Publications by authors named "William E Sonntag"

137 Publications

IGF1R signaling regulates astrocyte-mediated neurovascular coupling in mice: implications for brain aging.

Geroscience 2021 Mar 6. Epub 2021 Mar 6.

Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, Reynolds Oklahoma Center on Aging, Department of Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.

Aging is associated with a significant deficiency in circulating insulin-like growth factor-1 (IGF-1), which has an important role in the pathogenesis of age-related vascular cognitive impairment (VCI). Impairment of moment-to-moment adjustment of regional cerebral blood flow via neurovascular coupling (NVC) importantly contributes to VCI. Previous studies established a causal link between circulating IGF-1 deficiency and neurovascular dysfunction. Release of vasodilator mediators from activated astrocytes plays a key role in NVC. To determine the impact of impaired IGF-1 signaling on astrocytic function, astrocyte-mediated NVC responses were studied in a novel mouse model of astrocyte-specific knockout of IGF1R (GFAP-Cre/Igf1r) and accelerated neurovascular aging. We found that mice with disrupted astrocytic IGF1R signaling exhibit impaired NVC responses, decreased stimulated release of the vasodilator gliotransmitter epoxy-eicosatrienoic acids (EETs), and upregulation of soluble epoxy hydrolase (sEH), which metabolizes and inactivates EETs. Collectively, our findings provide additional evidence that IGF-1 promotes astrocyte health and maintains normal NVC, protecting cognitive health.
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http://dx.doi.org/10.1007/s11357-021-00350-0DOI Listing
March 2021

Neuroinvasive Listeria monocytogenes infection triggers accumulation of brain CD8 tissue-resident memory T cells in a miR-155-dependent fashion.

J Neuroinflammation 2020 Sep 2;17(1):259. Epub 2020 Sep 2.

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background: Brain inflammation is a key cause of cognitive decline after central nervous system (CNS) infections. A thorough understanding of immune responses to CNS infection is essential for developing anti-inflammatory interventions that improve outcomes. Tissue-resident memory T cells (T) are non-recirculating memory T cells that provide surveillance of previously infected tissues. However, in addition to protecting the brain against reinfection, brain T can contribute to post-infectious neuroinflammation. We hypothesized that accumulation of CD8 T in the brain could be reduced by inhibiting microRNA (miR)-155, a microRNA that influences development of cytotoxic CD8 T lymphocytes during infection.

Methods: C57BL/6J mice were infected by intraperitoneal injection with a lethal inoculum of Listeria monocytogenes (Lm) then treated with antibiotics. Flow cytometry was used to quantify specific populations of brain leukocytes 28-29 days (d) post-infection (p.i.). To test the degree to which miR-155 altered leukocyte influxes into the brain, infected mice were injected with a miR-155 inhibitor or locked nucleic acid (LNA) scramble control 2d, 4d, 6d, and 8d p.i. along with antibiotic treatment. Bacterial loads in spleen and liver and body weights were measured up to 7d p.i. Brain leukocytes were analyzed 14d and 28d p.i. Confirmatory studies were performed in mutated mice lacking miR-155 (miR-155) RESULTS: Lm infection significantly increased the numbers of brain CD3CD8 lymphocytes at 28d p.i. These cells were extravascular, and displayed markers characteristic of T, with the predominant phenotype of CD44CD62LCD69CX3CR1. Further analysis showed that > 75% of brain T also expressed CD49a, PD-1, Ly6C, CD103, and CD127. Mice injected with miR-155 inhibitor lost less weight through 7d p.i. than did control mice, whereas bacterial loads in brain, liver, and spleen were not different from controls. By 28d p.i., the numbers of brain CD8 T cells were significantly decreased in mice treated with the inhibitor compared with controls. Similarly, miR-155 mice showed significantly reduced numbers of brain CD8 T cells by 28d p.i.

Conclusions: Brain CD8 T populations are established during neuroinvasive Lm infection. Accumulation of brain CD8 T cells is reduced by blocking miR-155 and in miR-155 mice, indicating that this molecule has a critical role in development of these specialized cells. Administering anti-miR-155 during infection could provide a novel avenue for reducing post-infectious neuroinflammation.
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http://dx.doi.org/10.1186/s12974-020-01929-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466815PMC
September 2020

Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice.

J Lipid Res 2020 10 15;61(10):1308-1319. Epub 2020 Jul 15.

Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.
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http://dx.doi.org/10.1194/jlr.RA119000479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529050PMC
October 2020

Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation-induced impairment of neurovascular coupling responses protecting cognitive function in mice.

Geroscience 2020 04 20;42(2):409-428. Epub 2020 Jan 20.

Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Oklahoma Center for Geroscience, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street - BRC 1303, Oklahoma City, OK, 731042, USA.

