METABOLIC FLEXIBILITY IN CLASSICAL MONOCYTES IS NOT AFFECTED BY AGE

Abstract Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism and would have impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose starvation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose starvation, at least in an ex vivo context.

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Monocytes from Older Adults Maintain Capacity for Metabolic Compensation during Glucose Deprivation and Lipopolysaccharide Stimulation

10.1101/633354 ◽

2019 ◽

Author(s):

Johnathan R. Yarbro ◽

Brandt D. Pence

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Immune Cell ◽

Ex Vivo ◽

Glucose Deprivation ◽

Inflammatory Cells ◽

Acid Oxidation ◽

Low Grade ◽

Cell Functions ◽

Age Related

ABSTRACTInflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism along with impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose deprivation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose deprivation, at least in an ex vivo context.

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Abstract 12117: The Cardioprotection of Trimetazidine Against Ischemic Injury is Mediated by AMPK and ERK Signaling Pathway

Circulation ◽

10.1161/circ.130.suppl_2.12117 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Zhenling Liu ◽

Yina Ma ◽

Michelle Kuznicki ◽

Xingchi Chen ◽

Wanqing Sun ◽

...

Keyword(s):

Myocardial Infarction ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Ex Vivo ◽

Ischemic Injury ◽

Erk Signaling ◽

Acid Oxidation ◽

Ampk Signaling ◽

Heart Perfusion

Introduction: Trimetazidine (TMZ) is an anti-anginal drug that has been widely used in Europe and Asia. The TMZ can optimize energy metabolism via inhibition of long-chain 3-ketoacyl CoA thiolase (3-KAT) in the heart, with subsequent decrease in fatty acid oxidation and stimulation of glucose oxidation. However, the mechanism by which TMZ aids in cardioprotection against ischemic injury has not been characterized. Hypothesis: AMP-activated protein kinase (AMPK) is an energy sensor that control ATP supply from substrate metabolism and protect heart from energy stress. TMZ changes the cardiac AMP/ATP ratio via modulating fatty acid oxidation, thereby it may trigger AMPK signaling cascade that contribute to protection heart from ischemia/reperfusion (I/R) injury. Methods: The mouse in vivo regional ischemia and reperfusion by the ligation of the left anterior descending coronary artery (LAD) were used for determination of myocardial infarction. The infarct size was compared between C57BL/6J WT mice and AMPK kinase dead (KD) transgenic mice with or without TMZ treatment. The ex vivo working heart perfusion system was used to monitor the effect of TMZ on glucose oxidation and fatty acid oxidation in the heart. Results: TMZ treatment significantly stimulates cardiac AMPK and extracellular signal-regulated kinase (ERK) signaling pathways (p<0.05 vs. vehicle group). The administration of TMZ reduces myocardial infarction size in WT C57BL/6J hearts, the reduction of myocardial infarction size by TMZ in AMPK KD hearts was significantly impaired versus WT hearts (p<0.05). Intriguingly, the administration of ERK inhibitor, PD 98059, to AMPK KD mice abolished the cardioprotection of TMZ against I/R injury. The ex vivo working heart perfusion data demonstrated that TMZ treatment significantly activates AMPK signaling and modulating the substrate metabolism by shifting fatty acid oxidation to glucose oxidation during reperfusion, leading to reduction of oxidative stress in the I/R hearts. Conclusions: Both AMPK and ERK signaling pathways mediate the cardioprotection of TMZ against ischemic injury. The metabolic benefits of TMZ for angina patients could be due to the activation of energy sensor AMPK in the heart by TMZ administration.

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Western diet, but not high fat diet, causes derangements of fatty acid metabolism and contractile dysfunction in the heart of Wistar rats

Biochemical Journal ◽

10.1042/bj20070392 ◽

2007 ◽

Vol 406 (3) ◽

pp. 457-467 ◽

Cited By ~ 102

Author(s):

Christopher R. Wilson ◽

Mai K. Tran ◽

Katrina L. Salazar ◽

Martin E. Young ◽

Heinrich Taegtmeyer

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

High Fat Diet ◽

Ex Vivo ◽

Western Diet ◽

Acid Oxidation ◽

Contractile Dysfunction ◽

High Fat ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

Obesity and diabetes are associated with increased fatty acid availability in excess of muscle fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction and also in the development of skeletal-muscle insulin resistance. We tested the hypothesis that ‘Western’ and high fat diets differentially cause maladaptation of cardiac- and skeletal-muscle fatty acid oxidation, resulting in cardiac contractile dysfunction. Wistar rats were fed on low fat, ‘Western’ or high fat (10, 45 or 60% calories from fat respectively) diet for acute (1 day to 1 week), short (4–8 weeks), intermediate (16–24 weeks) or long (32–48 weeks) term. Oleate oxidation in heart muscle ex vivo increased with high fat diet at all time points investigated. In contrast, cardiac oleate oxidation increased with Western diet in the acute, short and intermediate term, but not in the long term. Consistent with fatty acid oxidation maladaptation, cardiac power decreased with long-term Western diet only. In contrast, soleus muscle oleate oxidation (ex vivo) increased only in the acute and short term with either Western or high fat feeding. Fatty acid-responsive genes, including PDHK4 (pyruvate dehydrogenase kinase 4) and CTE1 (cytosolic thioesterase 1), increased in heart and soleus muscle to a greater extent with feeding a high fat diet compared with a Western diet. In conclusion, we implicate inadequate induction of a cassette of fatty acid-responsive genes, and impaired activation of fatty acid oxidation, in the development of cardiac dysfunction with Western diet.

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6-gingerol ameliorates age-related hepatic steatosis: Association with regulating lipogenesis, fatty acid oxidation, oxidative stress and mitochondrial dysfunction

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2018.11.001 ◽

2019 ◽

Vol 362 ◽

pp. 125-135 ◽

Cited By ~ 9

Author(s):

Jinxiu Li ◽

Shang Wang ◽

Ling Yao ◽

Peng Ma ◽

Zhiwei Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Mitochondrial Dysfunction ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Age Related

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A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b17-00371 ◽

2018 ◽

Vol 41 (1) ◽

pp. 29-35 ◽

Cited By ~ 11

Author(s):

Hye Jin An ◽

Bonggi Lee ◽

Seong Min Kim ◽

Dae Hyun Kim ◽

Ki Wung Chung ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Lipid Accumulation ◽

Acid Oxidation ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation ◽

Age Related

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Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging

F1000Research ◽

10.12688/f1000research.11881.1 ◽

2018 ◽

Vol 7 ◽

pp. 125 ◽

Cited By ~ 13

Author(s):

Clovis S. Palmer ◽

Riya Palchaudhuri ◽

Hassan Albargy ◽

Mohamed Abdel-Mohsen ◽

Suzanne M. Crowe

Keyword(s):

Hiv Infection ◽

Immune Cells ◽

Cell Activation ◽

Viral Infections ◽

Immune Cell ◽

Metabolic Reprogramming ◽

Low Grade ◽

Hiv Cure ◽

Cell Functions ◽

Age Related

An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of “inflammaging”, a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV+individuals.

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