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FoxO3 AND Aging

Bradley J Willcox, Brian J Morris, Gregory J Tranah, Randi Chen, Kamal H Masaki, Qimei He, D Craig Willcox, Richard C Allsopp, Stefan Moisyadi, Mariana Gerschenson, Philip M C Davy, Leonard W Poon, Beatriz Rodriguez, Anne B Newman, Tamara B Harris, Steven R Cummings, Yongmei Liu, Neeta Parimi, Daniel S Evans, Timothy A Donlon
BACKGROUND: We recently reported that protection against coronary artery disease (CAD) mortality is the major contributor to longer life associated with FOXO3 genotype. The present study examined this relation in more detail. METHODS: We performed a 15-year observational study of 3,584 older American men of Japanese ancestry from the Kuakini Honolulu Heart Program cohort and 1,595 White and 1,067 Black elderly individuals from the Health Aging and Body Composition study...
September 30, 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Jie Zhuang, William M Kamp, Jie Li, Chengyu Liu, Ju-Gyeong Kang, Ping-Yuan Wang, Paul M Hwang
Although exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here, we report that exercise increases the nuclear localization and activity of p53 by acutely down regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exercise-induced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization...
September 29, 2016: Journal of Biological Chemistry
Hatice Duygu Saatcioglu, Ileana Cuevas, Diego H Castrillon
In mammals, females are born with finite numbers of oocytes stockpiled as primordial follicles. Oocytes are "reawakened" via an ovarian-intrinsic process that initiates their growth. The forkhead transcription factor Foxo3 controls reawakening downstream of PI3K-AKT signaling. However, the identity of the presumptive upstream cell surface receptor controlling the PI3K-AKT-Foxo3 axis has been questioned. Here we show that the receptor tyrosine kinase Kit controls reawakening. Oocyte-specific expression of a novel constitutively-active KitD818V allele resulted in female sterility and ovarian failure due to global oocyte reawakening...
August 2016: PLoS Genetics
Henrik Ahlenius, Soham Chanda, Ashley E Webb, Issa Yousif, Jesse Karmazin, Stanley B Prusiner, Anne Brunet, Thomas C Südhof, Marius Wernig
We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Taewon Jin, Min Jeong Kim, Won Il Heo, Kui Young Park, Sun Young Choi, Mi-Kyung Lee, Seung-Phil Hong, Seong-Jin Kim, Myung Im, Nam Ju Moon, Seong Jun Seo
Stress-induced premature senescence or aging causes dysfunction in the human somatic system. Adiponectin (Acrp30) plays a role in functional recovery, especially with adenosine 3',5'-monophosphate (AMP)-activated protein kinase (AMPK) and silent mating type information regulation 2 homolog 1 (SIRT1). Acrp30 stimulation reduced the premature senescence positive ratio induced by hydrogen peroxide (H2O2) and restituted human β-defensin 2 (hBD-2) levels in senescent keratinocytes. Acrp30 recovered AMPK activity in senescent keratinocytes and increased SIRT1 deacetylation activity...
September 2, 2016: Biochemical and Biophysical Research Communications
Alexander Teumer, Qibin Qi, Maria Nethander, Hugues Aschard, Stefania Bandinelli, Marian Beekman, Sonja I Berndt, Martin Bidlingmaier, Linda Broer, Anne Cappola, Gian Paolo Ceda, Stephen Chanock, Ming-Huei Chen, Tai C Chen, Yii-Der Ida Chen, Jonathan Chung, Fabiola Del Greco Miglianico, Joel Eriksson, Luigi Ferrucci, Nele Friedrich, Carsten Gnewuch, Mark O Goodarzi, Niels Grarup, Tingwei Guo, Elke Hammer, Richard B Hayes, Andrew A Hicks, Albert Hofman, Jeanine J Houwing-Duistermaat, Frank Hu, David J Hunter, Lise L Husemoen, Aaron Isaacs, Kevin B Jacobs, Joop A M J L Janssen, John-Olov Jansson, Nico Jehmlich, Simon Johnson, Anders Juul, Magnus Karlsson, Tuomas O Kilpelainen, Peter Kovacs, Peter Kraft, Chao Li, Allan Linneberg, Yongmei Liu, Ruth J F Loos, Mattias Lorentzon, Yingchang Lu, Marcello Maggio, Reedik Magi, James Meigs, Dan Mellström, Matthias Nauck, Anne B Newman, Michael N Pollak, Peter P Pramstaller, Inga Prokopenko, Bruce M Psaty, Martin Reincke, Eric B Rimm, Jerome I Rotter, Aude Saint Pierre, Claudia Schurmann, Sudha Seshadri, Klara Sjögren, P Eline Slagboom, Howard D Strickler, Michael Stumvoll, Yousin Suh, Qi Sun, Cuilin Zhang, Johan Svensson, Toshiko Tanaka, Archana Tare, Anke Tönjes, Hae-Won Uh, Cornelia M van Duijn, Diana van Heemst, Liesbeth Vandenput, Ramachandran S Vasan, Uwe Völker, Sara M Willems, Claes Ohlsson, Henri Wallaschofski, Robert C Kaplan
The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2)...