Whole brain irradiation (WBI, also known as whole brain radiation therapy or WBRT) is a mainstream therapy for patients with identifiable brain metastases and as a prophylaxis for microscopic malignancies. WBI accelerates brain aging, causing progressive cognitive dysfunction in ~ 50% of surviving patients, thus compromising quality of life. The mechanisms responsible for this WBI side effect remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that WBI induces astrocyte senescence, which contributes to impaired astrocytic neurovascular coupling (NVC) responses and the genesis of cognitive decline. To achieve this goal, we used transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells. We subjected these mice to a clinically relevant protocol of fractionated WBI (5 Gy twice weekly for 4 weeks). WBI-treated and control mice were tested for spatial memory performance (radial arm water maze), astrocyte-dependent NVC responses (whisker-stimulation-induced increases in cerebral blood flow, assessed by laser speckle contrast imaging), NVC-related gene expression, astrocytic release of eicosanoid gliotransmitters and the presence of senescent astrocytes (by flow cytometry, immunohistochemistry and gene expression profiling) at 6 months post-irradiation. WBI induced senescence in astrocytes, which associated with NVC dysfunction and impaired performance on cognitive tasks. To establish a causal relationship between WBI-induced senescence and NVC dysfunction, senescent cells were depleted from WBI-treated animals (at 3 months post-WBI) by genetic (ganciclovir treatment) or pharmacological (treatment with the BCL-2/BCL-xL inhibitor ABT263/Navitoclax, a known senolytic drug) means. In WBI-treated mice, both treatments effectively eliminated senescent astrocytes, rescued NVC responses, and improved cognitive performance. Our findings suggest that the use of senolytic drugs can be a promising strategy for preventing the cognitive impairment associated with WBI.
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http://dx.doi.org/10.1007/s11357-020-00154-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205933PMC
April 2020

Accelerated decline in cognition in a mouse model of increased oxidative stress.

Geroscience 2019 10 22;41(5):591-607. Epub 2019 Oct 22.

Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC-1372, Oklahoma City, OK, 73104, USA.

Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1KO mice) have a significant reduction in lifespan, exhibit many phenotypes of accelerated aging, and have high levels of oxidative stress in various tissues. Age-associated cognitive decline is a hallmark of aging and the increase in oxidative stress/damage with age is one of the mechanisms proposed for cognitive decline with age. Therefore, the goal of this study was to determine if Sod1KO mice exhibit an accelerated loss in cognitive function similar to that observed in aged animals. Cognition was assessed in Sod1KO and wild type (WT) mice using an automated home-cage testing apparatus (Noldus PhenoTyper) that included an initial discrimination and reversal task. Comparison of the total distance moved by the mice during light and dark phases of the study demonstrated that the Sod1KO mice do not show a deficit in movement. Assessment of cognitive function showed no significant difference between Sod1KO and WT mice during the initial discrimination phase of learning. However, during the reversal task, Sod1KO mice showed a significantly greater number of incorrect entries compared to WT mice indicating a decline in cognition similar to that observed in aged animals. Markers of oxidative stress (4-Hydroxynonenal, 4-HNE) and neuroinflammation [proinflammatory cytokines (IL6 and IL-1β) and neuroinflammatory markers (CD68, TLR4, and MCP1)] were significantly elevated in the hippocampus of male and female Sod1KO compared to WT mice. This study provides important evidence that increases in oxidative stress alone are sufficient to induce neuroinflammation and cognitive dysfunction that parallels the memory deficits seen in advanced aging and neurodegenerative diseases.
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http://dx.doi.org/10.1007/s11357-019-00105-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885085PMC
October 2019

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Geroscience 2019 04 10;41(2):185-208. Epub 2019 May 10.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Bldg, Rm 236, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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http://dx.doi.org/10.1007/s11357-019-00065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544744PMC
April 2019

Chemically induced carcinogenesis in rodent models of aging: assessing organismal resilience to genotoxic stressors in geroscience research.

Geroscience 2019 04 29;41(2):209-227. Epub 2019 Apr 29.

Department of Geriatric Medicine Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.

There is significant overlap between the cellular and molecular mechanisms of aging and pathways contributing to carcinogenesis, including the role of genome maintenance pathways. In the field of geroscience analysis of novel genetic mouse models with either a shortened, or an extended, lifespan provides a unique opportunity to evaluate the synergistic roles of longevity assurance pathways in cancer resistance and regulation of lifespan and to develop novel targets for interventions that both delay aging and prevent carcinogenesis. There is a growing need for robust assays to assess the susceptibility of cancer in these models. The present review focuses on a well-characterized method frequently used in cancer research, which can be adapted to study resilience to genotoxic stress and susceptibility to genotoxic stress-induced carcinogenesis in geroscience research namely, chemical carcinogenesis induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA). Recent progress in understanding how longer-living mice may achieve resistance to chemical carcinogenesis and how these pathways are modulated by anti-aging interventions is reviewed. Strain-specific differences in sensitivity to DMBA-induced carcinogenesis are also explored and contrasted with mouse lifespan. The clinical relevance of inhibition of DMBA-induced carcinogenesis for the pathogenesis of mammary adenocarcinomas in older human subjects is discussed. Finally, the potential role of insulin-like growth factor-1 (IGF-1) in the regulation of pathways responsible for cellular resilience to DMBA-induced mutagenesis is discussed.
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http://dx.doi.org/10.1007/s11357-019-00064-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544731PMC
April 2019

Age-related decline in peripheral vascular health predicts cognitive impairment.

