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Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice
Mammalian sirtuin 6 (Sirt6) is a conserved NAD(+)-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here,...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825207/ https://www.ncbi.nlm.nih.gov/pubmed/29474172 http://dx.doi.org/10.7554/eLife.32127 |
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author | Ghosh, Shrestha Wong, Sheung Kin Jiang, Zhixin Liu, Baohua Wang, Yi Hao, Quan Gorbunova, Vera Liu, Xinguang Zhou, Zhongjun |
author_facet | Ghosh, Shrestha Wong, Sheung Kin Jiang, Zhixin Liu, Baohua Wang, Yi Hao, Quan Gorbunova, Vera Liu, Xinguang Zhou, Zhongjun |
author_sort | Ghosh, Shrestha |
collection | PubMed |
description | Mammalian sirtuin 6 (Sirt6) is a conserved NAD(+)-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6-deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging. |
format | Online Article Text |
id | pubmed-5825207 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-58252072018-02-26 Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice Ghosh, Shrestha Wong, Sheung Kin Jiang, Zhixin Liu, Baohua Wang, Yi Hao, Quan Gorbunova, Vera Liu, Xinguang Zhou, Zhongjun eLife Biochemistry and Chemical Biology Mammalian sirtuin 6 (Sirt6) is a conserved NAD(+)-dependent deacylase and mono-ADP ribosylase that is known to be involved in DNA damage repair, metabolic homeostasis, inflammation, tumorigenesis, and aging. Loss of Sirt6 in mice results in accelerated aging and premature death within a month. Here, we show that haploinsufficiency (i.e., heterozygous deletion) of Trp53 dramatically extends the lifespan of both female and male Sirt6-deficient mice. Haploinsufficiency of Trp53 in Sirt6-deficient mice rescues several age-related phenotypes of Sirt6-deficient mice, including reduced body size and weight, lordokyphosis, colitis, premature senescence, apoptosis, and bone marrow stem cell decline. Mechanistically, SIRT6 deacetylates p53 at lysine 381 to negatively regulate the stability and activity of p53. These findings establish that elevated p53 activity contributes significantly to accelerated aging in Sirt6-deficient mice. Our study demonstrates that p53 is a substrate of SIRT6, and highlights the importance of SIRT6-p53 axis in the regulation of aging. eLife Sciences Publications, Ltd 2018-02-23 /pmc/articles/PMC5825207/ /pubmed/29474172 http://dx.doi.org/10.7554/eLife.32127 Text en © 2018, Ghosh et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Biochemistry and Chemical Biology Ghosh, Shrestha Wong, Sheung Kin Jiang, Zhixin Liu, Baohua Wang, Yi Hao, Quan Gorbunova, Vera Liu, Xinguang Zhou, Zhongjun Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice |
title | Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice |
title_full | Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice |
title_fullStr | Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice |
title_full_unstemmed | Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice |
title_short | Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice |
title_sort | haploinsufficiency of trp53 dramatically extends the lifespan of sirt6-deficient mice |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825207/ https://www.ncbi.nlm.nih.gov/pubmed/29474172 http://dx.doi.org/10.7554/eLife.32127 |
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