Abstract：
:Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases, including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Here we report that aging increases DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism, and physical fitness. DNA-PK phosphorylates threonines 5 and 7 of HSP90α, decreasing its chaperone function for clients such as AMP-activated protein kinase (AMPK), which is critical for mitochondrial biogenesis and energy metabolism. Decreasing DNA-PK activity increases AMPK activity and prevents weight gain, decline of mitochondrial function, and decline of physical fitness in middle-aged mice and protects against type 2 diabetes. In conclusion, DNA-PK is one of the drivers of the metabolic and fitness decline during aging, and therefore DNA-PK inhibitors may have therapeutic potential in obesity and low exercise capacity.
journal_name
Cell Metabjournal_title
Cell metabolismauthors
Park SJ,Gavrilova O,Brown AL,Soto JE,Bremner S,Kim J,Xu X,Yang S,Um JH,Koch LG,Britton SL,Lieber RL,Philp A,Baar K,Kohama SG,Abel ED,Kim MK,Chung JHdoi
10.1016/j.cmet.2017.04.008subject
Has Abstractpub_date
2017-05-02 00:00:00pages
1135-1146.e7issue
5eissn
1550-4131issn
1932-7420pii
S1550-4131(17)30213-9journal_volume
25pub_type
杂志文章相关文献
Cell Metabolism文献大全abstract：:C. difficile infection is a deadly disease that is influenced by the microbiome. In a recent article in Nature, Buffie et al. (2014) demonstrate that the ability of C. scindens to synthesize secondary bile acids is crucial to providing resistance to C. difficile infection. ...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2014.12.016
更新日期：2015-01-06 00:00:00
abstract：:Small-molecule ligands of nuclear hormone receptors (NHRs) govern the transcriptional regulation of metazoan development, cell differentiation, and metabolism. However, the physiological ligands of many NHRs remain poorly characterized, primarily due to lack of robust analytical techniques. Using comparative metabolom...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2013.11.024
更新日期：2014-01-07 00:00:00
abstract：:In this issue of Cell Metabolism, Mounier et al. (2013) show that AMPKα1 is a crucial contributor to the regeneration of damaged muscle tissues, acting in macrophages at the nexus between proinflammatory debris removal and resolution of muscle tissue inflammation. ...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2013.07.011
更新日期：2013-08-06 00:00:00
abstract：:In the face of the current obesity epidemic, the nature of the relationship between overnutrition and type 2 diabetes is of great importance. Obesity can be considered a state of excessive insulin action that elicits a series of cellular homeostatic responses, producing systemic insulin resistance. These responses occ...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2012.03.001
更新日期：2012-06-06 00:00:00
abstract：:Accumulation of unfolded protein within the endoplasmic reticulum (ER) attenuates mRNA translation through PERK-mediated phosphorylation of eukaryotic initiation factor 2 on Ser51 of the alpha subunit (eIF2alpha). To elucidate the role of eIF2alpha phosphorylation, we engineered mice for conditional expression of homo...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2009.06.002
更新日期：2009-07-01 00:00:00
abstract：:Glucose and hormone responsiveness of pancreatic β cells is acquired during postnatal maturation and is critical for appropriate insulin secretion. In a recent issue of Cell Metabolism, Yoshihara et al. (2016) report that estrogen-related receptor γ (ERRγ) promotes functional maturation of both mouse neonatal β cells ...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2016.04.026
更新日期：2016-05-10 00:00:00
abstract：:Mitochondrial fission is sustained through contact with several organelles, including the endoplasmic reticulum, lysosomes, and the actin cytoskeleton. Nagashima et al. (2020) now demonstrate that PI(4)P-containing Golgi-derived vesicles also modulate mitochondrial fission, driven by Arf1 and PI(4)KIIIβ activity, iden...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2020.05.010
更新日期：2020-06-02 00:00:00
abstract：:Reductionist in vitro T cell assays have identified metabolic pathways critical for T cell function within the tumor microenvironment. We discuss the challenges of testing these concepts using in vivo tumor models. ...
journal_title：Cell metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.cmet.2018.07.009
更新日期：2018-08-07 00:00:00
abstract：:Reducing obesity requires an elevation of energy expenditure and/or a suppression of food intake. Here we show that enhancing hepatic glycolysis reduces body weight and adiposity in obese mice. Overexpression of glucokinase or 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is used to increase hepatic glycolysis....
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2005.07.003
更新日期：2005-08-01 00:00:00
abstract：:Plasticity in growth and reproductive behavior is found in many vertebrate species, but is common in male teleost fish. Typically, "bourgeois" males are considerably larger and defend breeding territories while "parasitic" variants are small and use opportunistic breeding strategies. The P locus mediates this phenotyp...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2011.12.014
更新日期：2012-02-08 00:00:00
abstract：:With the identification of its receptor in a highly specific region of the brain, interesting issues come to light regarding the normal physiological functions of GDF15, a secreted protein long identified as a biomarker of diverse disease states. ...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2017.10.017
更新日期：2017-12-05 00:00:00
abstract：:Individuals with elevated LDL-cholesterol levels have an increased risk for cardiovascular disease. Despite lipid lowering strategies, however, a significant cardiovascular risk remains. Bekkering et al. show that monocytes from patients with familial hypercholesterolemia have a trained immunity phenotype and that lip...
