Gene regulation and DNA damage in the ageing human brain.
The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease. The time in life when brain ageing begins is undefined. 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.
Lu
Tao
T
Department of Neurology and Division of Neuroscience, The Children's Hospital and Harvard Medical School, Enders 260,300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Pan
Ying
Y
Kao
Shyan-Yuan
SY
Li
Cheng
C
Kohane
Isaac
I
Chan
Jennifer
J
Yankner
Bruce A
BA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000975:Antioxidants / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D007858:Learning; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
D000975:Antioxidants; D002118:Calcium