October 2016: Aging Cell
Yasuo Ido
Recent research in nutritional control of aging suggests that cytosolic increases in the reduced form of nicotinamide adenine dinucleotide and decreasing nicotinamide adenine dinucleotide metabolism plays a central role in controlling the longevity gene products sirtuin 1 (SIRT1), adenosine monophosphate-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). High nutrition conditions, such as the diabetic milieu, increase the ratio of reduced to oxidized forms of cytosolic nicotinamide adenine dinucleotide through cascades including the polyol pathway...
July 2016: Journal of Diabetes Investigation
Bradley J Willcox, Gregory J Tranah, Randi Chen, Brian J Morris, Kamal H Masaki, Qimei He, D Craig Willcox, Richard C Allsopp, Stefan Moisyadi, Leonard W Poon, Beatriz Rodriguez, Anne B Newman, Tamara B Harris, Steven R Cummings, Yongmei Liu, Neeta Parimi, Daniel S Evans, Phil Davy, Mariana Gerschenson, Timothy A Donlon
The G allele of the FOXO3 single nucleotide polymorphism (SNP) rs2802292 exhibits a consistently replicated genetic association with longevity in multiple populations worldwide. The aims of this study were to quantify the mortality risk for the longevity-associated genotype and to discover the particular cause(s) of death associated with this allele in older Americans of diverse ancestry. It involved a 17-year prospective cohort study of 3584 older American men of Japanese ancestry from the Honolulu Heart Program cohort, followed by a 17-year prospective replication study of 1595 white and 1056 black elderly individuals from the Health Aging and Body Composition cohort...
August 2016: Aging Cell
Tahnee Sente, An M Van Berendoncks, Erik Fransen, Christiaan J Vrints, Vicky Y Hoymans
Skeletal muscle metabolic changes are common in patients with chronic heart failure (HF). Previously, we demonstrated a functional skeletal muscle adiponectin resistance in HF patients with reduced left ventricular ejection fraction (HFrEF). We aimed to examine the impact of adiponectin receptor 1 (AdipoR1) deficiency and TNF-α treatment on adiponectin signaling, proliferative capacity, myogenic differentiation, and mitochondrial biogenesis in primary human skeletal muscle cells. Primary cultures of myoblasts and myotubes were initiated from the musculus vastus lateralis of 10 HFrEF patients (left ventricular ejection fraction; 31...
May 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
William W Du, Weining Yang, Yu Chen, Zhong-Kai Wu, Francis Stuart Foster, Zhenguo Yang, Xiangmin Li, Burton B Yang
AIMS: Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. METHODS AND RESULTS: Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence...
February 11, 2016: European Heart Journal
Brandt D Pence, Trisha E Gibbons, Tushar K Bhattacharya, Houston Mach, Jessica M Ossyra, Geraldine Petr, Stephen A Martin, Lin Wang, Stanislav S Rubakhin, Jonathan V Sweedler, Robert H McCusker, Keith W Kelley, Justin S Rhodes, Rodney W Johnson, Jeffrey A Woods
Aging leads to sarcopenia and loss of physical function. We examined whether voluntary wheel running, when combined with dietary supplementation with (-)-epigallocatechin-3-gallate (EGCG) and β-alanine (β-ALA), could improve muscle function and alter gene expression in the gastrocnemius of aged mice. Seventeen-month-old BALB/cByJ mice were given access to a running wheel or remained sedentary for 41 days while receiving either AIN-93M (standard feed) or AIN-93M containing 1.5 mg·kg(-1) EGCG and 3.43 mg·kg(-1) β-ALA...
February 2016: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Rute Martins, Gordon J Lithgow, Wolfgang Link
Aging constitutes the key risk factor for age-related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which "protective genes" are carried by long-lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity...
April 2016: Aging Cell
Jessica Lazarus, Karen A Mather, Anbupalam Thalamuthu, John B J Kwok
The exceptional longevity phenotype, defined as living beyond the age of 95, results from complex interactions between environmental and genetic factors. Epigenetic mechanisms, such as DNA methylation and histone modifications, mediate the interaction of these factors. This review will provide an overview of animal model studies used to examine age-related epigenetic modifications. Key human studies will be used to illustrate the progress made in the identification of the genetic loci associated with exceptional longevity, including APOE and FOXO3 and genes/loci that are also differentially methylated between long-lived individuals and younger controls...
2015: Epigenomics
Akira Wagatsuma, Masataka Shiozuka, Yuzo Takayama, Takayuki Hoshino, Kunihiko Mabuchi, Ryoichi Matsuda
Controversy exists as to whether the muscle-specific E3 ubiquitin ligases MAFbx and MuRF1 are transcriptionally upregulated in the process of sarcopenia. In the present study, we investigated the effects of ageing on mRNA/protein expression of muscle-specific E3 ubiquitin ligases and Akt/Foxo signalling in gastrocnemius muscles of female mice. Old mice exhibited a typical sarcopenic phenotype, characterized by loss of muscle mass and strength, decreased amount of myofibrillar proteins, incidence of aberrant muscle fibres, and genetic signature to sarcopenia...