journal_title：Cell metabolism
pub_type： 信件
doi：10.1016/j.cmet.2019.05.014
更新日期：2019-07-02 00:00:00
abstract：:As a preview of the upcoming Cell Symposium on Exercise Metabolism in Gothenburg, Sweden, May 21-23 (http://cell-symposia.com/exercisemetabolism-2017/), several of our speakers and other Cell Press exercise enthusiasts share a wide range of experiences from bench pressing goals to bench research insights. ...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2017.04.024
更新日期：2017-05-02 00:00:00
abstract：:Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as a...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2014.10.009
更新日期：2014-12-02 00:00:00
abstract：:Physical performance relies on the concerted action of myriad responses, many of which are under circadian clock control. Little is known, however, regarding the time-dependent effect on exercise performance at the molecular level. We found that both mice and humans exhibit daytime variance in exercise capacity betwee...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2019.03.012
更新日期：2019-07-02 00:00:00
abstract：:Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2015.01.009
更新日期：2015-02-03 00:00:00
abstract：:Light is a powerful synchronizer of the circadian rhythms, and bright light therapy is known to improve metabolic and hormonal status of circadian rhythm sleep disorders, although its mechanism is poorly understood. In the present study, we revealed that light induces gene expression in the adrenal gland via the supra...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2005.09.009
更新日期：2005-11-01 00:00:00
abstract：:Cancer cells that leave their natural environment during metastatic spread must adapt to numerous stresses to survive. In this issue, Labuschagne et al. (2019) highlight one adaptive mechanism to overcome these stresses that involves cell clustering, which induces a hypoxic environment and metabolic rewiring to buffer...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2019.09.008
更新日期：2019-10-01 00:00:00
abstract：:Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is sig...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2018.12.019
更新日期：2019-04-02 00:00:00
abstract：:Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2020.08.004
更新日期：2020-09-01 00:00:00
abstract：:Obesity and atherosclerosis-related diseases account for over one-third of deaths in the western world. Controlling these conditions remains a major challenge due to an incomplete understanding of the molecular pathways involved. Here, we show that Wip1 phosphatase, a known negative regulator of Atm-dependent signalin...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2012.06.003
更新日期：2012-07-03 00:00:00
abstract：:Although variants in the IGF2BP2/IMP2 gene confer risk for type 2 diabetes, IMP2, an RNA binding protein, is not known to regulate metabolism. Imp2(-/-) mice gain less lean mass after weaning and have increased lifespan. Imp2(-/-) mice are highly resistant to diet-induced obesity and fatty liver and display superior g...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2015.03.006
更新日期：2015-04-07 00:00:00
abstract：:Reduced folate levels can cause developmental defects and megaloblastic anemia. Padmanabhan et al. (2013) show that mutation in mice of a folate metabolism gene, Mtrr, which encodes for methionine synthase reductase, causes developmental defects not only in the mutant progeny, but also in genetically wild-type descend...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2013.09.016
更新日期：2013-10-01 00:00:00
abstract：:Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are major phospholipids in mammalian membranes. In liver, PC is synthesized via the choline pathway or by methylation of PE via phosphatidylethanolamine N-methyltransferase (PEMT). Pemt(-/-) mice fed a choline-deficient (CD) diet develop rapid steatohepatitis ...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2006.03.007
更新日期：2006-05-01 00:00:00
abstract：:Microglia play a crucial role in immune responses, including inflammation. Diet-induced obesity (DIO) triggers microglia activation and hypothalamic inflammation as early as 3 days after high-fat diet (HFD) exposure, before changes in body weight occur. The intracellular mechanism(s) responsible for HFD-induced microg...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2019.08.010
更新日期：2019-11-05 00:00:00
abstract：:Type 2 diabetes is a genetically heterogeneous disease, with several relatively rare monogenic forms and a number of more common forms resulting from a complex interaction of genetic and environmental factors. Previous studies using a candidate gene approach, family linkage studies, and gene expression profiling uncov...
journal_title：Cell metabolism
pub_type： 杂志文章,评审
doi：10.1016/j.cmet.2008.08.006
更新日期：2008-09-01 00:00:00
abstract：:In mice, interleukin-6 (IL-6) improves glucose tolerance via stimulation of glucagon-like peptide 1 (GLP-1) secretion. In this issue of Cell Metabolism, Lang Lehrskov et al. (2018) demonstrate that IL-6 infusion has GLP-1-dependent and -independent actions with opposing effects on glucose tolerance, resulting in an ov...
journal_title：Cell metabolism
pub_type： 评论,杂志文章
doi：10.1016/j.cmet.2018.05.013
更新日期：2018-06-05 00:00:00
abstract：:The conversion of lipolysis-derived fatty acids into ketone bodies (ketogenesis) is a crucial metabolic adaptation to prolonged periods of food scarcity. The process occurs primarily in liver mitochondria and is initiated by fatty-acid-mediated stimulation of the ligand-operated transcription factor, peroxisome prolif...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2018.09.014
更新日期：2019-01-08 00:00:00
abstract：:The Saccharomyces cerevisiae chromatin silencing factor Sir2 suppresses genomic instability and extends replicative life span. In contrast, we find that mouse embryonic fibroblasts (MEFs) deficient for SIRT1, a mammalian Sir2 homolog, have dramatically increased resistance to replicative senescence. Extended replicati...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2005.06.007
更新日期：2005-07-01 00:00:00
abstract：:The role of microbial load during aging of the adult fruit fly Drosophila melanogaster is incompletely understood. Here we show dramatic increases in aerobic and anaerobic bacterial load during aging, both inside the body and on the surface. Scanning electron microscopy and cell staining analyses of the surface of age...
journal_title：Cell metabolism
pub_type： 杂志文章
doi：10.1016/j.cmet.2007.06.006
更新日期：2007-08-01 00:00:00