Geroscience 2019 04 27;41(2):125-136. Epub 2019 Apr 27.

Translational Geroscience Laboratory, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th street, BRC 1311, Oklahoma City, OK, 73104, USA.

Preclinical studies demonstrate that generalized endothelial cell dysfunction and microvascular impairment are potentially reversible causes of age-related vascular cognitive impairment and dementia (VCID). The present study was designed to test the hypothesis that severity of age-related macro- and microvascular dysfunction measured in the peripheral circulation is an independent predictor of cognitive performance in older adults. In this study, we enrolled 63 healthy individuals into young (< 45 years old) and aged (> 65 years old) groups. We used principal component analysis (PCA) to construct a comprehensive peripheral vascular health index (VHI) encompassing peripheral microvascular reactivity, arterial endothelial function, and vascular stiffness, as a marker of aging-induced generalized vascular dysfunction. Peripheral macrovascular and microvascular endothelial function were assessed using flow-mediated dilation (FMD) and laser speckle contrast imaging tests. Pulse waveform analysis was used to evaluate the augmentation index (AIx), a measure of arterial stiffness. Cognitive function was measured using a panel of CANTAB cognitive tests, and PCA was then applied to generate a cognitive impairment index (CII) for each participant. Aged subjects exhibited significantly impaired macrovascular endothelial function (FMD, 5.6 ± 0.7% vs. 8.3 ± 0.6% in young, p = 0.0061), increased arterial stiffness (AIx 29.3 ± 1.8% vs 4.5 ± 2.6% in young, p < 0.0001), and microvascular dysfunction (2.8 ± 0.2 vs 3.4 ± 0.1-fold change of perfusion in young, p = 0.032). VHI showed a significant negative correlation with age (r = - 0.54, p < 0.0001) and CII significantly correlated with age (r = 0.79, p < 0.0001). VHI significantly correlated with the CII (r = - 0.46, p = 0.0003). A decline in peripheral vascular health may reflect generalized vascular dysfunction and predict cognitive impairment in older adults.
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http://dx.doi.org/10.1007/s11357-019-00063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544701PMC
April 2019

Age-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency.

Neurobiol Aging 2018 11 10;71:1-12. Epub 2018 Jul 10.

Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address:

Cerebral microcirculation is critical for the preservation of brain health, and vascular impairment is associated with age-related neurodegenerative diseases. Because the retina is a component of the central nervous system, cellular changes that occur in the aging retina are likely relevant to the aging brain, and the retina provides the advantage that the entire vascular bed is visible, en face. In this study, we tested the hypothesis that normal, healthy aging alters the contractile vascular smooth muscle cell (VSMC) coverage of retinal arterioles. We found that aging results in a significant reduction of contractile VSMCs in focal patches along arterioles. Focal loss of contractile VSMCs occurs at a younger age in mice deficient in the senescence-associated protein, caveolin-1. Age-related contractile VSMC loss is not exacerbated by genetic depletion of insulin-like growth factor-1. The patchy loss of contractile VSMCs provides a cellular explanation for previous clinical studies showing focal microirregularities in retinal arteriolar responsiveness in healthy aged human subjects and is likely to contribute to age-related retinal vascular complications.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162181PMC
November 2018

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

J Gerontol A Biol Sci Med Sci 2018 06;73(7):853-863

Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.
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http://dx.doi.org/10.1093/gerona/glx177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001893PMC
June 2018

Simultaneous assessment of cognitive function, circadian rhythm, and spontaneous activity in aging mice.

Geroscience 2018 04 24;40(2):123-137. Epub 2018 Apr 24.

Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, 975 NE 10TH Street, SLY-BRC 1303, Oklahoma City, OK, 73104, USA.

Cognitive function declines substantially with age in both humans and animal models. In humans, this decline is associated with decreases in independence and quality of life. Although the methodology for analysis of cognitive function in human models is relatively well established, similar analyses in animal models have many technical issues (e.g., unintended experimenter bias, motivational issues, stress, and testing during the light phase of the light dark cycle) that limit interpretation of the results. These caveats, and others, potentially bias the interpretation of studies in rodents and prevent the application of current tests of learning and memory as part of an overall healthspan assessment in rodent models of aging. The goal of this study was to establish the methodology to assess cognitive function in aging animals that addresses many of these concerns. Here, we use a food reward-based discrimination procedure with minimal stress in C57Bl/6J male mice at 6, 21, and 27 months of age, followed by a reversal task to assess behavioral flexibility. Importantly, the procedures minimize issues related to between-experimenter confounds and are conducted during both the dark and light phases of the light dark cycle in a home-cage setting. During cognitive testing, we were able to assess multiple measures of spontaneous movement and diurnal activity in young and aged mice including, distance moved, velocity, and acceleration over a 90-h period. Both initial discrimination and reversal learning significantly decreased with age and, similar to rats and humans, not all old mice demonstrated impairments in learning with age. These results permitted classification of animals based on their cognitive status. Analysis of movement parameters indicated decreases in distance moved as well as velocity and acceleration with increasing age. Based on these data, we developed preliminary models indicating, as in humans, a close relationship exists between age-related movement parameters and cognitive ability. Our results provide a reliable method for assessing cognitive performance with minimal stress and simultaneously provide key information on movement and diurnal activity. These methods represent a novel approach to developing non-invasive healthspan measures in rodent models that allow standardization across laboratories.
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http://dx.doi.org/10.1007/s11357-018-0019-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964055PMC
April 2018

Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice.

Aging Cell 2018 04 6;17(2). Epub 2018 Feb 6.

Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling has an essential role in maintenance of healthy cognitive function. In advanced age, increased oxidative stress and cerebromicrovascular endothelial dysfunction impair neurovascular coupling, likely contributing to age-related decline of higher cortical functions. There is increasing evidence showing that mitochondrial oxidative stress plays a critical role in a range of age-related cellular impairments, but its role in neurovascular uncoupling remains unexplored. This study was designed to test the hypothesis that attenuation of mitochondrial oxidative stress may exert beneficial effects on neurovascular coupling responses in aging. To test this hypothesis, 24-month-old C57BL/6 mice were treated with a cell-permeable, mitochondria-targeted antioxidant peptide (SS-31; 10 mg kg day , i.p.) or vehicle for 2 weeks. Neurovascular coupling was assessed by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS-31 significantly improved neurovascular coupling responses by increasing NO-mediated cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS-31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, mitochondrial oxidative stress contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. We propose that mitochondria-targeted antioxidants may be considered for pharmacological microvascular protection for the prevention/treatment of age-related vascular cognitive impairment (VCI).
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http://dx.doi.org/10.1111/acel.12731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847870PMC
April 2018

Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes.

Mol Metab 2018 03 2;9:141-155. Epub 2018 Feb 2.

Reynold's Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, USA; Department of Physiology, University of Oklahoma Health Sciences Center, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, USA.

Objective: A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory.

Methods: Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-Cre/igfr). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfr mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays.

Results: Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30-50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to HO-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and Aβ uptake, both critical functions of astrocytes in the brain.

Conclusions: Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies.
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http://dx.doi.org/10.1016/j.molmet.2018.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870102PMC
March 2018

Role of NADPH oxidase in radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain.

Int J Radiat Biol 2017 11;93(11):1257-1266

c Department of Biomedical Engineering and Mechanics , Virginia Tech , Blacksburg , VA , USA.

Purpose: The present study was designed to investigate our hypothesis that NADPH oxidase plays a role in radiation-induced pro-oxidative and pro-inflammatory environments in the brain.

Materials And Methods: C57BL/6 mice received either fractionated whole brain irradiation or sham-irradiation. The mRNA expression levels of pro-inflammatory mediators, such as TNF-α and MCP-1, were determined by quantitative real-time RT-PCR. The protein expression levels of TNF-α, MCP-1, NOX-2 and Iba1 were detected by immunofluorescence staining. The levels of ROS were visualized by in situ DHE fluorescence staining.

Results: A significant up-regulation of mRNA and protein expression levels of TNF-α and MCP-1 was observed in irradiated mouse brains. Additionally, immunofluorescence staining of Iba1 showed a marked increase of microglial activation in mouse brain after irradiation. Moreover, in situ DHE fluorescence staining revealed that fractionated whole brain irradiation significantly increased production of ROS. Furthermore, a significant increase in immunoreactivity of NOX-2 was detected in mouse brain after irradiation. On the contrary, an enhanced ROS generation in mouse brain after irradiation was markedly attenuated in the presence of NOX inhibitors or NOX-2 neutralizing antibody.

Conclusions: These results suggest that NOX-2 may play a role in fractionated whole brain irradiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain.
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http://dx.doi.org/10.1080/09553002.2017.1377360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080279PMC
November 2017

Endothelial Cell Inflammation and Antioxidant Capacity are Associated With 6-Minute Walk Performance in Patients With Symptomatic Peripheral Artery Disease.

Angiology 2018 May 24;69(5):416-423. Epub 2017 Aug 24.

1 Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK, USA.

