A metabolomic aging clock using human CSF

2021 ◽  
Author(s):  
Nathan Hwangbo ◽  
Xinyu Zhang ◽  
Daniel Raftery ◽  
Haiwei Gu ◽  
Shu-Ching Hu ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Healthy Aging ◽  
Prediction Models ◽  
Mass Spectrometry Analysis ◽  
Chronological Age ◽  
Healthy Human ◽  
Missing Data Imputation ◽  
Spectrometry Analysis ◽  
Residual Variation ◽  
Age Related

Abstract Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that in regression models using “-omic” platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these “omic clocks” provide measures of biological age. This paper presents predictive models for age using metabolomic profiles of cerebrospinal fluid from healthy human subjects, and finds that metabolite and lipid data are generally able to predict chronological age within 10 years. We use these models to predict the age of a cohort of subjects with Alzheimer’s and Parkinson’s disease and find an increase in prediction error, potentially indicating that the relationship between the metabolome and chronological age differs with these diseases. However, evidence is not found to support the hypothesis that our models will consistently over-predict the age of these subjects. In our analysis of control subjects, we find the carnitine shuttle, sucrose, biopterin, vitamin E metabolism, tryptophan, and tyrosine to be the most associated with age. We showcase the potential usefulness of age prediction models in a small dataset (n = 85), and discuss techniques for drift correction, missing data imputation, and regularized regression, which can be used to help mitigate the statistical challenges that commonly arise in this setting. To our knowledge, this work presents the first multivariate predictive metabolomic and lipidomic models for age using mass spectrometry analysis of cerebrospinal fluid.

scholarly journals An aging clock using metabolomic CSF

2021 ◽  
Author(s):  
Nathan Hwangbo ◽  
Xinyu Zhang ◽  
Daniel Raftery ◽  
Haiwei Gu ◽  
Shu-Ching Hu ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Healthy Aging ◽  
Prediction Models ◽  
Mass Spectrometry Analysis ◽  
Chronological Age ◽  
Healthy Human ◽  
Missing Data Imputation ◽  
Spectrometry Analysis ◽  
Residual Variation ◽  
Age Related

Quantifying the physiology of aging is essential for improving our understanding of age-related disease and the heterogeneity of healthy aging. Recent studies have shown that in regression models using "-omic" platforms to predict chronological age, residual variation in predicted age is correlated with health outcomes, and suggest that these "omic clocks" provide measures of biological age. This paper presents predictive models for age using metabolomic profiles of cerebrospinal fluid from healthy human subjects, and finds that metabolite and lipid data are generally able to predict chronological age within 10 years. We use these models to predict the age of a cohort of subjects with Alzheimer's and Parkinson's disease and find an increase in prediction error, potentially indicating that the relationship between the metabolome and chronological age differs with these diseases. In our analysis of control subjects, we find the carnitine shuttle, sucrose, biopterin, vitamin E metabolism, tryptophan, and tyrosine to be the most associated with age. We showcase the potential usefulness of age prediction models in a small dataset (n = 85), and discuss techniques for drift correction, missing data imputation, and regularized regression which can be used to help mitigate the statistical challenges that commonly arise in this setting. To our knowledge, this work presents the first multivariate predictive metabolomic and lipidomic models for age using mass spectrometry analysis of cerebrospinal fluid.

scholarly journals OTX2 homeoprotein functions in adult choroid plexus

2021 ◽  
Author(s):  
Anabelle Planques ◽  
Vanessa Oliveira Moreira ◽  
David Benacom ◽  
Clémence Bernard ◽  
Laurent Jourdren ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Stress Responses ◽  
Subventricular Zone ◽  
Adult Mouse ◽  
Mass Spectrometry Analysis ◽  
Mrna Isoforms ◽  
Spectrometry Analysis ◽  
Protein Partners ◽  
Brain Homeostasis

AbstractChoroid plexus secretes cerebrospinal fluid important for brain development and homeostasis. The OTX2 homeoprotein is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative roles for OTX2 in choroid plexus function, including cell signaling and adhesion, and show that it regulates the expression of factors secreted into cerebrospinal fluid, notably transthyretin. We show that Otx2 expression impacts choroid plexus immune and stress responses, and also affects splicing which leads to changes in mRNA isoforms of proteins implicated in oxidative stress response and DNA repair. Through mass spectrometry analysis of OTX2 protein partners in the choroid plexus, and in known non-cell autonomous target regions such as visual cortex and ventricular-subventricular zone, we identified putative targets involved in cell adhesion, chromatin structure and RNA processing. Thus, OTX2 retains important roles in choroid plexus function and brain homeostasis throughout life.

Mass spectrometry analysis of redox forms of High-Mobility Group Box-1 Protein in cerebrospinal fluid: initial experience.

