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NAD+ depletion AND aging

Li Q Zhang, Leon Van Haandel, Min Xiong, Peixin Huang, Daniel P Heruth, Charlie Bi, Roger Gaedigk, Xun Jiang, Ding-You Li, Gerald Wyckoff, Dmitry N Grigoryev, Li Gao, Linheng Li, Min Wu, J Steven Leeder, Shui Qing Ye
Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt(-/-)) resulted in lethality at an early stage of mouse embryonic development and death within 5-10 days in adult mice accompanied by a 25...
March 23, 2017: Cell Death & Disease
Aaron Long, Nina Klimova, Tibor Kristian
NAD(+) catabolism and mitochondrial dynamics are important parts of normal mitochondrial function and are both reported to be disrupted in aging, neurodegenerative diseases, and acute brain injury. While both processes have been extensively studied there has been little reported on how the mechanisms of these two processes are linked. This review focuses on how downstream NAD(+) catabolism via NUDIX hydrolases affects mitochondrial dynamics under pathologic conditions. Additionally, several potential targets in mitochondrial dysfunction and fragmentation are discussed, including the roles of mitochondrial poly(ADP-ribose) polymerase 1(mtPARP1), AMPK, AMP, and intra-mitochondrial GTP metabolism...
March 14, 2017: Neurochemistry International
Caitlin R Ondracek, Vincent Frappier, Alison E Ringel, Cynthia Wolberger, Leonard Guarente
Sirtuin enzymes depend on NAD(+) to catalyze protein deacetylation. Therefore, the lowering of NAD(+) during aging leads to decreased sirtuin activity and may speed up aging processes in laboratory animals and humans. In this study, we used a genetic screen to identify two mutations in the catalytic domain of yeast Sir2 that allow the enzyme to function in an NAD(+)-depleted environment. These mutant enzymes give rise to a significant increase of yeast replicative lifespan and increase deacetylation by the Sir2 ortholog, SIRT1, in mammalian cells...
March 7, 2017: Cell Reports
Cao Ma, Chenchen Pi, Yue Yang, Lin Lin, Yingai Shi, Yan Li, Yulin Li, Xu He
Senescence restricts the development of applications involving mesenchymal stem cells (MSCs) in research fields, such as tissue engineering, and stem cell therapeutic strategies. Understanding the mechanisms underlying natural aging processes may contribute to the development of novel approaches to preventing age-related diseases or slowing individual aging processes. Nampt is a rate-limiting NAD biosynthetic enzyme that plays critical roles in energy metabolism, cell senescence and maintaining life spans. However, it remains unknown whether Nampt influences stem cell senescence...
2017: PloS One
Ki-Hong Jang, Yun-Ju Do, Dongwon Son, Eunji Son, Jun-Sub Choi, Eunhee Kim
Cell death of retinal pigment epithelium (RPE) is characterized as an essential late-stage phenomenon of dry age-related macular degeneration (AMD). The aim of this study was to elucidate the molecular mechanism underlying RPE cell death after exposure to oxidative stress, which occurs often because of the anatomical location of RPE cells. ARPE-19, an established RPE cell line, exhibited necrotic features involving poly (ADP-ribose) polymerase-1 (PARP-1) activation in response to hydrogen peroxide (H2O2). ARPE-19 cells were resistant to H2O2 when PARP-1 was depleted using siRNA or inhibited by a pharmacological inhibitor of PARP-1, olaparib...
January 5, 2017: Cell Death & Disease
Emma L James, James A E Lane, Ryan D Michalek, Edward D Karoly, E Kenneth Parkinson
Cellular senescence occurs by proliferative exhaustion (PEsen) or following multiple cellular stresses but had not previously been subject to detailed metabolomic analysis. Therefore, we compared PEsen fibroblasts with proliferating and transiently growth arrested controls using a combination of different mass spectroscopy techniques. PEsen cells showed many specific alterations in both the NAD+ de novo and salvage pathways including striking accumulations of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) in the amidated salvage pathway despite no increase in nicotinamide phosphoribosyl transferase or in the NR transport protein, CD73...
December 7, 2016: Scientific Reports
David W Frederick, Emanuele Loro, Ling Liu, Antonio Davila, Karthikeyani Chellappa, Ian M Silverman, William J Quinn, Sager J Gosai, Elisia D Tichy, James G Davis, Foteini Mourkioti, Brian D Gregory, Ryan W Dellinger, Philip Redpath, Marie E Migaud, Eiko Nakamaru-Ogiso, Joshua D Rabinowitz, Tejvir S Khurana, Joseph A Baur
NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance...
