Eleanor Roosevelt Institute, University of Denver, Denver, CO, USA.
Mech Ageing Dev. 2012 Apr;133(4):133-7. doi: 10.1016/j.mad.2011.10.001. Epub 2011 Oct 12.
Down syndrome is a condition of intellectual disability characterized by accelerated aging. As with other aging syndromes, evidence accumulated over the past several decades points to a DNA repair defect inherent in Down syndrome. This evidence has led us to suggest that Down syndrome results in reduced DNA base excision repair (BER) capacity, and that this contributes to the genomic instability and the aging phenotype of Down syndrome. We propose important roles for microRNA and/or folate metabolism and oxidative stress in the dysregulation of BER in Down syndrome. Further, we suggest these pathways are involved in the leukemogenesis of Down syndrome. We have reviewed the role of BER in the processing of oxidative stress, and the impact of folate depletion on BER capacity. Further, we have reviewed the role that loss of BER, specifically DNA polymerase beta, plays in accelerating the rate of aging. Like that seen in the DNA polymerase beta heterozygous mouse, the aging phenotype of Down syndrome is subtle, unlike the aging phenotypes seen in the classical progeroid syndromes and mouse models of aging. As such, Down syndrome may provide a model for elucidating some of the basic mechanisms of aging.
唐氏综合征是一种智力障碍疾病，其特征为加速衰老。与其他衰老综合征一样，过去几十年积累的证据表明唐氏综合征存在固有 DNA 修复缺陷。这一证据使我们提出唐氏综合征导致 DNA 碱基切除修复（BER）能力降低，并认为这导致了唐氏综合征的基因组不稳定性和衰老表型。我们提出了 microRNA 和/或叶酸代谢和氧化应激在唐氏综合征 BER 失调中的重要作用。此外，我们还提出这些途径参与唐氏综合征的白血病发生。我们已经回顾了 BER 在氧化应激处理以及叶酸耗竭对 BER 能力的影响中的作用。此外，我们还回顾了 BER 缺失（特别是 DNA 聚合酶β）在加速衰老速度中的作用。与在 DNA 聚合酶β杂合子小鼠中观察到的情况一样，唐氏综合征的衰老表型很微妙，与经典的早老综合征和衰老小鼠模型中观察到的衰老表型不同。因此，唐氏综合征可能为阐明一些衰老的基本机制提供模型。
