1. Department of Neurology and Division of Neuroscience, The Children's Hospital and Harvard Medical School, Enders 260,300 Longwood Avenue, Boston, Massachusetts 02115, USA
2. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA
3. Department of Medicine, The Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
4. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Bruce A. Yankner¹ Email: Bruce.Yankner@childrens.harvard.edu

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 undefined^{2, 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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