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NAD+ depletion AND aging

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
K Nagai, T Matsushita, T Matsuzaki, K Takayama, T Matsumoto, R Kuroda, M Kurosaka
OBJECTIVE: SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. DESIGN: First, the localization of SIRT6 and proliferation cell nuclear antigen (PCNA) in human cartilages was examined by immunohistochemistry...
August 2015: Osteoarthritis and Cartilage
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...
December 2015: BMC Neurology
Roney Santos Coimbra, Bruno Frederico Aguilar Calegare, Talitah Michel Sanchez Candiani, Vânia D'Almeida
BACKGROUND: Acute bacterial meningitis frequently causes cortical and hippocampal neuron loss leading to permanent neurological sequelae. Neuron death in acute bacterial meningitis involves the excessive activation of NMDA receptors and p53-mediated apoptosis, and the latter is triggered by the depletion of NAD + and ATP cellular stores by the DNA repair enzyme poly(ADP-ribose) polymerase. This enzyme is activated during acute bacterial meningitis in response to DNA damage induced, on its turn, by reactive oxygen and nitrogen species...
2014: BMC Clinical Pathology
Leonard Guarente
Diseases due to DNA damage repair machinery defects can resemble premature aging. In this issue of Cell Metabolism, Scheibye-Knudsen et al. (2014) demonstrate that increasing NAD(+) levels may reverse the inactivation of Sirt1 and mitochondrial defects in Cockayne Syndrome B that stem from nuclear NAD(+) depletion by the DNA repair protein PARP.
November 4, 2014: Cell Metabolism
Nae-Cherng Yang, Tuzz-Ying Song, Yan-Zin Chang, Mei-Yau Chen, Miao-Lin Hu
Calorie restriction (CR) extends lifespan in a remarkable range of organisms. However, the mechanisms of CR related to the longevity effects are not fully elucidated to date. Using human fibroblast Hs68 (Hs68) cells cultured at a lower level of medium glucose (i.e., glucose restriction; GR) to mimic CR, we investigated the crucial role of nicotinamide phosphoribosyltransferase (Nampt), nicotinamide adenine dinucleotide (NAD(+)), and nicotinamide (NAM) in GR-extended replicative lifespan of Hs68 cells. We found that GR extended the lifespan of Hs68 cells, in parallel to significantly increased expression of Nampt, intracellular NAD(+) levels, and SIRT1 activities, and to significantly decreased NAM levels...
February 2015: Biogerontology
Morten Scheibye-Knudsen, Evandro Fei Fang, Deborah L Croteau, Vilhelm A Bohr
DNA repair is a prerequisite for life as we know it, and defects in DNA repair lead to accelerated aging. Xeroderma pigmentosum group A (XPA) is a classic DNA repair-deficient disorder with patients displaying sun sensitivity and cancer susceptibility. XPA patients also exhibit neurodegeneration, leading to cerebellar atrophy, neuropathy, and hearing loss, through a mechanism that has remained elusive. Using in silico, in vitro, and in vivo studies, we discovered defective mitophagy in XPA due to PARP1 hyperactivation and NAD(+) (and thus, SIRT1) depletion...
August 2014: Autophagy
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