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Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity
The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-a...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277648/ https://www.ncbi.nlm.nih.gov/pubmed/32443566 http://dx.doi.org/10.3390/biom10050780 |
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author | Menendez, Javier A. |
author_facet | Menendez, Javier A. |
author_sort | Menendez, Javier A. |
collection | PubMed |
description | The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time. |
format | Online Article Text |
id | pubmed-7277648 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-72776482020-06-12 Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity Menendez, Javier A. Biomolecules Opinion The biguanide metformin is the first drug to be tested as a gerotherapeutic in the clinical trial TAME (Targeting Aging with Metformin). The current consensus is that metformin exerts indirect pleiotropy on core metabolic hallmarks of aging, such as the insulin/insulin-like growth factor 1 and AMP-activated protein kinase/mammalian Target Of Rapamycin signaling pathways, downstream of its primary inhibitory effect on mitochondrial respiratory complex I. Alternatively, but not mutually exclusive, metformin can exert regulatory effects on components of the biologic machinery of aging itself such as chromatin-modifying enzymes. An integrative metabolo-epigenetic outlook supports a new model whereby metformin operates as a guardian of cell identity, capable of retarding cellular aging by preventing the loss of the information-theoretic nature of the epigenome. The ultimate anti-aging mechanism of metformin might involve the global preservation of the epigenome architecture, thereby ensuring cell fate commitment and phenotypic outcomes despite the challenging effects of aging noise. Metformin might therefore inspire the development of new gerotherapeutics capable of preserving the epigenome architecture for cell identity. Such gerotherapeutics should replicate the ability of metformin to halt the erosion of the epigenetic landscape, mitigate the loss of cell fate commitment, delay stochastic/environmental DNA methylation drifts, and alleviate cellular senescence. Yet, it remains a challenge to confirm if regulatory changes in higher-order genomic organizers can connect the capacity of metformin to dynamically regulate the three-dimensional nature of epigenetic landscapes with the 4th dimension, the aging time. MDPI 2020-05-18 /pmc/articles/PMC7277648/ /pubmed/32443566 http://dx.doi.org/10.3390/biom10050780 Text en © 2020 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Opinion Menendez, Javier A. Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity |
title | Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity |
title_full | Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity |
title_fullStr | Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity |
title_full_unstemmed | Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity |
title_short | Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity |
title_sort | metformin: sentinel of the epigenetic landscapes that underlie cell fate and identity |
topic | Opinion |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277648/ https://www.ncbi.nlm.nih.gov/pubmed/32443566 http://dx.doi.org/10.3390/biom10050780 |
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