Rochester, MN, United States
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Nin V.,Kogod Center on Aging | Chini C.C.S.,Kogod Center on Aging | Escande C.,Kogod Center on Aging | Capellini V.,Kogod Center on Aging | Chini E.N.,Kogod Center on Aging
Journal of Biological Chemistry | Year: 2014

Liver gluconeogenesis is essential to provide energy to glycolytic tissues during fasting periods. However, aberrant up-regulation of this metabolic pathway contributes to the progression of glucose intolerance in individuals with diabetes. Phosphoenolpyruvate carboxykinase (PEPCK) expression plays a critical role in the modulation of gluconeogenesis. Several pathways contribute to the regulation of PEPCK, including the nuclear receptor Rev-erbα and the histone deacetylase SIRT1. Deleted in breast cancer 1 (DBC1) is a nuclear protein that binds to and regulates both Rev-erbα and SIRT1 and, therefore, is a candidate to participate in the regulation of PEPCK. In this work, we provide evidence that DBC1 regulates glucose metabolism and the expression of PEPCK. We show that DBC1 levels decrease early in the fasting state. Also, DBC1 KO mice display higher gluconeogenesis in a normal and a high-fat diet. DBC1 absence leads to an increase in PEPCK mRNA and protein expression. Conversely, overexpression of DBC1 results in a decrease in PEPCK mRNA and protein levels. DBC1 regulates the levels of Rev-erbα, and manipulation of Rev-erbα activity or levels prevents the effect of DBC1 on PEPCK. In addition, Rev-erbα levels decrease in the first hours of fasting. Finally, knockdown of the deacetylase SIRT1 eliminates the effect of DBC1 knockdown on Rev-erbα levels and PEPCK expression, suggesting that the mechanism of PEPCK regulation is, at least in part, dependent on the activity of this enzyme. Our results point to DBC1 as a novel regulator of gluconeogenesis. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Takahashi P.Y.,Kogod Center on Aging
Advances in skin & wound care | Year: 2011

Older adults frequently experience pressure ulcers (PrUs) and suffer the risks of the ulceration. Risk factors for PrUs remain unclear in a community population. The objective of this study was to determine the risk factors for future pressure ulceration in a community sample. This was a retrospective cohort study. All patients older than 60 years in a primary care panel in Olmsted County, Minnesota, on January 1, 2005, were enrolled (n = 12,650). METHODS AND OUTCOMES: The primary outcome was a new diagnosis of pressure ulceration within 40 months of index date. The predictor risk variables included demographic and comorbid health risk factors. The data were analyzed using univariable and multivariable logistic regression. The authors created a final model based on multivariable risk factors. Of 12,650 patients, 366 patients developed an incident PrU (2.9%). In the final model, age, male sex, and long-term-care facility admission were significant factors. Prior pressure ulceration with an odds ratio of 5.60 (95% confidence interval, 3.86-8.14) was the largest risk factor. Diabetes, falls, cataracts, renal insufficiency, and peripheral vascular disease were also associated with PrU development. PrU development involves important risk factors of prior PrU development and long-term-care facility placement as the 2 largest risk factors. Both factors are easily determined by history. Increasing age and comorbid medical conditions also impact PrU development as important risk factors for PrU development.


Takahashi R.,Mayo Medical School | Takahashi R.,Kogod Center on Aging | Markovic S.N.,Mayo Medical School | Scrable H.J.,Mayo Medical School | Scrable H.J.,Kogod Center on Aging
Journal of Investigative Dermatology | Year: 2014