We determined whether 6-minute walk total distance and pain-free distance were associated with circulating biomarkers of antioxidant capacity and inflammation and with cultured endothelial cell inflammation, oxidative stress, and apoptosis in 251 patients with symptomatic peripheral artery disease (PAD). In multivariate analyses, pain-free distance during the 6-minute walk test was negatively associated with dyslipidemia ( P < .001), chronic kidney disease ( P = .004), and transient transfection, nuclear factor κ-Light-Chain-Enhancer of activated B (NF-κB) cultured endothelial cells ( P = .007) and was positively associated with height ( P = .008). Furthermore, total distance walked during the 6-minute walk test was negatively associated with cultured endothelial cell NF-κB ( P < .001), coronary artery disease ( P = .009), and body mass index ( P = .022) and was positively associated with ankle-brachial index ( P < .001), male sex ( P < .001), and hydroxyl radical antioxidant capacity ( P < .001). The 6-minute walk performance in symptomatic patients with PAD was associated with vascular biomarkers, as walking distances were negatively associated with cultured endothelial cell inflammation and positively associated with circulating antioxidant capacity. The clinical implication is that behavioral interventions designed to alleviate endothelial cell inflammation and increase circulating antioxidant capacity, such as exercise and antioxidant intake, may improve ambulation of patients with PAD during submaximal exercise that is typically performed during daily activities.
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http://dx.doi.org/10.1177/0003319717726934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004123PMC
May 2018

Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging.

J Neuroinflammation 2017 07 21;14(1):141. Epub 2017 Jul 21.

Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Background: The necessity of including both males and females in molecular neuroscience research is now well understood. However, there is relatively limited basic biological data on brain sex differences across the lifespan despite the differences in age-related neurological dysfunction and disease between males and females.

Methods: Whole genome gene expression of young (3 months), adult (12 months), and old (24 months) male and female C57BL6 mice hippocampus was analyzed. Subsequent bioinformatic analyses and confirmations of age-related changes and sex differences in hippocampal gene and protein expression were performed.

Results: Males and females demonstrate both common expression changes with aging and marked sex differences in the nature and magnitude of the aging responses. Age-related hippocampal induction of neuroinflammatory gene expression was sexually divergent and enriched for microglia-specific genes such as complement pathway components. Sexually divergent C1q protein expression was confirmed by immunoblotting and immunohistochemistry. Similar patterns of cortical sexually divergent gene expression were also evident. Additionally, inter-animal gene expression variability increased with aging in males, but not females.

Conclusions: These findings demonstrate sexually divergent neuroinflammation with aging that may contribute to sex differences in age-related neurological diseases such as stroke and Alzheimer's, specifically in the complement system. The increased expression variability in males suggests a loss of fidelity in gene expression regulation with aging. These findings reveal a central role of sex in the transcriptomic response of the hippocampus to aging that warrants further, in depth, investigations.
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http://dx.doi.org/10.1186/s12974-017-0920-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521082PMC
July 2017

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan.

Geroscience 2017 04 13;39(2):129-145. Epub 2017 Apr 13.

Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, SLY-BRC 1303, Oklahoma City, OK, 73104, USA.

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.
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http://dx.doi.org/10.1007/s11357-017-9971-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411370PMC
April 2017

Insulin-like growth factor 1 deficiency exacerbates hypertension-induced cerebral microhemorrhages in mice, mimicking the aging phenotype.

Aging Cell 2017 06 14;16(3):469-479. Epub 2017 Mar 14.

Reynolds Oklahoma Center on Aging, Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1  + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment. In IGF-1-deficient mice, the same level of hypertension led to significantly earlier onset and increased incidence and neurological consequences of CMHs, as compared to control mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Previous studies showed that in aging, increased oxidative stress-mediated matrix metalloprotease (MMP) activation importantly contributes to the pathogenesis of CMHs. Thus, it is significant that hypertension-induced cerebrovascular oxidative stress and MMP activation were increased in IGF-1-deficient mice. We found that IGF-1 deficiency impaired hypertension-induced adaptive media hypertrophy and extracellular matrix remodeling, which together with the increased MMP activation likely also contributes to increased fragility of intracerebral arterioles. Collectively, IGF-1 deficiency promotes the pathogenesis of CMHs, mimicking the aging phenotype, which likely contribute to its deleterious effect on cognitive function. Therapeutic strategies that upregulate IGF-1 signaling in the cerebral vessels and/or reduce microvascular oxidative stress, and MMP activation may be useful for the prevention of CMHs, protecting cognitive function in high-risk elderly patients.
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http://dx.doi.org/10.1111/acel.12583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418199PMC
June 2017

Association between daily walking and antioxidant capacity in patients with symptomatic peripheral artery disease.

J Vasc Surg 2017 06 1;65(6):1762-1768. Epub 2017 Mar 1.

Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Okla.

Objective: The primary aim of the study was to assess whether both the amount and pace of daily walking were associated with circulating antioxidant capacity in symptomatic patients with peripheral artery disease (PAD).

Methods: Community-based walking was measured in 244 men and women who were limited by symptomatic PAD during a 1-week period in which they wore an ankle-mounted step activity monitor. Patients were further characterized by circulating antioxidant capacity with the OxiSelect (Cell Biolabs Inc, San Diego, Calif) hydroxyl radical antioxidant capacity (HORAC) activity assay.

