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NAD+ depletion AND aging

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https://www.readbyqxmd.com/read/29080400/aging-and-stem-cell-therapy-ampk-as-an-applicable-pharmacological-target-for-rejuvenation-of-aged-stem-cells-and-achieving-higher-efficacy-in-stem-cell-therapy
#1
REVIEW
Mohammadhossein Khorraminejad-Shirazi, Mohammad Farahmandnia, Bahareh Kardeh, Alireza Estedlal, Sina Kardeh, Ahmad Monabati
In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy...
October 19, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/28984064/loss-of-sirt2-leads-to-axonal-degeneration-and-locomotor-disability-associated-with-redox-and-energy-imbalance
#2
Stéphane Fourcade, Laia Morató, Janani Parameswaran, Montserrat Ruiz, Tatiana Ruiz-Cortés, Mariona Jové, Alba Naudí, Paloma Martínez-Redondo, Mara Dierssen, Isidre Ferrer, Francesc Villarroya, Reinald Pamplona, Alejandro Vaquero, Manel Portero-Otín, Aurora Pujol
Sirtuin 2 (SIRT2) is a member of a family of NAD(+) -dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice...
December 2017: Aging Cell
https://www.readbyqxmd.com/read/28899755/nad-in-aging-molecular-mechanisms-and-translational-implications
#3
REVIEW
Evandro F Fang, Sofie Lautrup, Yujun Hou, Tyler G Demarest, Deborah L Croteau, Mark P Mattson, Vilhelm A Bohr
The coenzyme NAD(+) is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD(+) levels is important for cells with high energy demands and for proficient neuronal function. NAD(+) depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD(+) decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD(+) levels might retard aspects of aging and forestall some age-related diseases...
October 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28758328/the-path-from-mitochondrial-ros-to-aging-runs-through-the-mitochondrial-permeability-transition-pore
#4
REVIEW
Hagai Rottenberg, Jan B Hoek
Excessive production of mitochondrial reactive oxygen species (mROS) is strongly associated with mitochondrial and cellular oxidative damage, aging, and degenerative diseases. However, mROS also induces pathways of protection of mitochondria that slow aging, inhibit cell death, and increase lifespan. Recent studies show that the activation of the mitochondrial permeability transition pore (mPTP), which is triggered by mROS and mitochondrial calcium overloading, is enhanced in aged animals and humans and in aging-related degenerative diseases...
October 2017: Aging Cell
https://www.readbyqxmd.com/read/28752046/nicotinamide-riboside-kinases-display-redundancy-in-mediating-nicotinamide-mononucleotide-and-nicotinamide-riboside-metabolism-in-skeletal-muscle-cells
#5
Rachel S Fletcher, Joanna Ratajczak, Craig L Doig, Lucy A Oakey, Rebecca Callingham, Gabriella Da Silva Xavier, Antje Garten, Yasir S Elhassan, Philip Redpath, Marie E Migaud, Andrew Philp, Charles Brenner, Carles Canto, Gareth G Lavery
OBJECTIVE: Augmenting nicotinamide adenine dinucleotide (NAD(+)) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD(+) precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD(+). Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD(+) from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. METHODS: We exploited expression profiling of muscle NAD(+) biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD(+) recycling to evaluate NMN and NR utilization...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28552621/intestinal-epithelial-sirtuin-1-regulates-intestinal-inflammation-during-aging-in-mice-by-altering-the-intestinal-microbiota
#6
Alicia S Wellman, Mallikarjuna R Metukuri, Nevzat Kazgan, Xiaojiang Xu, Qing Xu, Natalie S X Ren, Agnieszka Czopik, Michael T Shanahan, Ashley Kang, Willa Chen, M Andrea Azcarate-Peril, Ajay S Gulati, David C Fargo, Leonard Guarente, Xiaoling Li
BACKGROUND & AIMS: Intestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD(+)-dependent protein deacetylase, senses environmental stress to alter intestinal integrity. METHODS: We performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1(flox/flox) mice) and control mice (villin-Cre-, Sirt1(flox/flox)) on a C57BL/6 background...
September 2017: Gastroenterology
https://www.readbyqxmd.com/read/28333140/metabolic-and-molecular-insights-into-an-essential-role-of-nicotinamide-phosphoribosyltransferase
#7
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
https://www.readbyqxmd.com/read/28302504/mitochondrial-nudix-hydrolases-a-metabolic-link-between-nad-catabolism-gtp-and-mitochondrial-dynamics
#8
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...
October 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28273448/mutations-that-allow-sir2-orthologs-to-function-in-a-nad-depleted-environment
#9
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
https://www.readbyqxmd.com/read/28125705/nampt-expression-decreases-age-related-senescence-in-rat-bone-marrow-mesenchymal-stem-cells-by-targeting-sirt1
#10
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
https://www.readbyqxmd.com/read/28055012/aif-independent-parthanatos-in-the-pathogenesis-of-dry-age-related-macular-degeneration
#11
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
https://www.readbyqxmd.com/read/27924925/replicatively-senescent-human-fibroblasts-reveal-a-distinct-intracellular-metabolic-profile-with-alterations-in-nad-and-nicotinamide-metabolism
#12
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
https://www.readbyqxmd.com/read/27508874/loss-of-nad-homeostasis-leads-to-progressive-and-reversible-degeneration-of-skeletal-muscle
#13
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
https://www.readbyqxmd.com/read/27339462/%C3%AE-7-nicotinic-acetylcholine-receptor-relieves-angiotensin-ii-induced-senescence-in-vascular-smooth-muscle-cells-by-raising-nicotinamide-adenine-dinucleotide-dependent-sirt1-activity
#14
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
https://www.readbyqxmd.com/read/27240523/exogenous-nad-decreases-oxidative-stress-and-protects-h2o2-treated-rpe-cells-against-necrotic-death-through-the-up-regulation-of-autophagy
#15
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
https://www.readbyqxmd.com/read/27229617/increased-expression-of-sirt2-is-a-novel-marker-of-cellular-senescence-and-is-dependent-on-wild-type-p53-status
#16
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
https://www.readbyqxmd.com/read/27183225/cyclophilin-d-knock-out-mice-show-enhanced-resistance-to-osteoporosis-and-to-metabolic-changes-observed-in-aging-bone
#17
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
https://www.readbyqxmd.com/read/26725653/nad-as-the-link-between-oxidative-stress-inflammation-caloric-restriction-exercise-dna-repair-longevity-and-health-span
#18
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
https://www.readbyqxmd.com/read/26463981/the-sirtuins-markers-of-metabolic-health
#19
REVIEW
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
https://www.readbyqxmd.com/read/26356318/decreased-urinary-sodium-to-urinary-creatinine-ratio-identifies-sodium-depletion-in-pediatric-acute-gastroenteritis
#20
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
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