August 9, 2016: Cell Metabolism
Dong-Jie Li, Fang Huang, Min Ni, Hui Fu, Liang-Sheng Zhang, Fu-Ming Shen
OBJECTIVE: α7 nicotinic acetylcholine receptor (α7nAChR) is a subtype of nAChR and has been reported to be involved in hypertension end-organ damage. In this study, we tested the role of α7nAChR in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: Expression of α7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated β-galactosidase activity, phosphorylation of H2A...
August 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Ying Zhu, Ke-Ke Zhao, Yao Tong, Ya-Li Zhou, Yi-Xiao Wang, Pei-Quan Zhao, Zhao-Yang Wang
Increased oxidative stress, which can lead to the retinal pigment epithelium (RPE) cell death by inducing ATP depletion and DNA repair, is believed to be a prominent pathology in age-related macular degeneration (AMD). In the present study, we showed that and 0.1 mM nicotinamide adenine dinucleotide (NAD(+)) administration significantly blocked RPE cell death induced by 300 μM H2O2. Further investigation showed that H2O2 resulted in increased intracellular ROS level, activation of PARP-1 and subsequently necrotic death of RPE cells...
2016: Scientific Reports
Tarique Anwar, Sanjeev Khosla, Gayatri Ramakrishna
Sirtuins (SIRT) belonging to the NAD+ dependent histone deacetylase III class of enzymes have emerged as master regulators of metabolism and longevity. However, their role in prevention of organismal aging and cellular senescence still remains controversial. In the present study, we now report upregulation of SIRT2 as a specific feature associated with stress induced premature senescence but not with either quiescence or cell death. Additionally, increase in SIRT2 expression was noted in different types of senescent conditions such as replicative and oncogene induced senescence using multiple cell lines...
July 17, 2016: Cell Cycle
Laura C Shum, Noelle S White, Sergiy M Nadtochiy, Karen L de Mesy Bentley, Paul S Brookes, Jennifer H Jonason, Roman A Eliseev
Pathogenic factors associated with aging, such as oxidative stress and hormone depletion converge on mitochondria and impair their function via opening of the mitochondrial permeability transition pore (MPTP). The MPTP is a large non-selective pore regulated by cyclophilin D (CypD) that disrupts mitochondrial membrane integrity. MPTP involvement has been firmly established in degenerative processes in heart, brain, and muscle. Bone has high energy demands and is therefore expected to be highly sensitive to mitochondrial dysfunction...
2016: PloS One
Borut Poljsak, Irina Milisav
Oxidative stress and decreased DNA damage repair in vertebrates increase with age also due to lowered cellular NAD+. NAD+ depletion may play a major role in the aging process at the cellular level by limiting (1) energy production, (2) DNA repair, and (3) genomic signaling. In this study, we hypothesize that it is not NAD+ as a cofactor in redox reactions and coenzyme in metabolic processes that has the ultimate role in aging, but rather the role of NAD+ in cellular signaling when used as substrate for sirtuins (SIRT1-7 in mammals) and PARPs [Poly(ADP-ribose) polymerases]...
March 16, 2016: Rejuvenation Research
Jeffrey D Covington, Sudip Bajpeyi
The sirtuins represent a class of proteins first discovered orthologus to the yeast silent information regulator 2 protein that have been retained in mammalian species. Currently, seven sirtuins have been identified in humans, and their functions currently surpass their originally identified role as histone deacetylase and chromatin silencers to encompass nutrient sensing and metabolic function. All seven sirtuins require NAD(+) in order to carry out their enzymatic activity, and thus become activated in conditions of nutrient depletion, starvation, and cellular stress...
January 2016: Molecular Nutrition & Food Research
P Heinz-Erian, Z Akdar, B Haerter, S Waldegger, T Giner, S Scholl-Bürgi, T Mueller
UNLABELLED: In acute gastroenteritis (AG) fecal losses may cause depletion of sodium (NaD) which may not be recognized because of normal plasma Na (pNa) concentrations. We studied the incidence of this state of normonatremic sodium depletion (NNaD) and the suitability of the urinary Na/urinary creatinine ratio (uNa/uCr) for diagnosing NNaD. PATIENTS: 16 AG- and 16 healthy control children aged 0.8-15.0 years. METHODS: Prospective cross sectional pilot study...
