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Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment

Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that...

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Autores principales: Quarles, Ellen, Basisty, Nathan, Chiao, Ying Ann, Merrihew, Gennifer, Gu, Haiwei, Sweetwyne, Mariya T., Fredrickson, Jeanne, Nguyen, Ngoc‐Han, Razumova, Maria, Kooiker, Kristina, Moussavi‐Harami, Farid, Regnier, Michael, Quarles, Christopher, MacCoss, Michael, Rabinovitch, Peter S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996961/
https://www.ncbi.nlm.nih.gov/pubmed/31823466
http://dx.doi.org/10.1111/acel.13086
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author Quarles, Ellen
Basisty, Nathan
Chiao, Ying Ann
Merrihew, Gennifer
Gu, Haiwei
Sweetwyne, Mariya T.
Fredrickson, Jeanne
Nguyen, Ngoc‐Han
Razumova, Maria
Kooiker, Kristina
Moussavi‐Harami, Farid
Regnier, Michael
Quarles, Christopher
MacCoss, Michael
Rabinovitch, Peter S.
author_facet Quarles, Ellen
Basisty, Nathan
Chiao, Ying Ann
Merrihew, Gennifer
Gu, Haiwei
Sweetwyne, Mariya T.
Fredrickson, Jeanne
Nguyen, Ngoc‐Han
Razumova, Maria
Kooiker, Kristina
Moussavi‐Harami, Farid
Regnier, Michael
Quarles, Christopher
MacCoss, Michael
Rabinovitch, Peter S.
author_sort Quarles, Ellen
collection PubMed
description Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that short‐term (10‐week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. In this report, we demonstrate that the rapamycin‐dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8 weeks after cessation of an 8‐week treatment of rapamycin in both male and female 22‐ to 24‐month‐old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after 8 further weeks without the drug. However, rapamycin did lead to a persistent increase in abundance of electron transport chain (ETC) complex components, most of which belonged to Complex I. Although ETC protein abundance and Complex I activity were each differentially affected in males and females, the ratio of Complex I activity to Complex I protein abundance was equally and persistently reduced after rapamycin treatment in both sexes. Thus, rapamycin treatment in the aged mice persistently improved diastolic function and myocardial stiffness, persistently altered the cardiac proteome in the absence of persistent metabolic changes, and led to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short‐term treatments.
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spelling pubmed-69969612020-02-05 Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment Quarles, Ellen Basisty, Nathan Chiao, Ying Ann Merrihew, Gennifer Gu, Haiwei Sweetwyne, Mariya T. Fredrickson, Jeanne Nguyen, Ngoc‐Han Razumova, Maria Kooiker, Kristina Moussavi‐Harami, Farid Regnier, Michael Quarles, Christopher MacCoss, Michael Rabinovitch, Peter S. Aging Cell Original Articles Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that short‐term (10‐week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. In this report, we demonstrate that the rapamycin‐dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8 weeks after cessation of an 8‐week treatment of rapamycin in both male and female 22‐ to 24‐month‐old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after 8 further weeks without the drug. However, rapamycin did lead to a persistent increase in abundance of electron transport chain (ETC) complex components, most of which belonged to Complex I. Although ETC protein abundance and Complex I activity were each differentially affected in males and females, the ratio of Complex I activity to Complex I protein abundance was equally and persistently reduced after rapamycin treatment in both sexes. Thus, rapamycin treatment in the aged mice persistently improved diastolic function and myocardial stiffness, persistently altered the cardiac proteome in the absence of persistent metabolic changes, and led to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short‐term treatments. John Wiley and Sons Inc. 2019-12-10 2020-02 /pmc/articles/PMC6996961/ /pubmed/31823466 http://dx.doi.org/10.1111/acel.13086 Text en © 2019 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 Articles
Quarles, Ellen
Basisty, Nathan
Chiao, Ying Ann
Merrihew, Gennifer
Gu, Haiwei
Sweetwyne, Mariya T.
Fredrickson, Jeanne
Nguyen, Ngoc‐Han
Razumova, Maria
Kooiker, Kristina
Moussavi‐Harami, Farid
Regnier, Michael
Quarles, Christopher
MacCoss, Michael
Rabinovitch, Peter S.
Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
title Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
title_full Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
title_fullStr Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
title_full_unstemmed Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
title_short Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
title_sort rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996961/
https://www.ncbi.nlm.nih.gov/pubmed/31823466
http://dx.doi.org/10.1111/acel.13086
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