2019 ◽  
Vol 88 (3) ◽  
pp. 171-176
Author(s):  
Agata Światły ◽  
Norbert Wąsik ◽  
Joanna Hajduk ◽  
Eliza Matuszewska ◽  
Paweł Dereziński ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
High Mobility ◽  
High Mobility Group ◽  
Mass Spectrometry Analysis ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Top Down ◽  
Spectrometry Analysis ◽  
Redox Forms

Introduction. High-mobility group box 1 (HMGB1) is an alarmin with proinflammatory potential determined by redox status of the cysteines at position 23 and 45. It may also play a role as a biomarker in biological fluids. The aim of this study was the identification of different HMGB1 redox forms in cerebrospinal fluid (CSF) obtained from subarachnoid hemorrhage patients. Material and Methods. 6 CSF samples were collected from aneurysmal subarachnoid haemorrhage patients. Commercially available HMGB1 isoforms served as a positive control. Immunoprecipitation and electrophoretic isolation of HMGB1 protein were performed, then both CSF and control were analyzed using mass spectrometry technique. To distinguish between fully reduced (thiol group at C23 and C45) and disulfide (disulfide bond connecting C23 and C45) HMGB1 forms, top-down sequencing of the spectra was performed. Results. Top-down sequencing analysis allowed to distinguish between HMGB1 isoforms only in commercially available standard without preceding immunoprecipitation and electrophoresis. MALDI spectra differ i.e. on the fully reduced HMGB1 spectrum fragmentation occurs before and beyond C22, which is not present on the disulfide HMGB1 spectrum. Analysis of HMGB1 isolated from CSF obtained from subarachnoid hemorrhage patients gave no results. Conclusions. Top-down sequencing enables to distinguish between redox forms of HMGB1. Electrophoresis and tryptic digestion cannot precede mass spectrometry analysis of redox forms of HMGB1 due to the reduction of disulfide bonds during these processes. Preferred method of isolation of HMGB1 for direct analysis using top-down sequencing mustn’t include protein digestion or degradation.

scholarly journals Resveratrol: A Sirtuin Activator and The Fountain of Youth

2015 ◽  
Vol 7 (1) ◽  
pp. 1 ◽  
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Caloric Restriction ◽  
Healthy Aging ◽  
Myocardial Infarct ◽  
Functional Decline ◽  
Steady Increase ◽  
Healthy Human ◽  
Aging Research ◽  
Human Lifespan ◽  
Age Related ◽  
Fountain Of Youth

BACKGROUND: An organism’s lifespan is inevitably accompanied by the aging process, which involves functional decline, a steady increase of a plethora of chronic diseases, and ultimately death. Thus, it has been an ongoing dream of mankind to improve healthspan and extend life.CONTENT: There are only a few proposed aging interventions: caloric restriction, exercise, and the use of low-molecular-weight compounds, including spermidine, metformin, resveratrol, and rapamycin. Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Resveratrol have been shown to prevent and reduce the severity of age-related diseases such as atherosclerosis, stroke, myocardial infarct, diabetes, neurodegenerative diseases, osteoarthritis, tumors and metabolic syndrome, along with their ability to extend lifespan.SUMMARY: The purpose of aging research is the identification of interventions that may avoid or ameliorate the ravages of time. In other words, the quest is for healthy aging, where improved longevity is coupled to a corresponding healthspan extension. It is only by extending the healthy human lifespan that we will truly meet the premise of the Roman poet Cicero: “No one is so old as to think that he may not live a year.”KEYWORDS: aging, caloric restriction, mimetic, healthspan, sirtuin activator

scholarly journals Multiple sclerosis has a distinct lipid signature in plasma and cerebrospinal fluid

2019 ◽  
Vol 77 (10) ◽  
pp. 696-704 ◽  
Author(s):  
Enedina Maria Lobato de OLIVEIRA ◽  
Daniela Antunes MONTANI ◽  
Diogo OLIVEIRA-SILVA ◽  
André Filipe RODRIGUES-OLIVEIRA ◽  
Sandro Luiz de Andrade MATAS ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Fatty Acids ◽  
Cerebrospinal Fluid ◽  
Permutation Test ◽  
Inflammatory Diseases ◽  
Neurological Diseases ◽  
Area Under The Curve ◽  
Mass Spectrometry Analysis ◽  
Detection Methods ◽  
Spectrometry Analysis