Results: To assess the amount of walking, patients were grouped into low (≤2440 strides/d), middle (2441-3835 strides/d), and high (>3835 strides/d) stride tertiles. HORAC was higher in the middle (P = .03) and high (P = .01) stride tertiles than in the low tertile, but there was no difference between middle and high tertiles (P = .44). To assess the pace of walking, patients were grouped into slow (<25.0 strides/min), middle (25.0-31.6 strides/min), and fast (>31.6 strides/min) cadence tertiles. HORAC was higher in the high cadence tertile than in the low (P < .01) and middle (P < .01) tertiles, but there was no difference between low and middle tertiles (P = .48). Similar findings were obtained on group differences in HORAC after adjusting for age, sex, race, and ankle-brachial index for both the amount and pace of daily walking.

Conclusions: Walking >2440 strides each day and walking at a cadence faster than 31.6 strides/min for 30 minutes each day are both associated with greater circulating antioxidant capacity in symptomatic patients with PAD. The clinical significance is that a home-based walking program may be one approach to increase endogenous antioxidant capacity.
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http://dx.doi.org/10.1016/j.jvs.2016.12.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438884PMC
June 2017

The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer.

Geroscience 2017 04 23;39(2):147-160. Epub 2017 Feb 23.

Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, 975 N. E. 10th Street-BRC 1303, Oklahoma City, OK, 73104, USA.

Experimental, clinical, and epidemiological findings support the concept of developmental origins of health and disease (DOHAD), suggesting that early-life hormonal influences during a sensitive period around adolescence have a powerful impact on cancer morbidity later in life. The endocrine changes that occur during puberty are highly conserved across mammalian species and include dramatic increases in circulating GH and IGF-1 levels. Importantly, patients with developmental IGF-1 deficiency due to GH insensitivity (Laron syndrome) do not develop cancer during aging. Rodents with developmental GH/IGF-1 deficiency also exhibit significantly decreased cancer incidence at old age, marked resistance to chemically induced carcinogenesis, and cellular resistance to genotoxic stressors. Early-life treatment of GH/IGF-1-deficient mice and rats with GH reverses the cancer resistance phenotype; however, the underlying molecular mechanisms remain elusive. The present study was designed to test the hypothesis that developmental GH/IGF-1 status impacts cellular DNA repair mechanisms. To achieve that goal, we assessed repair of γ-irradiation-induced DNA damage (single-cell gel electrophoresis/comet assay) and basal and post-irradiation expression of DNA repair-related genes (qPCR) in primary fibroblasts derived from control rats, Lewis dwarf rats (a model of developmental GH/IGF-1 deficiency), and GH-replete dwarf rats (GH administered beginning at 5 weeks of age, for 30 days). We found that developmental GH/IGF-1 deficiency resulted in persisting increases in cellular DNA repair capacity and upregulation of several DNA repair-related genes (e.g., Gadd45a, Bbc3). Peripubertal GH treatment reversed the radiation resistance phenotype. Fibroblasts of GH/IGF-1-deficient Snell dwarf mice also exhibited improved DNA repair capacity, showing that the persisting influence of peripubertal GH/IGF-1 status is not species-dependent. Collectively, GH/IGF-1 levels during a critical period during early life determine cellular DNA repair capacity in rodents, presumably by transcriptional control of genes involved in DNA repair. Because lifestyle factors (e.g., nutrition and childhood obesity) cause huge variation in peripubertal GH/IGF-1 levels in children, further studies are warranted to determine their persisting influence on cellular cancer resistance pathways.
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http://dx.doi.org/10.1007/s11357-017-9966-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411369PMC
April 2017

Regional changes in CNS and retinal glycerophospholipid profiles with age: a molecular blueprint.

J Lipid Res 2017 04 15;58(4):668-680. Epub 2017 Feb 15.

Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

We present here a quantitative molecular blueprint of the three major glycerophospholipid (GPL) classes, phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylethanolamine (PE), in retina and six regions of the brain in C57Bl6 mice at 2, 10, and 26 months of age. We found an age-related increase in molecular species containing saturated and monoenoic FAs and an overall decrease in the longer-chain PUFA molecular species across brain regions, with loss of DHA-containing molecular species as the most consistent and dramatic finding. Although we found very-long-chain PUFAs (VLC-PUFAs) (C28) in PC in the retina, no detectable levels were found in any brain region at any of the ages examined. All brain regions (except hippocampus and retina) showed a significant increase with age in PE plasmalogens. All three retina GPLs had di-PUFA molecular species (predominantly 44:12), which were most abundant in PS (∼30%). In contrast, low levels of di-PUFA GPL (1-2%) were found in all regions of the brain. This study provides a regional and age-related assessment of the brain's lipidome with a level of detail, inclusion, and quantification that has not heretofore been published.
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http://dx.doi.org/10.1194/jlr.M070714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392743PMC
April 2017

GeroScience: understanding the interaction of processes of aging and chronic diseases.

Age (Dordr) 2016 12;38(5-6):377-378

University of Oklahoma Health Science Center, Oklahoma, OK, USA.

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http://dx.doi.org/10.1007/s11357-016-9953-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266222PMC
December 2016

The Protein Tyrosine Phosphatase MEG2 Regulates the Transport and Signal Transduction of Tropomyosin Receptor Kinase A.

