Crosstalk between short- and long-term calorie restriction transcriptomic signatures with anxiety-like behavior, aging, and neurodegeneration: implications for drug repurposing

Agnes Hazi; Esmaeil Ebrahimie; Elizabeth A Levay; Manijeh Mohammadi-Dehcheshmeh; Matt Zelko; Antonina Govic; Helen Nasser

doi:10.3389/fnbeh.2023.1257881

Crosstalk between short- and long-term calorie restriction transcriptomic signatures with anxiety-like behavior, aging, and neurodegeneration: implications for drug repurposing

Front Behav Neurosci. 2023 Nov 29:17:1257881. doi: 10.3389/fnbeh.2023.1257881. eCollection 2023.

Authors

Agnes Hazi¹, Esmaeil Ebrahimie^{2

3

4}, Elizabeth A Levay^{1

5}, Manijeh Mohammadi-Dehcheshmeh^{2

3}, Matt Zelko⁵, Antonina Govic^{1

5}, Helen Nasser^{1

5}

Affiliations

¹ School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia.
² Genomics Research Platform, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia.
³ School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide, SA, Australia.
⁴ School of BioSciences, The University of Melbourne, Melbourne, VIC, Australia.
⁵ Epigenes Australia Pty Ltd., Melbourne, VIC, Australia.

Abstract

Calorie restriction (CR) is considered an effective intervention for anxiety, aging, and obesity. We investigated the effects of short- and long-term CR on behavior as well as transcriptome profiles in the hypothalamus, amygdala, prefrontal cortex, pituitary, and adrenal glands of Hooded Wistar and Long Evans male rats. A reduction in anxiety-like behavior, as assessed via the elevated plus maze, was observed in both short- and long-term CR. Despite this, short- and long-term CR regulated different sets of genes, leading to distinct transcriptomic signatures. The employed models were able to simultaneously analyze categorical and numerical variables, evaluating the effect of tissue type along with expression data. In all tissues, transcription factors, zinc finger protein 45-like and zinc finger BTB domain-containing two, were the top selected genes by the models in short and long-term CR treatments, respectively. Text mining identified associations between genes of the short-term CR signature and neurodegeneration, stress, and obesity and between genes of the long-term signature and the nervous system. Literature mining-based drug repurposing showed that alongside known CR mimetics such as resveratrol and rapamycin, candidates not typically associated with CR mimetics may be repurposed based on their interaction with transcriptomic signatures of CR. This study goes some way to unravelling the global effects of CR and opens new avenues for treatment for emotional disorders, neurodegeneration, and obesity.

Keywords: aging; anxiety-like behavior; calorie restriction; energy uptake; functional genomics; neurodegeneration; obesity.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study received funding from Epigenes Australia through a La Trobe University Collaborative Research Agreement (LTU project number: #20115). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. This study was supported by Oracle for Research Grant (Award Number: CPQ-2618253) and by the use of the Nectar Research Cloud, a collaborative Australian research platform supported by the National Collaborative Research Infrastructure Strategy (NCRIS). Additionally, this research was supported by resources provided by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia.