Effects of β-hydroxy-β-methyl butyrate on working memory and cognitive flexibility in an animal model of aging

Abstract

Objectives: Normal aging results in cognitive decline and nutritional interventions have been suggested as potential approaches for mitigating these deficits. Here, we used rats to investigate the effects of short- and long-term dietary supplementation with the leucine metabolite β-hydroxy-β-methyl butyrate (HMB) on working memory and cognitive flexibility.

Methods: Beginning ∼12 months of age, male and female Long–Evans rats were given twice daily access to sipper tubes containing calcium HMB (450 mg/kg) or vehicle (285 mg/kg calcium lactate) in a sucrose solution (20% w/v). Supplementation continued for 1 or 7 months (middle- and old-age (OA) groups, respectively) before testing began. Working memory was assessed by requiring rats to respond on a previously sampled lever following various delays. Cognitive flexibility was assessed by training rats to earn food according to a visual strategy and then, once acquired, shifting to an egocentric response strategy.

Results: Treatment with HMB improved working memory performance in middle-age (MA) males and OA rats of both sexes. In the cognitive flexibility task, there was a significant age-dependent deficit in acquisition of the visual strategy that was not apparent in OA males treated with HMB. Furthermore, HMB ameliorated an apparent deficit in visual strategy acquisition in MA females.

Discussion: Together, these findings suggest that daily nutritional supplementation with HMB facilitates learning and improves working memory performance. As such, HMB supplementation may mitigate age-related cognitive deficits and may therefore be an effective tool to combat this undesirable feature of the aging process.

Keywords:

• Aging
• β-Hydroxy-β-methyl butyrate
• Working memory
• Cognitive flexibility
• Prefrontal cortex

Acknowledgments

The authors would like to thank Laura Cortes, Christopher Keeley, Nicole Kofsky, Joseph Brodsky, Brandon Redweik, Amin Ghane, Stephanie Boas, Susanne Nolan, Ronak Patel, Evan Jones, Paige Tieman, Madeline Lloyd, Hailey Mulliner, and Kyle Gruber for excellent technical assistance. This work was supported by a grant from Abbott Nutrition through the Center for Nutrition, Learning, and Memory at the University of Illinois.

Disclaimer statements

Contributors E.R.H. assisted with data collection, statistical analysis, interpreting data, and writing the manuscript. L.K.S. assisted with data collection, statistical analysis, interpreting data, and editing the manuscript. L.A.R., R.M.H., T.K., L.R.H., and D.G.K. assisted with data collection. J.M.J. designed the study, obtained funding for the project, assisted with data interpretation, and helped revise the manuscript. J.M.G. designed the study, obtained funding for the project, assisted with data analysis and interpretation, and helped with writing and revising the manuscript.

Funding None.

Conflicts of interest We would like to declare the possible conflict of interest. This research was funded by a grant from Abbott Nutrition through the Center for Nutrition, Learning, and Memory at the University of Illinois.

Ethics approval The research described in the manuscript is in compliance with APA ethical standards in the treatment of animal subjects and was approved by the Institutional Animal Care and Use Committee at the University of Illinois, Urbana–Champaign.

ORCID

Joshua M. Gulley http://orcid.org/0000-0003-3929-8791