Gene regulation and DNA damage in the ageing human brain

Tao Lu, Ying Pan, Shyan-Yuan Kao, Cheng Li, Isaac Kohane, Jennifer Chan and Bruce A. Yankner ()
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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

Nature, 2004, vol. 429, issue 6994, 883-891

Abstract: 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.

Date: 2004
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DOI: 10.1038/nature02661

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