Gene regulation and DNA damage in the ageing human brain

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.

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Figure 1: Ageing and gene expression in the human brain.
Figure 2: Confirmation of microarray results for synaptic, calcium homeostasis and transport-related genes.
Figure 3: DNA damage in the ageing human cortex.
Figure 4: Promoters of age-downregulated genes show increased vulnerability to oxidative DNA damage.

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Acknowledgements

We thank G. Verdine and D. Gabuzda for discussions, and M. Yuan, S. Weninger, P. Stieg, P. Dickes, C. Geula and L.-W. Jin for assistance with procurement and dissection of tissue samples. We also acknowledge the Kathleen Price Bryan Brain Bank at Duke University, the Harvard Brain Tissue Resource Center, the Massachusetts General Hospital ADRC Brain Bank, the University of Washington Brain Bank, and the University of Maryland Brain Bank for providing tissue samples. This work was supported in part by grants from the NIH (NIA and NINDS) to B.A.Y. T.L. was supported by a fellowship from the National Institute on Aging, and S.Y.K. was supported by a fellowship from the Leukemia and Lymphoma Society.

Author information

Correspondence to Bruce A. Yankner.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Methods (DOC 58 kb)

Supplementary Figure 1

Effects of limited oxidative stress and hOGG1 overexpression on cell survival. (PDF 176 kb)

Supplementary Figure 2

Knockdown of mitochondrial F1 ATP synthase α increases DNA damage. (PDF 239 kb)

Supplementary Table 1

Human brain samples (DOC 33 kb)

Supplementary Table 2

Age-regulated genes (XLS 84 kb)

Supplementary Table 3

Significance analysis of microarrays (XLS 867 kb)

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Lu, T., Pan, Y., Kao, S. et al. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883–891 (2004). https://doi.org/10.1038/nature02661

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