Reynolds Oklahoma Center on Aging

Oklahoma City, OK, United States

Reynolds Oklahoma Center on Aging

Oklahoma City, OK, United States
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Hadad N.,Oklahoma Center for Neuroscience | Hadad N.,Reynolds Oklahoma Center on Aging | Masser D.R.,Reynolds Oklahoma Center on Aging | Masser D.R.,The University of Oklahoma Health Sciences Center | And 23 more authors.
Epigenetics and Chromatin | Year: 2016

Background: Changes to the epigenome with aging, and DNA modifications in particular, have been proposed as a central regulator of the aging process, a predictor of mortality, and a contributor to the pathogenesis of age-related diseases. In the central nervous system, control of learning and memory, neurogenesis, and plasticity require changes in cytosine methylation and hydroxymethylation. Although genome-wide decreases in methylation with aging are often reported as scientific dogma, primary research reports describe decreases, increases, or lack of change in methylation and hydroxymethylation and their principle regulators, DNA methyltransferases and ten-eleven translocation dioxygenases in the hippocampus. Furthermore, existing data are limited to only male animals. Results: Through examination of the hippocampus in young, adult, and old male and female mice by antibody-based, pyrosequencing, and whole-genome oxidative bisulfite sequencing methods, we provide compelling evidence that contradicts the genomic hypomethylation theory of aging. We also demonstrate that expression of DNA methyltransferases and ten-eleven translocation dioxygenases is not differentially regulated with aging or between the sexes, including the proposed cognitive aging regulator DNMT3a2. Using oxidative bisulfite sequencing that discriminates methylation from hydroxymethylation and by cytosine (CG and non-CG) context, we observe sex differences in average CG methylation and hydroxymethylation of the X chromosome, and small age-related differences in hydroxymethylation of CG island shores and shelves, and methylation of promoter regions. Conclusion: These findings clarify a long-standing misconception of the epigenomic response to aging and demonstrate the need for studies of base-specific methylation and hydroxymethylation with aging in both sexes. © 2016 The Author(s).


Rindler P.M.,Oklahoma Medical Research Foundation | Plafker S.M.,Oklahoma Medical Research Foundation | Plafker S.M.,University of Oklahoma | Szweda L.I.,University of Oklahoma | And 4 more authors.
Journal of Biological Chemistry | Year: 2013

Background: High dietary fat is linked to cardiac oxidative stress, however, little is known about the endogenous antioxidant response. Results: High fat feeding and fasting rapidly up-regulate catalase. Conclusion: Up-regulation of catalase is designed to protect mitochondria from oxidative damage while not perturbing H2O2-mediated signaling. Significance: Coupling fatty acid oxidation to H2O2 production creates a mechanism for sensing and communicating diet composition. Obesity is a predictor of diabetes and cardiovascular disease. One consequence of obesity is dyslipidemia characterized by high blood triglycerides. It has been proposed that oxidative stress, driven by utilization of lipids for energy, contributes to these diseases. The effects of oxidative stress are mitigated by an endogenous antioxidant enzyme network, but little is known about its response to high fat utilization. Our experiments used a multiplexed quantitative proteomics method to measure antioxidant enzyme expression in heart tissue in a mouse model of diet-induced obesity. This experiment showed a rapid and specific up-regulation of catalase protein, with subsequent assays showing increases in activity and mRNA. Catalase, traditionally considered a peroxisomal protein, was found to be present in cardiac mitochondria and significantly increased in content and activity during high fat feeding. These data, coupled with the fact that fatty acid oxidation enhances mitochondrialH 2O2 production, suggest that a localized catalase increase is needed to consume excessive mitochondrial H2O2 produced by increased fat metabolism. To determine whether the catalase-specific response is a common feature of physiological conditions that increase blood triglycerides and fatty acid oxidation, we measured changes in antioxidant expression in fasted versus fed mice. Indeed, a similar specific catalase increase was observed in mice fasted for 24 h. Our findings suggest a fundamental metabolic process in which catalase expression is regulated to prevent damage while preserving anH2O2-mediated sensing of diet composition that appropriately adjusts insulin sensitivity in the short term as needed to prioritize lipid metabolism for complete utilization. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.


