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

Benjamin Kioussis
, Camilla S.L. Tuttle
, Daniel S. Heard
, Brian K. Kennedy
, Nicola T. Lautenschlager
, Andrea B. Maier^*

^*Corresponding author for this work

Research output: Contribution to Journal › Review article › Academic › peer-review

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.

Original language	English
Article number	101302
Pages (from-to)	1-18
Number of pages	18
Journal	Ageing Research Reviews
Volume	67
Early online date	17 Feb 2021
DOIs	https://doi.org/10.1016/j.arr.2021.101302
Publication status	Published - May 2021

Bibliographical note

Funding Information:
An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy.

Funding Information:
An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy.

Publisher Copyright:
© 2021 The Author(s)

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy. An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy.

Keywords

Aging
Clinical trial
Cognition
Dementia
Organic chemicals
Therapeutics

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10.1016/j.arr.2021.101302

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Cite this

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

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 {\textquoteleft}metformin{\textquoteright}, {\textquoteleft}GLP1{\textquoteright}, {\textquoteleft}insulin{\textquoteright} and the dementias including {\textquoteleft}Alzheimer's disease{\textquoteright} and {\textquoteleft}Parkinson's disease{\textquoteright}. 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 {\textquoteleft}modulation of nutrient sensing pathway{\textquoteright} 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",

author = "Benjamin Kioussis and Tuttle, \{Camilla S.L.\} and Heard, \{Daniel S.\} and Kennedy, \{Brian K.\} and Lautenschlager, \{Nicola T.\} and Maier, \{Andrea B.\}",

note = "Funding Information: An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy. Funding Information: An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy. Publisher Copyright: {\textcopyright} 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

doi = "10.1016/j.arr.2021.101302",

language = "English",

volume = "67",

pages = "1--18",

journal = "Ageing Research Reviews",

issn = "1568-1637",

publisher = "Elsevier Ireland Ltd",

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T1 - Targeting impaired nutrient sensing with repurposed therapeutics to prevent or treat age-related cognitive decline and dementia

T2 - A systematic review

AU - Kioussis, Benjamin

AU - Tuttle, Camilla S.L.

AU - Heard, Daniel S.

AU - Kennedy, Brian K.

AU - Lautenschlager, Nicola T.

AU - Maier, Andrea B.

N1 - Funding Information: An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy. Funding Information: An unrestricted grant by the University of Melbourne supported the work. We thank Patrick Condron from the Brownless Biomedical Library, University of Melbourne, for his assistance with the search strategy. Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

KW - Aging

KW - Clinical trial

KW - Cognition

KW - Dementia

KW - Organic chemicals

KW - Therapeutics

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JO - Ageing Research Reviews

JF - Ageing Research Reviews

M1 - 101302

ER -

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

Abstract

Bibliographical note

Funding

Keywords

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