January 2016: Molecular and Cellular Biochemistry
Brian J Morris, Randi Chen, Timothy A Donlon, Daniel S Evans, Gregory J Tranah, Neeta Parimi, Georg B Ehret, Christopher Newton-Cheh, Todd Seto, D Craig Willcox, Kamal H Masaki, Kei Kamide, Hirochika Ryuno, Ryosuke Oguro, Chikako Nakama, Mai Kabayama, Koichi Yamamoto, Ken Sugimoto, Kazunori Ikebe, Yukie Masui, Yasumichi Arai, Tatsuro Ishizaki, Yasuyuki Gondo, Hiromi Rakugi, Bradley J Willcox
BACKGROUND: The minor alleles of 3 FOXO3 single nucleotide polymorphisms (SNPs)-rs2802292, rs2253310, and rs2802288-are associated with human longevity. The aim of the present study was to test these SNPs for association with blood pressure (BP) and essential hypertension (EHT). METHODS: In a primary study involving Americans of Japanese ancestry drawn from the Family Blood Pressure Program II we genotyped 411 female and 432 male subjects aged 40-79 years and tested for statistical association by contingency table analysis and generalized linear models that included logistic regression adjusting for sibling correlation in the data set...
October 16, 2015: American Journal of Hypertension
Young Suk Choi, Joo Eun Song, Byung Soo Kong, Jae Won Hong, Silvia Novelli, Eun Jig Lee
PURPOSE: Foxo3 in female reproduction has been reported to regulate proliferation of granulose cells that form follicles. There are no reports so far that discuss on the role of Foxo3 in males. This study was designed to outline the role of Foxo3 in the testes. MATERIALS AND METHODS: Testes from mice at birth to postpartum week (PPW) 5 were isolated and examined for the expression of Foxo3 using immunostaining. To elucidate role of Foxo3 in Leydig cells, R2C cells were treated with luteinizing hormone (LH) and the phosphorylation of Foxo3...
November 2015: Yonsei Medical Journal
Y M Yuan, L Luo, Z Guo, M Yang, Y F Lin, C Luo
We investigated the effects of smoking and aging on proteins involved in the forkhead box O3 (FOXO3) signaling pathways in the lungs. Sixteen senescence-accelerated mouse-resistant 1 (SAMR1) and senescence-accelerated mouse-prone 8 (SAMP8) mice at 3 months of age were divided into a normally aged, smoke-exposed group (4 SAMR1 mice), a normally aged, air-exposed group (4 SAMR1 mice), an aging-accelerated, smoke-exposed group (4 SAMP8 mice), and an aging-accelerated, air-exposed group (4 SAMP8 mice). Expression of genes and proteins related to the FOXO3 signaling pathways in each group was examined by western blot analysis and immunohistochemistry...
2015: Genetics and Molecular Research: GMR
Ninu Poulose, Raghavan Raju
Sirtuins or Sir2 family of proteins are a class of NAD(+) dependent protein deacetylases which are evolutionarily conserved from bacteria to humans. Some sirtuins also exhibit mono-ADP ribosyl transferase, demalonylation and desuccinylation activities. Originally identified in the yeast, these proteins regulate key cellular processes like cell cycle, apoptosis, metabolic regulation and inflammation. Humans encode seven sirtuin isoforms SIRT1-SIRT7 with varying intracellular distribution. Apart from their classic role as histone deacetylases regulating transcription, a number of cytoplasmic and mitochondrial targets of sirtuins have also been identified...
November 2015: Biochimica et Biophysica Acta
Ha-Neui Kim, Li Han, Srividhya Iyer, Rafael de Cabo, Haibo Zhao, Charles A O'Brien, Stavros C Manolagas, Maria Almeida
Activation of Sirtuin1 (Sirt1), an nicotinamide adenine dinucleotide oxidized-dependent deacetylase, by natural or synthetic compounds like resveratrol, SRT2104, or SRT3025 attenuates the loss of bone mass caused by ovariectomy, aging, or unloading in mice. Conversely, Sirt1 deletion in osteoclast progenitors increases osteoclast number and bone resorption. Sirt1 deacetylates forkhead box protein (Fox) O1, FoxO3, and FoxO4, and thereby modulates their activity. FoxOs restrain osteoclastogenesis and bone resorption...
October 2015: Molecular Endocrinology
Octavian Bucur, Andreea Lucia Stancu, Maria Sinziana Muraru, Armelle Melet, Stefana Maria Petrescu, Roya Khosravi-Far
FOXO family members (FOXOs: FOXO1, FOXO3, FOXO4 and FOXO6) are important transcription factors and tumor suppressors controlling cell homeostasis and cell fate. They are characterized by an extraordinary functional diversity, being involved in regulation of cell cycle, proliferation, apoptosis, DNA damage response, oxidative detoxification, cell differentiation and stem cell maintenance, cell metabolism, angiogenesis, cardiac and other organ's development, aging, and other critical cellular processes. FOXOs are tightly regulated by reversible phosphorylation, ubiquitination, acetylation and methylation...
April 2014: Discoveries
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