Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey

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Abstract
Conventional studies of brain changes in normal aging have concentrated on gray matter as the locus for cognitive dysfunction. However, there is accumulating evidence from studies of normal aging in the rhesus monkey that changes in white matter may be a more critical factor in cognitive decline. Such changes include ultrastructural and biochemical evidence of myelin breakdown with age, as well as more recent magnetic resonance imaging of global loss of forebrain white matter volume and magnetic resonance diffusion tension imaging evidence of increased diffusivity in white matter. Moreover, many of these white matter changes correlate with age‐related cognitive dysfunction. Based on these diverse white matter findings, the present work utilized high‐density oligonucleotide microarrays to assess gene profile changes associated with age in the white matter of the corpus callosum. This approach identified several classes of genes that were differentially expressed in aging. Broadly characterized, these genes were predominantly related to an increase in stress factors and a decrease in cell function. The cell function changes included increased cell cycle inhibition and proteolysis, as well as decreased mitochondrial function, signal transduction, and protein translation. While most of these categories have previously been reported in functional brain aging, this is the first time they have been associated directly with white matter. Microarray analysis has also enabled the identification of neuroprotective response pathways activated by age in white matter, as well as several genes implicated in lifespan. Of particular interest was the identification of Klotho, a multifunctional protein that regulates phosphate and calcium metabolism, as well as insulin resistance, and is known to defend against oxidative stress and apoptosis. Combining the findings from the microarray study enabled us to formulate a model of white matter aging where specific genes are suggested as primary factors in disrupting white matter function. In conclusion, the overall changes described in this study could provide an explanation for aging changes in white matter that might be initiated or enhanced by an altered expression of life span associated genes such as Klotho.