J Biol Chem 2016 Nov 21;291(46):23895-23905. Epub 2016 Sep 21.

the Departments of Biochemistry and Molecular Biology,

Protein tyrosine phosphatase MEG2 (PTP-MEG2) is a unique nonreceptor tyrosine phosphatase associated with transport vesicles, where it facilitates membrane trafficking by dephosphorylation of the N-ethylmaleimide-sensitive fusion factor. In this study, we identify the neurotrophin receptor TrkA as a novel cargo whose transport to the cell surface requires PTP-MEG2 activity. In addition, TrkA is also a novel substrate of PTP-MEG2, which dephosphorylates both Tyr-490 and Tyr-674/Tyr-675 of TrkA. As a result, overexpression of PTP-MEG2 down-regulates NGF/TrkA signaling and blocks neurite outgrowth and differentiation in PC12 cells and cortical neurons.
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http://dx.doi.org/10.1074/jbc.M116.728550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104914PMC
November 2016

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging.

Age (Dordr) 2016 Aug 9;38(4):273-289. Epub 2016 Sep 9.

Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.

Strong epidemiological and experimental evidence indicate that both age and hypertension lead to significant functional and structural impairment of the cerebral microcirculation, predisposing to the development of vascular cognitive impairment (VCI) and Alzheimer's disease. Preclinical studies establish a causal link between cognitive decline and microvascular rarefaction in the hippocampus, an area of brain important for learning and memory. Age-related decline in circulating IGF-1 levels results in functional impairment of the cerebral microvessels; however, the mechanistic role of IGF-1 deficiency in impaired hippocampal microvascularization remains elusive. The present study was designed to characterize the additive/synergistic effects of IGF-1 deficiency and hypertension on microvascular density and expression of genes involved in angiogenesis and microvascular regression in the hippocampus. To achieve that goal, we induced hypertension in control and IGF-1 deficient mice (Igf1  + TBG-Cre-AAV8) by chronic infusion of angiotensin II. We found that circulating IGF-1 deficiency is associated with decreased microvascular density and exacerbates hypertension-induced microvascular rarefaction both in the hippocampus and the neocortex. The anti-angiogenic hippocampal gene expression signature observed in hypertensive IGF-1 deficient mice in the present study provides important clues for subsequent studies to elucidate mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of VCI. In conclusion, adult-onset, isolated endocrine IGF-1 deficiency exerts deleterious effects on the cerebral microcirculation, leading to a significant decline in cortical and hippocampal capillarity and exacerbating hypertension-induced cerebromicrovascular rarefaction. The morphological impairment of the cerebral microvasculature induced by IGF-1 deficiency and hypertension reported here, in combination with neurovascular uncoupling, increased blood-brain barrier disruption and neuroinflammation reported in previous studies likely contribute to the pathogenesis of vascular cognitive impairment in elderly hypertensive humans.
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http://dx.doi.org/10.1007/s11357-016-9931-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061685PMC
August 2016

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis.

Age (Dordr) 2016 Aug 26;38(4):239-258. Epub 2016 Aug 26.

Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.

Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 mice crossed with mice expressing albumin-driven Cre recombinase). This model exhibits low-circulating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from those in mice with adult-onset IGF-1 deficiency (TBG-Cre-AAV8-mediated knockdown of IGF-1 at 5 month of age in Igf1 mice). Using a novel computational approach, we identified miRNA target genes that are co-expressed with IGF-1 and associate with aging and vascular pathophysiology. We found that among the predicted targets, the expression of multiple extracellular matrix-related genes, including collagen-encoding genes, were downregulated in mice with developmental IGF-1 deficiency. Collectively, IGF-1 deficiency during a critical period during early in life results in persistent changes in post-transcriptional miRNA-mediated control of genes critical targets for vascular health, which likely contribute to the deleterious late-life cardiovascular effects known to occur with developmental IGF-1 deficiency.
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http://dx.doi.org/10.1007/s11357-016-9943-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061677PMC
August 2016

Absence of genomic hypomethylation or regulation of cytosine-modifying enzymes with aging in male and female mice.

Epigenetics Chromatin 2016 13;9:30. Epub 2016 Jul 13.

Oklahoma Center for Neuroscience, Oklahoma City, OK USA ; Reynolds Oklahoma Center on Aging, SLY-BRC 1370, 975 NE 10th St, Oklahoma City, OK 73104 USA ; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA ; Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK USA.

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.
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http://dx.doi.org/10.1186/s13072-016-0080-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942942PMC
July 2016

Bisulfite oligonucleotide-capture sequencing for targeted base- and strand-specific absolute 5-methylcytosine quantitation.

Age (Dordr) 2016 Jun 18;38(3):49. Epub 2016 Apr 18.

Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

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 170 Mb 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.
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http://dx.doi.org/10.1007/s11357-016-9914-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005917PMC
June 2016

Effects of age and insulin-like growth factor-1 on rat neurotrophin receptor expression after nerve injury.

