Bio-Metal Dyshomeostasis-Associated Acceleration of Aging and Cognitive Decline in Down Syndrome

Down syndrome (DS), which is caused by triplication of human chromosome 21 (Hsa21), exhibits some physical signs of accelerated aging, such as graying hair, wrinkles and menopause at an unusually young age. Development of early-onset Alzheimer's disease, which is frequently observed in adults with DS, is also suggested to occur due to accelerated aging of the brain. Several Hsa21 genes are suggested to be responsible for the accelerated aging in DS. In this review, we summarize these candidate genes and possible molecular mechanisms, and discuss the related key factors. In particular, we focus on copper, an essential trace element, as a key factor in the accelerated aging in DS. In addition, the physiological significance of brain copper accumulation in cognitive impairment is discussed. We herein provide our hypothesis on the copper dyshomeostasis-based pathophysiology of DS.