ABSTRACT The diagnosis of multiple sclerosis (MS) has changed over the last decade, but remains a composite of clinical assessment and magnetic resonance imaging to prove dissemination of lesions in time and space. The intrathecal synthesis of immunoglobulin may be a nonspecific marker and there are no plasma biomarkers that are useful in the diagnosis of MS, presenting additional challenges to their early detection. Methods We performed a preliminary untargeted qualitative lipidomics mass spectrometry analysis, comparing cerebrospinal fluid (CSF) and plasma samples from patients with MS, other inflammatory neurological diseases and idiopathic intracranial hypertension. Results Lipid identification revealed that fatty acids and sphingolipids were the most abundant classes of lipids in the CSF and that glycerolipids and fatty acids were the main class of lipids in the plasma of patients with MS. The area under the curve was 0.995 (0.912–1) and 0.78 (0.583–0.917), respectively. The permutation test indicated that this ion combination was useful for distinguishing MS from other inflammatory diseases (p < 0.001 and 0.055, respectively). Conclusion This study concluded that the CSF and plasma from patients with MS bear a unique lipid signature that can be useful as a diagnostic biomarker.

scholarly journals Human Skin, Oral, and Gut Microbiomes Predict Chronological Age

mSystems ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Shi Huang ◽  
Niina Haiminen ◽  
Anna-Paola Carrieri ◽  
Rebecca Hu ◽  
Lingjing Jiang ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Prediction Models ◽  
The Body ◽  
Oral Microbiome ◽  
Chronological Age ◽  
Future Research ◽  
Skin Microbiome ◽  
Age Related ◽  
Relative Value

ABSTRACT Human gut microbiomes are known to change with age, yet the relative value of human microbiomes across the body as predictors of age, and prediction robustness across populations is unknown. In this study, we tested the ability of the oral, gut, and skin (hand and forehead) microbiomes to predict age in adults using random forest regression on data combined from multiple publicly available studies, evaluating the models in each cohort individually. Intriguingly, the skin microbiome provides the best prediction of age (mean ± standard deviation, 3.8 ± 0.45 years, versus 4.5 ± 0.14 years for the oral microbiome and 11.5 ± 0.12 years for the gut microbiome). This also agrees with forensic studies showing that the skin microbiome predicts postmortem interval better than microbiomes from other body sites. Age prediction models constructed from the hand microbiome generalized to the forehead and vice versa, across cohorts, and results from the gut microbiome generalized across multiple cohorts (United States, United Kingdom, and China). Interestingly, taxa enriched in young individuals (18 to 30 years) tend to be more abundant and more prevalent than taxa enriched in elderly individuals (>60 yrs), suggesting a model in which physiological aging occurs concomitantly with the loss of key taxa over a lifetime, enabling potential microbiome-targeted therapeutic strategies to prevent aging. IMPORTANCE Considerable evidence suggests that the gut microbiome changes with age or even accelerates aging in adults. Whether the age-related changes in the gut microbiome are more or less prominent than those for other body sites and whether predictions can be made about a person’s age from a microbiome sample remain unknown. We therefore combined several large studies from different countries to determine which body site’s microbiome could most accurately predict age. We found that the skin was the best, on average yielding predictions within 4 years of chronological age. This study sets the stage for future research on the role of the microbiome in accelerating or decelerating the aging process and in the susceptibility for age-related diseases.

scholarly journals Allotype-specific processing of the CD16a N45-glycan from primary human natural killer cells and monocytes

Glycobiology ◽  
2020 ◽  
Vol 30 (7) ◽  
pp. 427-432
Author(s):  
Kashyap R Patel ◽  
Jacob T Roberts ◽  
Adam W Barb
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Surface Receptor ◽  
Mass Spectrometry Analysis ◽  
Healthy Human ◽  
Killer Cells ◽  
Spectrometry Analysis

Abstract Fc γ receptor IIIa/CD16a is an activating cell surface receptor with a well-defined role in natural killer (NK) cell and monocyte effector function. The extracellular domain is decorated with five asparagine (N)-linked glycans; N-glycans at N162 and N45 directly contribute to high-affinity antibody binding and protein stability. N-glycan structures at N162 showed significant donor-dependent variation in a recent study of CD16a isolated from primary human NK cells, but structures at N45 were relatively homogeneous. In this study, we identified variations in N45 glycan structures associated with a polymorphism coding for histidine instead of leucine at position 48 of CD16a from two heterozygous donors. It is known that H48 homozygous individuals suffer from immunodeficiency and recurrent viral infections. A mass spectrometry analysis of protein isolated from the primary natural killer cells of individuals expressing both CD16a L48 and H48 variants demonstrated clear processing differences at N45. CD16a H48 displayed a greater proportion of complex-type N45 glycans compared to the more common L48 allotype with predominantly hybrid N45-glycoforms. Structures at the four other N-glycosylation sites showed minimal differences from data collected on donors expressing only the predominant L48 variant. CD16a H48 purified from a pool of monocytes similarly displayed increased processing at N45. Here, we provide evidence that CD16a processing is affected by the H48 residue in primary NK cells and monocytes from healthy human donors.

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