Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging

@article{Patterson2012DownSA,
  title={Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging},
  author={David Patterson and Diane C. Cabelof},
  journal={Mechanisms of Ageing and Development},
  year={2012},
  volume={133},
  pages={133-137}
}
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… 
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The Impact Of Down Syndrome And Folate Depletion On Genomic Stabilizing Pathways Of Lymphoblastoid Cells
TLDR
This study investigates more to propose a mechanism of folate deficiency and POLβ inhibition derived from high dosage of MIR155 and CBS genes, which is hypothesized to provoke some kind of metabolic imbalance in DS by which may explain the reduced activity of BER and reduced thymidine incorporation in DS lymphocytes.
Down syndrome, accelerated aging and immunosenescence
TLDR
This review summarizes knowledge on immunologic disturbances commonly observed in subjects with Down syndrome, and in innate and adaptive immunity, as well as regarding chronic inflammation, and discusses the role of accelerated aging in these observed abnormalities.
DNA Hydroxymethylation Levels Are Altered in Blood Cells From Down Syndrome Persons Enrolled in the MARK-AGE Project
TLDR
Investigation of the levels of 5-hydroxymethylcytosine and of the Ten-eleven translocation dioxygenase enzymes found a decrease, indicating that aberrant DNA methylation patterns in DS, which may have consequences on the transcriptional status of immune cells, may be due to a global disturbance of methylation control in DS.
Defective DNA repair and increased chromatin binding of DNA repair factors in Down syndrome fibroblasts.
TLDR
It is reported that DS fibroblasts from both fetal and adult donors show the presence of oxidative DNA base damage, and activation of a DNA damage response (DDR), already during unperturbed growth conditions, indicating that DS cells exhibit a BER deficiency, which is associated with prolonged chromatin association of core BER factors.
Epigenetic signature in persons with Down Syndrome
TLDR
An epigenetic signature of Down Syndrome in blood cells that sustains a link between developmental defects and disease phenotype, including segmental premature aging is identified.
DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes
TLDR
It is demonstrated that a modest decrement in base excision repair capacity can render the brain more vulnerable to AD-related molecular and cellular alterations.
Accelerated epigenetic aging in Down syndrome
TLDR
A quantitative molecular marker of aging (known as the epigenetic clock) is utilized to demonstrate that trisomy 21 significantly increases the age of blood and brain tissue in Down Syndrome.
Metabolomics of Mammalian and Cellular Models of Aging
TLDR
Changes in the both global and targeted metabolomics in the brains of the Ts65Dn mouse are reported, and long-term treatment with microencapsulated dietary rapamycin changes the metabolomic profiles in a manner consistent with increases in healthspan.
Loss of DNA polymerase β induces cellular senescence
TLDR
It is found that primary fibroblasts from Down syndrome individuals exhibit greater SA‐β‐gal staining, increased p16 transcript abundance, and a robust increase in the number of senescent cells compared to wild‐type, demonstrating that loss DNA polymerase β is sufficient to induce senescence.
Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging
TLDR
Using HPLC coupled with electrochemical detection, it is identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age, and demonstrates that prolonged treatment with rapamycin reduces accumulation of toxic metabolites in aged mice.
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TLDR
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TLDR
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