Muscle Nerve 2016 10 3;54(4):769-75. Epub 2016 Aug 3.

Department of Orthopaedic Surgery, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, North Carolina, 27157, USA.

Introduction: Neurotrophin receptors, such as p75(NTR) , direct neuronal response to injury. Insulin-like growth factor-1 receptor (IGF-1R) mediates the increase in p75(NTR) during aging. The aim of this study was to examine the effect of aging and insulin-like growth factor-1 (IGF-1) treatment on recovery after peripheral nerve injury.

Methods: Young and aged rats underwent tibial nerve transection with either local saline or IGF-1 treatment. Neurotrophin receptor mRNA and protein expression were quantified.

Results: Aged rats expressed elevated baseline IGF-1R (34% higher, P = 0.01) and p75(NTR) (68% higher, P < 0.01) compared with young rats. Post-injury, aged animals expressed significantly higher p75(NTR) levels (68.5% above baseline at 4 weeks). IGF-1 treatment suppressed p75(NTR) gene expression at 4 weeks (17.2% above baseline, P = 0.002) post-injury.

Conclusions: Local IGF-1 treatment reverses age-related declines in recovery after peripheral nerve injuries by suppressing p75(NTR) upregulation and pro-apoptotic complexes. IGF-1 may be considered a viable adjuvant therapy to current treatment modalities. Muscle Nerve 54: 769-775, 2016.
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http://dx.doi.org/10.1002/mus.25106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381828PMC
October 2016

Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice.

Age (Dordr) 2016 Apr 11;38(2):38. Epub 2016 Mar 11.

Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, SLY-BRC 1303, Oklahoma City, OK, 73104, USA.

Advanced aging is associated with the loss of structural and biomechanical properties in bones, which increases the risk for bone fracture. Aging is also associated with reductions in circulating levels of the anabolic signaling hormone, insulin-like growth factor (IGF)-1. While the role of IGF-1 in bone development has been well characterized, the impact of the age-related loss of IGF-1 on bone aging remains controversial. Here, we describe the effects of reducing IGF-1 at multiple time points in the mouse life span--early in postnatal development, early adulthood, or late adulthood on tibia bone aging in both male and female igf (f/f) mice. Bone structure was analyzed at 27 months of age using microCT. We find that age-related reductions in cortical bone fraction, cortical thickness, and tissue mineral density were more pronounced when IGF-1 was reduced early in life and not in late adulthood. Three-point bone bending assays revealed that IGF-1 deficiency early in life resulted in reduced maximum force, maximum bending moment, and bone stiffness in aged males and females. The effects of IGF-1 on bone aging are microenvironment specific, as early-life loss of IGF-1 resulted in decreased cortical bone structure and strength along the diaphysis while significantly increasing trabecular bone fraction and trabecular number at the proximal metaphysis. The increases in trabecular bone were limited to males, as early-life loss of IGF-1 did not alter bone fraction or number in females. Together, our data suggest that the age-related loss of IGF-1 influences tibia bone aging in a sex-specific, microenvironment-specific, and time-dependent manner.
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http://dx.doi.org/10.1007/s11357-016-9902-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005911PMC
April 2016

INFLUENCE OF DIABETES ON AMBULATION AND INFLAMMATION IN MEN AND WOMEN WITH SYMPTOMATIC PERIPHERAL ARTERY DISEASE.

J Clin Transl Endocrinol 2015 Dec;2(4):137-143

Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK.

Objective: To determine whether diabetes and sex were factors associated with ambulatory function, endothelial cell inflammation, oxidative stress, and apoptosis, and with circulating biomarkers of inflammation and antioxidant capacity in patients with peripheral artery disease (PAD) and claudication.

Materials/methods: Ambulatory function of 180 symptomatic men and women with PAD was assessed during a graded maximal treadmill test, 6-minute walk test, and 4-meter walk test. Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells, and on circulating inflammatory and vascular biomarkers.

Results: Men and women with diabetes had greater prevalence (p = 0.007 and p = 0.015, respectively) of coronary artery disease (CAD) than patients without diabetes. To assure that this difference did not influence planned comparisons, the data set was stratified on CAD. Diabetic men with CAD had a lower peak walking time (PWT) during the treadmill test and a slower 4-meter gait speed compared to non-diabetic men with CAD (p < 0.05). Diabetic women with CAD had a lower PWT compared to their non-diabetic counterparts (p < 0.01). Additionally, diabetic men with CAD had higher pigment epithelium-derived factor (p < 0.05) than their non-diabetic counterparts, and diabetic women with CAD had higher leptin (p < 0.01) and interleukin-8 levels (p < 0.05).

Conclusions: In patients with PAD, diabetic men and women with CAD had more severe claudication than their non-diabetic counterparts, as measured by shorter PWT, and the men had further ambulatory impairment manifested by slower 4-meter gait speed. Furthermore, the diabetic patients with CAD had elevations in interleukin-8, leptin, and PEDF.
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http://dx.doi.org/10.1016/j.jcte.2015.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4730895PMC
December 2015