PubMed | Reynolds Oklahoma Center on Aging, The University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation
Type: Journal Article | Journal: Age (Dordrecht, Netherlands) | Year: 2016

Epigenetic regulation through DNA methylation (5mC) plays an important role in development, aging, and a variety of diseases. Genome-wide studies of base- and strand-specific 5mC are limited by the extensive sequencing required. Targeting bisulfite sequencing to specific genomic regions through sequence capture with complimentary oligonucleotide probes retains the advantages of bisulfite sequencing while focusing sequencing reads on regions of interest, enables analysis of more samples by decreasing the amount of sequence required per sample, and provides base- and strand-specific absolute quantitation of CG and non-CG methylation levels. As an example, an oligonucleotide capture set to interrogate 5mC levels in all rat RefSeq gene promoter regions (18,814) and CG islands, shores, and shelves (18,411) was generated. Validation using whole-genome methylation standards and biological samples demonstrates enrichment of the targeted regions and accurate base-specific quantitation of CG and non-CG methylation for both forward and reverse genomic strands. A total of 170Mb of the rat genome is covered including 6.6 million CGs and over 67 million non-CG sites, while reducing the amount of sequencing required by ~85% as compared to existing whole-genome sequencing methods. This oligonucleotide capture targeting approach and quantitative validation workflow can also be applied to any genome of interest.


PubMed | The University of Oklahoma Health Sciences Center, Oklahoma Center for Neuroscience, Reynolds Oklahoma Center on Aging, Pennsylvania State University and 2 more.
Type: | Journal: Epigenetics & chromatin | Year: 2016

Changes to the epigenome with aging, and DNA modifications in particular, have been proposed as a central regulator of the aging process, a predictor of mortality, and a contributor to the pathogenesis of age-related diseases. In the central nervous system, control of learning and memory, neurogenesis, and plasticity require changes in cytosine methylation and hydroxymethylation. Although genome-wide decreases in methylation with aging are often reported as scientific dogma, primary research reports describe decreases, increases, or lack of change in methylation and hydroxymethylation and their principle regulators, DNA methyltransferases and ten-eleven translocation dioxygenases in the hippocampus. Furthermore, existing data are limited to only male animals.Through examination of the hippocampus in young, adult, and old male and female mice by antibody-based, pyrosequencing, and whole-genome oxidative bisulfite sequencing methods, we provide compelling evidence that contradicts the genomic hypomethylation theory of aging. We also demonstrate that expression of DNA methyltransferases and ten-eleven translocation dioxygenases is not differentially regulated with aging or between the sexes, including the proposed cognitive aging regulator DNMT3a2. Using oxidative bisulfite sequencing that discriminates methylation from hydroxymethylation and by cytosine (CG and non-CG) context, we observe sex differences in average CG methylation and hydroxymethylation of the X chromosome, and small age-related differences in hydroxymethylation of CG island shores and shelves, and methylation of promoter regions.These findings clarify a long-standing misconception of the epigenomic response to aging and demonstrate the need for studies of base-specific methylation and hydroxymethylation with aging in both sexes.


