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Gene regulation and DNA damage in the ageing human brain

Author

Listed:
  • Tao Lu

    (The Children's Hospital and Harvard Medical School)

  • Ying Pan

    (The Children's Hospital and Harvard Medical School)

  • Shyan-Yuan Kao

    (The Children's Hospital and Harvard Medical School)

  • Cheng Li

    (Harvard School of Public Health)

  • Isaac Kohane

    (The Children's Hospital and Harvard Medical School)

  • Jennifer Chan

    (Brigham and Women's Hospital and Harvard Medical School)

  • Bruce A. Yankner

    (The Children's Hospital and Harvard Medical School)

Abstract

The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease1. The time in life when brain ageing begins is undefined2,3,4. Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.

Suggested Citation

  • Tao Lu & Ying Pan & Shyan-Yuan Kao & Cheng Li & Isaac Kohane & Jennifer Chan & Bruce A. Yankner, 2004. "Gene regulation and DNA damage in the ageing human brain," Nature, Nature, vol. 429(6994), pages 883-891, June.
    • Handle: RePEc:nat:nature:v:429:y:2004:i:6994:d:10.1038_nature02661
    DOI: 10.1038/nature02661
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    Cited by:

    1. Melissa G Naylor & Xihong Lin & Scott T Weiss & Benjamin A Raby & Christoph Lange, 2010. "Using Canonical Correlation Analysis to Discover Genetic Regulatory Variants," PLOS ONE, Public Library of Science, vol. 5(5), pages 1-6, May.
    2. Zuber Verena & Strimmer Korbinian, 2011. "High-Dimensional Regression and Variable Selection Using CAR Scores," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 10(1), pages 1-27, July.
    3. Mun-Gwan Hong & Amanda J Myers & Patrik K E Magnusson & Jonathan A Prince, 2008. "Transcriptome-Wide Assessment of Human Brain and Lymphocyte Senescence," PLOS ONE, Public Library of Science, vol. 3(8), pages 1-13, August.
    4. Raihan K Uddin & Shiva M Singh, 2013. "Hippocampal Gene Expression Meta-Analysis Identifies Aging and Age-Associated Spatial Learning Impairment (ASLI) Genes and Pathways," PLOS ONE, Public Library of Science, vol. 8(7), pages 1-16, July.
    5. Mike Males, 2015. "Age, Poverty, Homicide, and Gun Homicide," SAGE Open, , vol. 5(1), pages 21582440155, March.
    6. Di-Xian Wang & Zhao-Jun Dong & Sui-Xin Deng & Ying-Ming Tian & Yu-Jie Xiao & Xinran Li & Xiao-Ru Ma & Liang Li & Pengxiao Li & Hui-Zhong Chang & Longqi Liu & Fan Wang & Yang Wu & Xiang Gao & Shuang-Sh, 2023. "GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21," Nature Communications, Nature, vol. 14(1), pages 1-24, December.
    7. Masataka Kikuchi & Soichi Ogishima & Tadashi Miyamoto & Akinori Miyashita & Ryozo Kuwano & Jun Nakaya & Hiroshi Tanaka, 2013. "Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer’s Disease," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-1, November.

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