2. Academic Validation
  3. Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice

Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice

  • Elife. 2018 Feb 23;7:e32127. doi: 10.7554/eLife.32127.
Shrestha Ghosh 1 2,  Sheung Kin Wong 1 2,  Zhixin Jiang 1 2,  Baohua Liu 3,  Yi Wang 1,  Quan Hao 1,  Vera Gorbunova 4,  Xinguang Liu 5,  Zhongjun Zhou 1 2
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
  • 2 Shenzhen Institute of Research and Innovation, The University of Hong Kong, Pok Fu Lam, Hong Kong.
  • 3 School of Medicine, Shenzhen University, Shenzhen, China.
  • 4 Rochester Aging Research Center, University of Rochester, Rochester, United States.
  • 5 Institute for Aging Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China.
PMID: 29474172 DOI: 10.7554/eLife.32127
Abstract

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.

Keywords

SIRT6; Trp53; acetylation; biochemistry; chemical biology; developmental biology; human; lifespan extention; mice; mouse; premature aging; stem cells.

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