DNA Damage Theory of Aging - Age-associated Accumulation of DNA Damage and Decline in Gene Expression - Brain

Brain

The adult brain is composed in large part of terminally differentiated non-dividing neurons. Many of the conspicuous features of aging reflect a decline in neuronal function. Accumulation of DNA damage with age in the mammalian brain has been reported during the period 1971 to the present in at least 29 studies, too many to describe here. A review of the role of DNA damage in aging, including a comprehensive summary of the studies showing DNA damage accumulation with age in brain, muscle, liver and kidney, was presented by Bernstein et al. (2008). Here, we mention only some recent studies involving rodents plus one human study. Rutten et al. (2007) showed that single-strand breaks accumulate in the mouse brain with age. Sen et al. (2007) showed that DNA damages which block the polymerase chain reaction in rat brain accumulate with age. Swain and Rao (2011) observed marked increases in several types of DNA damages in aging rat brain, including single-strand breaks, double-strand breaks and modified bases (8-OHdG and uracil). Wolf et al. (2005) also showed that the oxidative DNA damage 8-OHdG accumulates in rat brain with age. Similarly, it was shown that as humans age from 48–97 years, 8-OHdG accumulates in the brain (Mecocci et al., 1993).

Decrements in function were noted in aging human brain, where transcription of a set of evaluated genes declines with age from 40 to 106 years (Lu et al., 2004). These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. In the brain, promoters of genes with reduced expression have markedly increased DNA damage (Lu et al., 2004). In cultured human neurons, these gene promoters are selectively damaged by oxidative stress. Thus Lu et al. (2004) concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a program of brain aging that starts early in adult life.