Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review

Benjamin Kioussis; Camilla S L Tuttle; Daniel S Heard; Brian K Kennedy; Nicola T Lautenschlager; Andrea B Maier

doi:10.1016/j.arr.2021.101302

Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia: A systematic review

Ageing Res Rev. 2021 May:67:101302. doi: 10.1016/j.arr.2021.101302. Epub 2021 Feb 17.

Authors

Benjamin Kioussis¹, Camilla S L Tuttle², Daniel S Heard³, Brian K Kennedy⁴, Nicola T Lautenschlager⁵, Andrea B Maier⁶

Affiliations

¹ Department of Medicine and Aged Care, @AgeMelbourne, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia; University Hospital Geelong, Barwon Health, Melbourne, Victoria, Australia.
² Department of Medicine and Aged Care, @AgeMelbourne, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia; Centre for Quantitative Neuroimaging, Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia.
³ Department of Medicine and Aged Care, @AgeMelbourne, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia; North West Mental Health, Melbourne Health, Melbourne, Victoria, Australia; Older Persons Mental Health Service, Canberra Health Services, Canberra, ACT, Australia.
⁴ Healthy Longevity Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore; Singapore Institute of Clinical Sciences, A⁎STAR, Singapore.
⁵ North West Mental Health, Melbourne Health, Melbourne, Victoria, Australia; Academic Unit for Psychiatry of Old Age, Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia.
⁶ Department of Medicine and Aged Care, @AgeMelbourne, Royal Melbourne Hospital, University of Melbourne, Victoria, Australia; Healthy Longevity Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore; Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Amsterdam, The Netherlands. Electronic address: a.b.maier@vu.nl.

PMID: 33609776
DOI: 10.1016/j.arr.2021.101302

Abstract

Background: Dementia is a debilitating syndrome that significantly impacts individuals over the age of 65 years. There are currently no disease-modifying treatments for dementia. Impairment of nutrient sensing pathways has been implicated in the pathogenesis of dementia, and may offer a novel treatment approach for dementia.

Aims: This systematic review collates all available evidence for Food and Drug Administration (FDA)-approved therapeutics that modify nutrient sensing in the context of preventing cognitive decline or improving cognition in ageing, mild cognitive impairment (MCI), and dementia populations.

Methods: PubMed, Embase and Web of Science databases were searched using key search terms focusing on available therapeutics such as 'metformin', 'GLP1', 'insulin' and the dementias including 'Alzheimer's disease' and 'Parkinson's disease'. Articles were screened using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). The risk of bias was assessed using the Cochrane Risk of Bias tool v 2.0 for human studies and SYRCLE's risk of bias tool for animal studies.

Results: Out of 2619 articles, 114 were included describing 31 different 'modulation of nutrient sensing pathway' therapeutics, 13 of which specifically were utilized in human interventional trials for normal ageing or dementia. Growth hormone secretagogues improved cognitive outcomes in human mild cognitive impairment, and potentially normal ageing populations. In animals, all investigated therapeutic classes exhibited some cognitive benefits in dementia models. While the risk of bias was relatively low in human studies, this risk in animal studies was largely unclear.

Conclusions: Modulation of nutrient sensing pathway therapeutics, particularly growth hormone secretagogues, have the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.

Keywords: Aging; Clinical trial; Cognition; Dementia; Organic chemicals; Therapeutics.

Publication types

Research Support, Non-U.S. Gov't
Review
Systematic Review

MeSH terms

Aged
Alzheimer Disease*
Cognitive Dysfunction* / drug therapy
Dementia*
Disease Progression
Humans
Nutrients