Ungvari Z.,Reynolds Oklahoma Center on Aging | Ungvari Z.,The University of Oklahoma Health Sciences Center | Bailey-Downs L.,Reynolds Oklahoma Center on Aging | Bailey-Downs L.,The University of Oklahoma Health Sciences Center | And 14 more authors.
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2011

Aging promotes oxidative stress in vascular endothelial and smooth muscle cells, which contribute to the development of cardiovascular diseases. NF-E2-related factor 2 (Nrf2) is a transcription factor, which is activated by reactive oxygen species in the vasculature of young animals, leading to adaptive upregulation of numerous reactive oxygen species detoxifying and antioxidant genes. The present study was designed to elucidate age-associated changes in the homeostatic role of Nrf2-driven free radical detoxification mechanisms in the vasculature of nonhuman primates. We found that carotid arteries of aged rhesus macaques (Macaca mulatta, age: ≥20 years) exhibit significant oxidative stress (as indicated by the increased 8-iso-PGF2α and 4-HNE content and decreased glutathione and ascorbate levels) as compared with vessels of young macaques (age: ∼10 years) that is associated with activation of the redox-sensitive proinflammatory transcription factor, nuclear factor-kappaB. However, age-related oxidative stress does not activate Nrf2 and does not induce Nrf2 target genes (NQO1, GCLC, and HMOX1). In cultured vascular smooth muscle cells (VSMCs) derived from young M mulatta, treatment with H 2O 2 and high glucose significantly increases transcriptional activity of Nrf2 and upregulates the expression of Nrf2 target genes. In contrast, in cultured vascular smooth muscle cells cells derived from aged macaques, H 2O 2- and high glucose-induced Nrf2 activity and Nrf2-driven gene expression are blunted. High glucose-induced H 2O 2 production was significantly increased in aged vascular smooth muscle cells compared with that in vascular smooth muscle cells from young M mulatta. Taken together, aging is associated with Nrf2 dysfunction in M mulatta arteries, which likely exacerbates age-related cellular oxidative stress, promoting nuclear factor-kappaB activation and vascular inflammation in aging. © The Author 2011. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.


Sonntag W.E.,Reynolds Oklahoma Center on Aging | Csiszar A.,Reynolds Oklahoma Center on Aging | De Cabo R.,U.S. National Institute on Aging | Ferrucci L.,U.S. National Institute on Aging | Ungvari Z.,Reynolds Oklahoma Center on Aging
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2012

Because the initial reports demonstrating that circulating growth hormone and insulin-like growth factor-1 decrease with age in laboratory animals and humans, there have been numerous studies related to the importance of these hormones for healthy aging. Nevertheless, the role of these potent anabolic hormones in the genesis of the aging phenotype remains controversial. In this chapter, we review the studies demonstrating the beneficial and deleterious effects of growth hormone and insulin-like growth factor-1 deficiency and explore their effects on specific tissues and pathology as well as their potentially unique effects early during development. Based on this review, we conclude that the perceived contradictory roles of growth hormone and insulin-like growth factor-1 in the genesis of the aging phenotype should not be interpreted as a controversy on whether growth hormone or insulin-like growth factor-1 increases or decreases life span but rather as an opportunity to explore the complex roles of these hormones during specific stages of the life span. © 2011 The Author.


Masser D.R.,Penn State College of Medicine | Masser D.R.,University of Oklahoma | Masser D.R.,Reynolds Oklahoma Center on Aging | VanGuilder Starkey H.D.,Penn State College of Medicine | And 6 more authors.
Experimental Eye Research | Year: 2014

Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition. © 2014 Elsevier Ltd.


Gardner A.W.,Reynolds Oklahoma Center on Aging | Waldstein S.R.,University of Maryland Baltimore County | Montgomery P.S.,Reynolds Oklahoma Center on Aging | Zhao Y.D.,The University of Oklahoma Health Sciences Center
Journal of Vascular Surgery | Year: 2016