January 2016: Klinische Pädiatrie
Alejandra P Oyarzún, Francisco Westermeier, Christian Pennanen, Camila López-Crisosto, Valentina Parra, Cristian Sotomayor-Flores, Gina Sánchez, Zully Pedrozo, Rodrigo Troncoso, Sergio Lavandero
AIM: FK866 is an inhibitor of the NAD(+) synthesis rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Using FK866 to target NAD(+) synthesis has been proposed as a treatment for inflammatory diseases and cancer. However, use of FK866 may pose cardiovascular risks, as NAMPT expression is decreased in various cardiomyopathies, with low NAD(+) levels playing an important role in cardiovascular disease progression. In addition, low NAD(+) levels are associated with cardiovascular risk conditions such as aging, dyslipidemia, and type II diabetes mellitus...
November 1, 2015: Biochemical Pharmacology
Joanne Clark-Matott, Ayesha Saleem, Ying Dai, Yevgeniya Shurubor, Xiaoxing Ma, Adeel Safdar, Myron Flint Beal, Mark Tarnopolsky, David K Simon
Mitochondrial DNA (mtDNA) mutator mice express a mutated form of mtDNA polymerase gamma that results an accelerated accumulation of somatic mtDNA mutations in association with a premature aging phenotype. An exploratory metabolomic analysis of cortical metabolites in sedentary and exercised mtDNA mutator mice and wild-type littermate controls at 9-10 months of age was performed. Pathway analysis revealed deficits in the neurotransmitters acetylcholine, glutamate, and aspartate that were ameliorated by exercise...
November 2015: Neurobiology of Aging
David P Enot, Mireia Niso-Santano, Sylvère Durand, Alexis Chery, Federico Pietrocola, Erika Vacchelli, Frank Madeo, Lorenzo Galluzzi, Guido Kroemer
Recently, we reported that saturated and unsaturated fatty acids trigger autophagy through distinct signal transduction pathways. Saturated fatty acids like palmitate (PA) induce autophagic responses that rely on phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3, best known as VPS34) and beclin 1 (BECN1). Conversely, unsaturated fatty acids like oleate (OL) promote non-canonical, PIK3C3- and BECN1-independent autophagy. Here, we explored the metabolic effects of autophagy-inducing doses of PA and OL in mice...
August 3, 2015: Cell Cycle
Sandra G Gonzalez Malagon, Anna N Melidoni, Diana Hernandez, Bilal A Omar, Lyndsey Houseman, Sunil Veeravalli, Flora Scott, Dorsa Varshavi, Jeremy Everett, Yugo Tsuchiya, John F Timms, Ian R Phillips, Elizabeth A Shephard
We report the production and metabolic phenotype of a mouse line in which the Fmo5 gene is disrupted. In comparison with wild-type (WT) mice, Fmo5(-/-) mice exhibit a lean phenotype, which is age-related, becoming apparent after 20 weeks of age. Despite greater food intake, Fmo5(-/-) mice weigh less, store less fat in white adipose tissue (WAT), have lower plasma glucose and cholesterol concentrations and enhanced whole-body energy expenditure, due mostly to increased resting energy expenditure, with no increase in physical activity...
August 1, 2015: Biochemical Pharmacology
Christoph Koentges, Katharina Pfeil, Tilman Schnick, Sebastian Wiese, Rabea Dahlbock, Maria C Cimolai, Maximilian Meyer-Steenbuck, Katarina Cenkerova, Michael M Hoffmann, Carsten Jaeger, Katja E Odening, Bernd Kammerer, Lutz Hein, Christoph Bode, Heiko Bugger
Sirtuin 3 (SIRT3) is a mitochondrial NAD(+)-dependent deacetylase that regulates energy metabolic enzymes by reversible protein lysine acetylation in various extracardiac tissues. The role of SIRT3 in myocardial energetics and in the development of mitochondrial dysfunction in cardiac pathologies, such as the failing heart, remains to be elucidated. To investigate the role of SIRT3 in the regulation of myocardial energetics and function SIRT3(-/-) mice developed progressive age-related deterioration of cardiac function, as evidenced by a decrease in ejection fraction and an increase in enddiastolic volume at 24 but not 8 weeks of age using echocardiography...
2015: Basic Research in Cardiology
Aaron N Long, Katrina Owens, Anna E Schlappal, Tibor Kristian, Paul S Fishman, Rosemary A Schuh
BACKGROUND: Mitochondrial dysfunction is a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with morphological and functional abnormalities limiting the electron transport chain and ATP production. A contributing factor of mitochondrial abnormalities is loss of nicotinamide adenine dinucleotide (NAD), an important cofactor in multiple metabolic reactions. Depletion of mitochondrial and consequently cellular NAD(H) levels by activated NAD glycohydrolases then culminates in bioenergetic failure and cell death...
2015: BMC Neurology
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