The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain.

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain.

Phosphorylation of the Human DNA Glycosylase NEIL2 Is Affected by Oxidative Stress and Modulates Its Activity.

The DNA glycosylase NEIL2 plays a central role in maintaining genome integrity, in particular during oxidative stress, by recognizing oxidized base lesions and initiating repair of these via the base excision repair (BER) pathway. Post-translational modifications are important molecular switches that regulate and coordinate the BER pathway, and thereby enable a rapid and fine-tuned response to DNA damage. Here, we report for the first time that human NEIL2 is regulated by phosphorylation.

Bowhead NEIL1: molecular cloning, characterization, and enzymatic properties.

Nei Like DNA Glycosylase 1 (NEIL1) is a DNA glycosylase, which specifically processes oxidative DNA damage by initiating base excision repair. NEIL1 recognizes and removes bases, primarily oxidized pyrimidines, which have been damaged by endogenous oxidation or exogenous mutagenic agents. NEIL1 functions through a combined glycosylase/AP (apurinic/apyrimidinic)-lyase activity, whereby it cleaves the N-glycosylic bond between the DNA backbone and the damaged base via its glycosylase activity and hydrolysis of the DNA backbone through beta-delta elimination due to its AP-lyase activity.

Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians.

Oxidative stress is an important factor in age-associated neurodegeneration. Accordingly, mitochondrial dysfunction and genomic instability have been considered as key hallmarks of aging and have important roles in age-associated cognitive decline and neurodegenerative disorders. In order to evaluate whether maintenance of cognitive abilities at very old age is associated with key hallmarks of aging, we measured mitochondrial bioenergetics, mitochondrial DNA copy number and DNA repair capacity in peripheral blood mononuclear cells from centenarians in a Danish 1915 birth cohort (n = 120).

Human skeletal muscle CD90 fibro-adipogenic progenitors are associated with muscle degeneration in type 2 diabetic patients.

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)-the FAP.

Measuring the Activity of DNA Repair Enzymes in Isolated Mitochondria.

Nuclear, mitochondrial and plastidic DNA is constantly exposed to conditions, such as ultraviolet radiation or reactive oxygen species, which will induce chemical modifications to the nucleotides. Unless repaired, these modifications can lead to mutations, so the nucleus, mitochondria and plastids each contains a number of DNA repair systems. We here describe assays for measuring the enzyme activities associated with the base-excision repair pathway in potato tuber mitochondria.

Endothelin-1 induces a strong pressor effect in ball pythons (Python regius).

Endothelin-1 (ET-1) is a very potent vasoactive peptide released from endothelial cells, and ET-1 plays an important role in the maintenance and regulation of blood pressure in mammals. ET-1 signaling is mediated by two receptors: ET and ET. In mammals, ET receptors are located on vascular smooth muscle where they mediate vasoconstriction.

Studying Werner syndrome to elucidate mechanisms and therapeutics of human aging and age-related diseases.

Aging is a natural and unavoidable part of life. However, aging is also the primary driver of the dominant human diseases, such as cardiovascular disease, cancer, and neurodegenerative diseases, including Alzheimer's disease. Unraveling the sophisticated molecular mechanisms of the human aging process may provide novel strategies to extend 'healthy aging' and the cure of human aging-related diseases.

DNA repair in plant mitochondria - a complete base excision repair pathway in potato tuber mitochondria.

Mitochondria are one of the major sites of reactive oxygen species (ROS) production in the plant cell. ROS can damage DNA, and this damage is in many organisms mainly repaired by the base excision repair (BER) pathway. We know very little about DNA repair in plants especially in the mitochondria.

Two Cockayne Syndrome patients with a novel splice site mutation - clinical and metabolic analyses.

Cockayne Syndrome (CS) is a rare autosomal recessive disorder, which leads to neurodegeneration, growth failure and premature aging. Most of the cases are due to mutations in the ERCC6 gene, which encodes the protein CSB. CSB is involved in several functions including DNA repair and transcription.

NAD supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency.

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer's disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ mice have a reduced cerebral NAD/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment.

Role of Estrogen and Other Sex Hormones in Brain Aging. Neuroprotection and DNA Repair.

Aging is an inevitable biological process characterized by a progressive decline in physiological function and increased susceptibility to disease. The detrimental effects of aging are observed in all tissues, the brain being the most important one due to its main role in the homeostasis of the organism. As our knowledge about the underlying mechanisms of brain aging increases, potential approaches to preserve brain function rise significantly.

Mitophagy in neurodegeneration and aging.

Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis.

The Caenorhabditis elegans Werner syndrome protein participates in DNA damage checkpoint and DNA repair in response to CPT-induced double-strand breaks.

The RecQ helicases play roles in maintenance of genomic stability in species ranging from Escherichia coli to humans and interact with proteins involved in DNA metabolic pathways such as DNA repair, recombination, and replication. Our previous studies found that the Caenorhabditis elegans WRN-1 RecQ protein (a human WRN ortholog) exhibits ATP-dependent 3'-5' helicase activity and that the WRN-1 helicase is stimulated by RPA-1 on a long forked DNA duplex. However, the role of WRN-1 in response to S-phase associated with DSBs is unclear.

Unilateral ureteral obstruction induces DNA repair by APE1.

Ureteral obstruction is associated with oxidative stress and the development of fibrosis of the kidney parenchyma. Apurinic/apyrimidinic endonuclease (APE1) is an essential DNA repair enzyme for repair of oxidative DNA lesions and regulates several transcription factors. The aim of the present study was to investigate whether APE1 is regulated by acute (24 h) and chronic (7 days) unilateral ureteral obstruction (UUO).

Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals.

FOXO3A variation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3A variation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3A tagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92-93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/spine/hip/wrist) fracture.

Regulation of the human Suv3 helicase on DNA by inorganic cofactors.

Mitochondria are essential organelles and consequently proper expression and maintenance of the mitochondrial genome are indispensable for proper cell function. The mitochondrial Suv3 (SUPV3L1) helicase is known to have a central role in mitochondrial RNA metabolism and to be essential for maintenance of mitochondrial DNA stability. Here we have performed biochemical investigations to determine the potential regulation of the human Suv3 (hSuv3) helicase function by inorganic cofactors.

Associations of subjective vitality with DNA damage, cardiovascular risk factors and physical performance.

Aim: To examine associations of DNA damage, cardiovascular risk factors and physical performance with vitality, in middle-aged men. We also sought to elucidate underlying factors of physical performance by comparing physical performance parameters to DNA damage parameters and cardiovascular risk factors.

Methods: We studied 2487 participants from the Metropolit cohort of 11 532 men born in 1953 in the Copenhagen Metropolitan area.

Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis.

DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous recombinational repair (HRR), RecQ helicase activities (RECQ), telomere functioning and mitochondrial DNA processes.

Cockayne Syndrome group B protein stimulates NEIL2 DNA glycosylase activity.

Cockayne Syndrome is a segmental premature aging syndrome, which can be caused by loss of function of the CSB protein. CSB is essential for genome maintenance and has numerous interaction partners with established roles in different DNA repair pathways including transcription coupled nucleotide excision repair and base excision repair. Here, we describe a new interaction partner for CSB, the DNA glycosylase NEIL2.