Polypharmacy Results in Functional Impairment in Mice: Novel Insights Into Age and Sex Interactions

Author:

Wu Harry12,Mach John2,Gemikonakli Gizem2,Tran Trang2,Allore Heather34ORCID,Gnjidic Danijela56,Howlett Susan E7ORCID,de Cabo Rafael8ORCID,Le Couteur David G69ORCID,Hilmer Sarah N12ORCID

Affiliation:

1. Departments of Clinical Pharmacology and Aged Care, Royal North Shore Hospital, St Leonards, New South Wales, Australia

2. Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, Australia

3. Department of Internal Medicine, Yale University, New Haven, Connecticut, USA

4. Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut,USA

5. Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia

6. Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia

7. Departments of Pharmacology and Medicine (Geriatric Medicine), Dalhousie University, Halifax, Nova Scotia, Canada

8. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA

9. Ageing and Alzheimer’s Institute (AAAI), Centre for Education and Research on Ageing (CERA) and ANZAC Research Institute, Concord Hospital, Sydney, New South Wales, Australia

Abstract

Abstract Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment and whether they are paralleled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, and citalopram; n = 6–8/group) for 4–6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, and total distance), middle zone distance (increased anxiety), and nesting score (reduced activities of daily living) in mice of both ages and sexes (p < .001). Old animals had a greater decline in nesting score (p < .05) and midzone distance (p < .001) than young animals. Grip strength declined more in males than females (p < .05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of the pathogenesis of functional impairment from polypharmacy may improve management strategies in both sexes.

Funder

Penney Ageing Research Unit, Royal North Shore Hospital

National Institute on Aging

National Institutes of Health

Australian National Health and Medical Research Council Dementia Leadership Fellowship

Publisher

Oxford University Press (OUP)

Subject

Geriatrics and Gerontology,Aging

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