What’s the Cause of Normal Aging?—Part 2

Abstract & Commentary

Synopsis: These findings are amongst the most direct data to date that oxidative damage plays a critical role in normal human aging.

Source: Lu T, et al. Gene Regulation and DNA Damage in the Aging Human Brain. Nature. 2004;429(6994):883-891.

In the present report, Lu and colleagues examined postmortem frontal cortex samples taken from normal donors 26-106 years of age. They analyzed 30 samples in all, with Affeymatrix gene arrays, to determine how gene expression changed with age. Compared with people younger than 42, Lu et al found that in people older than 76, about 4% of the genes were differentially expressed in the frontal cortex. Many of these were downregulated, including genes involved in synaptic plasticity, long-term potentiation, and microtubular function. Another group of genes which were downregulated were those involved in mitochondrial function. Genes, which were upregulated included chaperones, antioxidant enzymes, and DNA repair genes.

Due to the induction of DNA repair mechanisms, Lu et al examined whether the gene expression changes were tied to DNA damage. They isolated genomic DNA under conditions to prevent in vitro oxidation and incubated it with enzymes that specifically excised damaged bases, particularly 8-oxoguanine. In using real time polymerase chain reaction, they were able to identify and quantify stretches of damaged DNA by their failure to amplify. Lu et al found that there was increased DNA damage in the genes, which were downregulated. This was particularly true in the promoter regions. This may be the case since they are not subject to transcription coupled repair, the major repair mechanism in neurons. Of 30 promoters examined, many showed an age-related increase in DNA damage by age 40, and all genes showed damage by 70. Lu et al then examined the effects of direct oxidative damage to the promoter regions in cultured human neuroblastoma cells in primary human cortical neurons treated for their mild oxidative stress. Again, they found that the genes that were downregulated in aging were damaged to a greater extent than genes that did not change in aged brain. Lastly, they examined whether a reduction in expression of some mitochondrial genes, that Lu et al observed in the aging brain, could induce DNA damage. They found that the decreases in the expression of these genes using siRNA, created oxidative damage to DNA.

Commentary

These findings are amongst the most direct data to date that oxidative damage plays a critical role in normal human aging. — M. Flint Beal

Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.