Low plasma lysophosphatidylcholines are associated with impaired mitochondrial oxidative capacity in adults in the Baltimore Longitudinal Study of Aging

Semba, Richard D.; Zhang, Pingbo; Adelnia, Fatemeh; Sun, Kai; González-Freire, Marta; Salem, Norman; Brennan, Nicholas A.; Spencer, Richard G.; Fishbein, Kenneth W.; Khadeer, Mohammed; Shardell, Michelle; Moaddel, Ruin; Ferrucci, Luigi

doi:10.1111/acel.12915

Cited by 44 publications

(29 citation statements)

References 35 publications

(42 reference statements)

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“…[37][38][39] Additionally, Semba et al have recently shown that low plasma LPC levels in humans, particularly LPC(16:1) and LPC(20:3), are associated with impaired mitochondrial oxidative capacity in skeletal muscle during ageing. 40 This dysregulation was also shown to be involved in muscle atrophy of tumour-bearing animals; however, this has yet to be confirmed in cancer patients. 41 In the present study, TAG species containing FA (18:3) and FA (20:5) in particular, were reduced in the plasma of cachectic cancer patients.…”

Section: Discussionmentioning

confidence: 99%

High levels of modified ceramides are a defining feature of murine and human cancer cachexia

Morigny

Zuber

Haid

et al. 2020

J cachexia sarcopenia muscle

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Background Cancer cachexia (CCx) is a multifactorial energy-wasting syndrome reducing the efficiency of anti-cancer therapies, quality of life, and survival of cancer patients. In the past years, most studies focused on the identification of tumour and host-derived proteins contributing to CCx. However, there is still a lack of studies addressing the changes in bioactive lipids. The aim of this study was to identify specific lipid species as a hallmark of CCx by performing a broad range lipid analysis of plasma from well-established CCx mouse models as well as cachectic and weight stable cancer patients. Methods Plasma from non-cachectic (PBS-injected mice, NC26 tumour-bearing mice), pre-cachectic and cachectic mice (C26 and LLC tumour-bearing mice, Apc Min/+ mutant mice), and plasma from weight stable and cachectic patients with gastrointestinal cancer, were analysed using the Lipidyzer ™ platform. In total, 13 lipid classes and more than 1100 lipid species, including sphingolipids, neutral and polar glycerolipids, were covered by the analysis. Correlation analysis between specific lipid species and readouts of CCx were performed. Lipidomics data were confirmed by gene expression analysis of metabolic organs to analyse enzymes involved in sphingolipid synthesis and degradation. Results A decrease in several lysophosphatidylcholine (LPC) species and an increase in numerous sphingolipids including sphingomyelins (SMs), ceramides (CERs), hexosyl-ceramides (HCERs) and lactosyl-ceramides (LCERs), were mutual features of CCx in both mice and cancer patients. Notably, sphingolipid levels gradually increased during cachexia development. Key enzymes involved in ceramide synthesis were elevated in liver but not in adipose, muscle, or tumour tissues, suggesting that ceramide turnover in the liver is a major contributor to elevated sphingolipid levels in

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Section: Discussionmentioning

confidence: 99%

High levels of modified ceramides are a defining feature of murine and human cancer cachexia

Morigny

Zuber

Haid

et al. 2020

J cachexia sarcopenia muscle

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“…The sets of features (variables) were imputed into four algorithms from the CARET package (v6.0-86), neural networks (NN) [ 124 , 125 , 126 ], Bayesian general linear model [ 127 ], C5.0 and RF [ 128 ]. In the feature selection step, RF is used to select features, whereas in the training step it is used as a classification algorithm.…”

Section: Methodsmentioning

confidence: 99%

Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach

Urmán

Herranz

Uriarte

et al. 2020

Cancers

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Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n = 36) and malignant conditions, CCA (n = 36) or PDAC (n = 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n = 10) and proteins (n = 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.

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“…With regard to phospholipids, low plasma levels of lysophosphatidylcholines were found to be associated with impaired mitochondrial oxidative capacity in adults (Semba et al, ). Lower levels of blood phospholipids, including the lysophosphatidylcholine 18:2, were separately shown to be highly predictive of memory impairment in older adults (Mapstone et al, ).…”

Section: Lipid Biomarkers Of Aging In Humansmentioning

confidence: 99%

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

2019

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An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.

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Low plasma lysophosphatidylcholines are associated with impaired mitochondrial oxidative capacity in adults in the Baltimore Longitudinal Study of Aging

Cited by 44 publications

References 35 publications

High levels of modified ceramides are a defining feature of murine and human cancer cachexia

High levels of modified ceramides are a defining feature of murine and human cancer cachexia

Pilot Multi-Omic Analysis of Human Bile from Benign and Malignant Biliary Strictures: A Machine-Learning Approach

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

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