Burden Index (measure of total exposure to sedative and anticholinergic medications). At 21 months of age, mice were stratified to continue treatment or to have treatment gradually withdrawn (deprescribed). At 24 months, mice were assessed using the LABORAS automated animal behavioral recognition system for 23 hours. We found that polypharmacy with increasing DBI substantially altered activity and could not be extrapolated from monotherapy response. After deprescribing, while some of the drug effects were reversible, others were irreversible, and we observed some novel changes. Exploring the relationship between frailty and LABORAS behavioral outcomes revealed unique correlations for each intervention group. Four key clusters were identified with different frailty trajectories and attributes, deficits and LABORAS outcomes. This preclinical study demonstrates that medication use and deprescribing can impact activity, frailty and frailty trajectories. The context of polypharmacy and deprescribing are important considerations to enhance translation of pre-clinical studies of frailty.

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Mach, J., Winardi, K., Hilmer, S. N.. 2025-12-25. Frailty, polypharmacy, deprescribing and 23-hour activity: insights from a mouse model. https://doi.org/10.64898/2025.12.22.696115

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