Cargando…

Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus

Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age‐related cognitive impairment. However, metformin's therapeutic use as an anti‐aging drug is yet to be accepted because of conflicting animal and huma...

Descripción completa

Detalles Bibliográficos
Autores principales: Kodali, Maheedhar, Attaluri, Sahithi, Madhu, Leelavathi N., Shuai, Bing, Upadhya, Raghavendra, Gonzalez, Jenny Jaimes, Rao, Xiaolan, Shetty, Ashok K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884047/
https://www.ncbi.nlm.nih.gov/pubmed/33443781
http://dx.doi.org/10.1111/acel.13277
_version_ 1783651332357357568
author Kodali, Maheedhar
Attaluri, Sahithi
Madhu, Leelavathi N.
Shuai, Bing
Upadhya, Raghavendra
Gonzalez, Jenny Jaimes
Rao, Xiaolan
Shetty, Ashok K.
author_facet Kodali, Maheedhar
Attaluri, Sahithi
Madhu, Leelavathi N.
Shuai, Bing
Upadhya, Raghavendra
Gonzalez, Jenny Jaimes
Rao, Xiaolan
Shetty, Ashok K.
author_sort Kodali, Maheedhar
collection PubMed
description Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age‐related cognitive impairment. However, metformin's therapeutic use as an anti‐aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen‐month‐old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate‐activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
format Online
Article
Text
id pubmed-7884047
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-78840472021-02-19 Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus Kodali, Maheedhar Attaluri, Sahithi Madhu, Leelavathi N. Shuai, Bing Upadhya, Raghavendra Gonzalez, Jenny Jaimes Rao, Xiaolan Shetty, Ashok K. Aging Cell Original Paper Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age‐related cognitive impairment. However, metformin's therapeutic use as an anti‐aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen‐month‐old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate‐activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain. John Wiley and Sons Inc. 2021-01-14 2021-02 /pmc/articles/PMC7884047/ /pubmed/33443781 http://dx.doi.org/10.1111/acel.13277 Text en © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Paper
Kodali, Maheedhar
Attaluri, Sahithi
Madhu, Leelavathi N.
Shuai, Bing
Upadhya, Raghavendra
Gonzalez, Jenny Jaimes
Rao, Xiaolan
Shetty, Ashok K.
Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
title Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
title_full Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
title_fullStr Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
title_full_unstemmed Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
title_short Metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
title_sort metformin treatment in late middle age improves cognitive function with alleviation of microglial activation and enhancement of autophagy in the hippocampus
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884047/
https://www.ncbi.nlm.nih.gov/pubmed/33443781
http://dx.doi.org/10.1111/acel.13277
work_keys_str_mv AT kodalimaheedhar metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT attalurisahithi metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT madhuleelavathin metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT shuaibing metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT upadhyaraghavendra metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT gonzalezjennyjaimes metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT raoxiaolan metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus
AT shettyashokk metformintreatmentinlatemiddleageimprovescognitivefunctionwithalleviationofmicroglialactivationandenhancementofautophagyinthehippocampus