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Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice
Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 compone...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004569/ https://www.ncbi.nlm.nih.gov/pubmed/35305083 http://dx.doi.org/10.18632/aging.203959 |
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author | Shi, Xiaofang Endicott, S. Joseph Miller, Richard A. |
author_facet | Shi, Xiaofang Endicott, S. Joseph Miller, Richard A. |
author_sort | Shi, Xiaofang |
collection | PubMed |
description | Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice. |
format | Online Article Text |
id | pubmed-9004569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Impact Journals |
record_format | MEDLINE/PubMed |
spelling | pubmed-90045692022-04-13 Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice Shi, Xiaofang Endicott, S. Joseph Miller, Richard A. Aging (Albany NY) Priority Research Paper Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice. Impact Journals 2022-03-19 /pmc/articles/PMC9004569/ /pubmed/35305083 http://dx.doi.org/10.18632/aging.203959 Text en Copyright: © 2022 Shi et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Shi, Xiaofang Endicott, S. Joseph Miller, Richard A. Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice |
title | Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice |
title_full | Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice |
title_fullStr | Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice |
title_full_unstemmed | Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice |
title_short | Regulation of mTOR complexes in long-lived growth hormone receptor knockout and Snell dwarf mice |
title_sort | regulation of mtor complexes in long-lived growth hormone receptor knockout and snell dwarf mice |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004569/ https://www.ncbi.nlm.nih.gov/pubmed/35305083 http://dx.doi.org/10.18632/aging.203959 |
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