Background We determined whether scores on a cognitive screening measure were associated with the primary outcome measure of peak walking time (PWT) and with secondary outcome measures related to mobility, community-based ambulation, health-related quality of life (QoL), and vascular function in patients with claudication and peripheral artery disease (PAD). Methods Gross cognitive status of 246 PAD patients was assessed with the Mini-Mental State Examination (MMSE) questionnaire. Patients were grouped according to whether they had a perfect MMSE score of 30 points (n = 123) or whether they missed one or more points (n = 123). Patients were characterized on numerous outcomes, including PWT during a treadmill test and QoL. Results Compared with the group with the higher MMSE scores, there was a trend for lower PWT in the group with the lower MMSE scores (P =.06) after adjusting for age, sex, race, and education level (model 1), which became significant (380 ± 250 seconds vs 460 ± 270 seconds; P <.05) after adjusting for model 1 plus coronary artery disease, chronic obstructive pulmonary disease, and arthritis (model 2). Multiple domains of QoL were lower (P <.05) in the group with the lower MMSE scores after adjusting for model 1, but only mental health remained lower (75 ± 20% vs 80 ± 5%; P =.02) after further adjustment with model 2. Conclusions In symptomatic patients with PAD, lower cognitive screening scores were associated with greater ambulatory impairment than in patients with higher MMSE scores. Furthermore, worse cognitive status was associated with lower scores in multiple dimensions of health-related QoL, all of which except mental health were explained by the comorbid conditions of coronary artery disease, chronic obstructive pulmonary disease, and arthritis. The clinical significance is that there is a need for enhanced cognitive and mental health screening as potential indicators of poor outcome among symptomatic patients with PAD. Furthermore, patients identified as having worse cognitive status might be in greatest need of intervention to improve ambulation and QoL related to mental health. Copyright © 2016 by the Society for Vascular Surgery. Published by Elsevier Inc.


PubMed | Reynolds Oklahoma Center on Aging
Type: | Journal: Annals of the New York Academy of Sciences | Year: 2011

Cardiovascular diseases are the most common cause of death among the elderly in the Western world. Resveratrol (3,5,4-trihydroxystilbene) is a plant-derived polyphenol that was shown to exert diverse anti-aging activity mimicking some of the molecular and functional effects of caloric restriction. This mini-review focuses on the molecular and cellular mechanisms activated by resveratrol in the vascular system, and explores the links between its anti-oxidative and anti-inflammatory effects, which could be exploited for the prevention or amelioration of vascular aging in the elderly.


PubMed | Reynolds Oklahoma Center on Aging, The University of Oklahoma Health Sciences Center and University of Maryland Baltimore County
Type: Journal Article | Journal: Journal of vascular surgery | Year: 2015

We determined whether scores on a cognitive screening measure were associated with the primary outcome measure of peak walking time (PWT) and with secondary outcome measures related to mobility, community-based ambulation, health-related quality of life (QoL), and vascular function in patients with claudication and peripheral artery disease (PAD).Gross cognitive status of 246 PAD patients was assessed with the Mini-Mental State Examination (MMSE) questionnaire. Patients were grouped according to whether they had a perfect MMSE score of 30 points (n = 123) or whether they missed one or more points (n = 123). Patients were characterized on numerous outcomes, including PWT during a treadmill test and QoL.Compared with the group with the higher MMSE scores, there was a trend for lower PWT in the group with the lower MMSE scores (P = .06) after adjusting for age, sex, race, and education level (model 1), which became significant (380 250 seconds vs 460 270 seconds; P < .05) after adjusting for model 1 plus coronary artery disease, chronic obstructive pulmonary disease, and arthritis (model 2). Multiple domains of QoL were lower (P < .05) in the group with the lower MMSE scores after adjusting for model 1, but only mental health remained lower (75 20% vs 80 5%; P = .02) after further adjustment with model 2.In symptomatic patients with PAD, lower cognitive screening scores were associated with greater ambulatory impairment than in patients with higher MMSE scores. Furthermore, worse cognitive status was associated with lower scores in multiple dimensions of health-related QoL, all of which except mental health were explained by the comorbid conditions of coronary artery disease, chronic obstructive pulmonary disease, and arthritis. The clinical significance is that there is a need for enhanced cognitive and mental health screening as potential indicators of poor outcome among symptomatic patients with PAD. Furthermore, patients identified as having worse cognitive status might be in greatest need of intervention to improve ambulation and QoL related to mental health.

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