The TP53 gene encodes 12 distinct isoforms, some of which can alter p53 activity in the absence of genomic alteration. Endogenous p53 isoforms have been identified in cancers; however, the function of these isoforms remains unclear. In melanoma, the frequency of TP53 mutations is relatively low compared with other cancers, suggesting that these isoforms may have a larger role in regulating TP53 activity. We hypothesized that p53 function and therefore cell fate might be altered by the presence of Δ40p53, an embryonic isoform missing the first 40 N-terminal amino acids of the full-length protein including the transactivation and Mdm2-binding domains. To test this hypothesis, we transduced tumor and normal cells with a lentivirus encoding Δ40p53. We found that exogenous Δ40p53 caused apoptosis and increased the levels of endogenous, activated p53 in both cancerous and non-cancerous cells, which led to significant levels of cell death, particularly in cancer cells. Activated p53 molecules formed nuclear heterotetramers with Δ40p53 and altered downstream p53 transcription target levels including p53-induced protein with death domain and cyclin-dependent kinase inhibitor, p21. Δ40p53 altered the promoter occupancy of these downstream p53 target genes in such a way that it shifted cell fate toward apoptosis and away from cell cycle arrest. We show that tumor suppression by p53 can occur via an alternate route that relies on its interaction with Δ40p53. © 2014 The Society for Investigative Dermatology.


Takahashi P.Y.,Mayo Medical School | Takahashi P.Y.,Kogod Center on Aging | Tung E.E.,Mayo Medical School | Crane S.J.,Mayo Medical School | And 5 more authors.
Archives of Gerontology and Geriatrics | Year: 2012

The objective was to determine the relationship between a high score on the ERA index and 2-year mortality and nursing home placement. As of January 1, 2005, 12,650 community-dwelling patients over 60 years of age were impaneled with a primary care practice at the Mayo Clinic in Rochester, MN. This was a retrospective cohort study utilizing an administrative risk score, the ERA score. Primary outcomes were 2-year mortality and 2-year nursing home placement. The predictor variable was ERA score. Relative risk estimates were used to describe the association between the ERA index and mortality and nursing home placement. The relative risk of 2-year mortality was 51.4 (95% confidence interval = CI = 28.0-94.4) in patients in the highest risk group compared to the lowest group. The relative risk of nursing home placement was 113.2 (95% CI = 76.1-168.4). Patients with high ERA scores are at high risk for 2-year mortality and 2-year nursing home placement. These findings suggest that the utilization of an electronic risk score can help identify patients at risk for death or nursing home placement. Clinically, the identification of high risk individuals may be useful for utilization of clinical case management. © 2011 Elsevier Ireland Ltd.


Giannella L.,Cesare Magati Hospital | Beraldi R.,Kogod Center on Aging | Giulini S.,University of Modena and Reggio Emilia | Cerami L.B.,Cesare Magati Hospital | And 2 more authors.
International Journal of Gynecology and Obstetrics | Year: 2012

Objective: To evaluate the diagnostic accuracy of measuring cervical length (CL) in combination with cervical and plasma nitric oxide metabolite (NOx) levels to identify women undergoing preterm labor (PTL) who will deliver preterm. Methods: A hospital-based prospective cohort study of 730 women undergoing spontaneous PTL between 24 and 33 weeks + 6 days of pregnancy was conducted. Measurement of cervical and plasma NOx levels and ultrasonographic assessment of CL were performed to find the best model to predict preterm delivery (PTD). Optimal cut-off values were calculated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis and rank correlation tests were also performed. Results: CL of 15 mm or less, cervical NOx levels greater than 87.6 μmol/L, and plasma NOx levels greater than 123 μmol/L (P < 0.0001) were the only factors significantly associated with PTD within 7 days of sampling. This combined model provided high diagnostic accuracy (sensitivity 80.0%; specificity 99.2%). Both cervical and plasma NOx levels were negatively correlated with CL (r = - 0.453, P < 0.0001 and r = - 0.362, P < 0.0001, respectively). Conclusion: Combined measurement of CL and levels of cervical and plasma NOx could help identify women undergoing symptomatic PTL who are at increased risk of PTD. © 2011 International Federation of Gynecology and Obstetrics.


Ungewitter E.,Kogod Center on Aging | Ungewitter E.,University of Virginia | Scrable H.,Kogod Center on Aging
Genes and Development | Year: 2010

Δ40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that Δ40p53, in addition to being highly expressed in embryonic stem cells (ESCs), is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of Δ40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state. Haploinsufficiency for Δ40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increased dosage of Δ40p53 prolongs pluripotency and inhibits progression to a more differentiated state. Δ40p53 controls the switch from pluripotent ESCs to differentiated somatic cells by controlling the activity of full-length p53 at critical targets such as Nanog and the IGF-1 receptor (IGF-1R). The IGF axis plays a central role in the switch between pluripotency and differentiation in ESCs - and Δ40p53, by controlling the level of the IGF-1R, acts as a master regulator of this switch. We propose that this is the primary function of Δ40p53 in cells of the early embryo and stem cells, which are the only normal cells in which this isoform is expressed. © 2010 by Cold Spring Harbor Laboratory Press.


Tang J.,Kogod Center on Aging | Pei Y.,Guangdong Medical College | Zhou G.,Guangdong Medical College
Experimental Gerontology | Year: 2013

Diabetes mellitus is a metabolic disorder that is characterized by high blood glucose because of the insulin-resistance and insulin-deficiency in Type 2, while the insulin deficiency due to destruction of islet cells in the pancreas in Type 1. The development of Type 2 diabetes is caused by a combination of lifestyle and genetic factors. Aging patients with diabetes are at increased risk of developing cognitive and memory dysfunctions, which is one of the significant symptoms of Alzheimer disease (AD). Also, over 2/3 of AD patients were clinically indentified with impairment of glucose. Cognitive dysfunction would be associated with poor self-care ability in diabetes patients. This review will briefly summarize the current knowledge of the pathogenesis of these two diseases and highlight similarities in their pathophysiologies. Furthermore, we will shortly discuss recent progress in the insulin-targeted strategy, aiming to explore the inner linkage between these two diseases in aging populations. © 2013 Elsevier Inc.


Hinault C.,Harvard University | Kawamori D.,Harvard University | Liew C.W.,Harvard University | Maier B.,Indiana University | And 5 more authors.
Diabetes | Year: 2011

OBJECTIVE - Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. RESEARCH DESIGN AND METHODS - We phenotyped metabolic parameters in Δ40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine β-cell proliferation. RESULTS - Transgenic mice with an ectopic p53 gene encoding Δ40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from ∼14 months of age. Consistent with a dramatic decrease in β-cell mass and reduced β-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. CONCLUSIONS - These data indicate a significant and novel role for Δ40p53 in β-cell proliferation with implications for the development of age-dependent diabetes. © 2011 by the American Diabetes Association.


Davidge-Pitts C.,Endocrine Research Unit | Escande C.J.,Kogod Center on Aging | Conover C.A.,Endocrine Research Unit
Journal of Endocrinology | Year: 2014

Fat distribution differs between individuals, and those with visceral fat predominance develop metabolic profiles that increase the risk of adverse cardiovascular events. This is due, in part, to the proinflammatory state associated with visceral obesity as well as depot-specific adipogenesis. The IGF system is important in adipose tissue development and metabolic function. Pregnancy-associated plasma protein A (PAPPA) is a novel zinc metalloproteinase that regulates local IGF availability. The first aim of this study was to characterize PAPPA mRNA and protein expression in primary cultures of human preadipocytes isolated from omental, mesenteric, and subcutaneous depots. PAPPA expression was significantly increased in omental preadipocytes compared with mesenteric and subcutaneous preadipocytes. The second aim of this study was to investigate the factors regulating PAPPA expression, focusing on proinflammatory cytokines and resveratrol that have been shown to have negative and positive effects, respectively, on metabolism and diet-induced obesity. Treatment of cultured primary human preadipocytes with tumor necrosis factor a and interleukin 1b led to significant increases in PAPPA expression. Activated pathways mediating cytokine-induced PAPPA expression include the nuclear factor kB pathway and the MAPK family, particularly c-Jun NH2-terminal kinase and p38 MAPK. Resveratrol, a polyphenolic compound with beneficial cardiometabolic effects, significantly downregulated PAPPA expression under basal and stimulated conditions. Effects of resveratrol on PAPPA appeared to be mediated through pathways independent of silent mating type information regulation 2 homolog 1 (SIRT1) and AMP kinase activation. Depot-specific PAPPA expression in human preadipocytes may contribute to a depot-specific function. © 2014 Society for Endocrinology.


PubMed | Mayo Medical School, Kogod Center on Aging and Northumbria University
Type: Journal Article | Journal: Aging cell | Year: 2016

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

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