Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites.

Dementia is caused by factors that damage neurons. We quantified small molecular markers in whole blood of dementia patients, using nontargeted liquid chromatography-mass spectroscopy (LC-MS). Thirty-three metabolites, classified into five groups (A to E), differed significantly in dementia patients, compared with healthy elderly subjects. Seven A metabolites present in plasma, including quinolinic acid, kynurenine, and indoxyl-sulfate, increased. Possibly they act as neurotoxins in the central nervous system (CNS). The remaining 26 compounds (B to E) decreased, possibly causing a loss of support or protection of the brain in dementia. Six B metabolites, normally enriched in red blood cells (RBCs), all contain trimethylated ammonium moieties. These metabolites include ergothioneine and structurally related compounds that have scarcely been investigated as dementia markers, validating the examination of RBC metabolites. Ergothioneine, a potent antioxidant, is significantly decreased in various cognition-related disorders, such as mild cognitive impairment and frailty. C compounds also include some oxidoreductants and are normally abundant in RBCs (NADP+, glutathione, adenosine triphosphate, pantothenate, S-adenosyl-methionine, and gluconate). Their decreased levels in dementia patients may also contribute to depressed brain function. Twelve D metabolites contains plasma compounds, such as amino acids, glycerophosphocholine, dodecanoyl-carnitine, and 2-hydroxybutyrate, which normally protect the brain, but their diminution in dementia may reduce that protection. Seven D compounds have been identified previously as dementia markers. B to E compounds may be critical to maintain the CNS by acting directly or indirectly. How RBC metabolites act in the CNS and why they diminish significantly in dementia remain to be determined.

Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility.

As human society ages globally, age-related disorders are becoming increasingly common. Due to decreasing physiological reserves and increasing organ system dysfunction associated with age, frailty affects many elderly people, compromising their ability to cope with acute stressors. Frail elderly people commonly manifest complex clinical symptoms, including cognitive dysfunction, hypomobility, and impaired daily activity, the metabolic basis of which remains poorly understood. We applied untargeted, comprehensive LC-MS metabolomic analysis to human blood from 19 frail and nonfrail elderly patients who were clinically evaluated using the Edmonton Frail Scale, the MoCA-J for cognition, and the TUG for mobility. Among 131 metabolites assayed, we identified 22 markers for frailty, cognition, and hypomobility, most of which were abundant in blood. Frailty markers included 5 of 6 markers specifically related to cognition and 6 of 12 markers associated with hypomobility. These overlapping sets of markers included metabolites related to antioxidation, muscle or nitrogen metabolism, and amino acids, most of which are decreased in frail elderly people. Five frailty-related metabolites that decreased-1,5-anhydroglucitol, acetyl-carnosine, ophthalmic acid, leucine, and isoleucine-have been previously reported as markers of aging, providing a metabolic link between human aging and frailty. Our findings clearly indicate that metabolite profiles efficiently distinguish frailty from nonfrailty. Importantly, the antioxidant ergothioneine, which decreases in frailty, is neuroprotective. Oxidative stress resulting from diminished antioxidant levels could be a key vulnerability for the pathogenesis of frailty, exacerbating illnesses related to human aging.

A newly designed compact CEY-XAFS cell in the soft X-ray region and its application to surface XAFS measurements under ambient-pressure conditions without photoinduced side effects.

We report a newly designed compact cell to measure XAFS spectra with the conversion electron yield (CEY) method in the soft X-ray region under ambient-pressure gas conditions. Secondary electrons generated from the gas and sample by collision of X-ray-absorption-induced Auger electrons are collected by a positively biased collector electrode to obtain XAFS spectra. It was confirmed that this cell is applicable to soft X-ray surface XAFS measurements for different types of materials such as insulating organic materials and metal oxides under 1 bar gas conditions. During the measurements, photoinduced side effects were observed; i.e. photoinduced degradation of organic materials and photoinduced reduction/oxidation of metal oxides. We found that these photoinduced side effects can be sufficiently suppressed by controlling the measuring conditions. The presented measuring approach will enable surface XAFS spectra to be obtained in the soft X-ray region for various types of functional materials under ambient-pressure working conditions.

Assessing nickel oxide electrocatalysts incorporating diamines and having improved oxygen evolution activity using operando UV/visible and X-ray absorption spectroscopy.

The electrolysis of water using renewable energy is a promising approach to developing a sustainable hydrogen-based economy. To improve the efficiency of this process, it will be necessary to develop highly active electrocatalysts that promote the oxygen evolution reaction (OER). In the present study, the OER activity of a nickel oxide electrocatalyst was dramatically improved following the addition of a diamine to the electrolyte solution during electrodeposition. Operando UV/vis absorption spectroscopy was used to assess a number of nickel catalysts containing various diamines and other organic compounds. The data indicate that Ni(II) complexes were formed with the diamines during electrodeposition. Consequently, the catalytic activity of these materials was enhanced based on increased concentrations of active reaction sites for the OER process. Ni K-edge X-ray absorption spectra showed that these catalysts were composed of γ-NiOOH with a Ni3.6+ valence state. The coordination of the diamine molecules to the γ-NiOOH produced structural distortion that contributed to improved OER activity. This structural distortion is likely the most important factor in enhancing the OER activity of inorganic-organic composite catalysts.

Efficient and rapid assessment of multiple aspects of frailty using the Kyoto Frailty Scale, developed from the Edmonton Frail Scale.

[Purpose] Global aging has led to a dramatic increase in the number of frail people, who are likely to become bedridden. Since frailty can be partially reversed, early intervention would be beneficial for patients, family members, and clinicians. This study was designed to develop a screening tool for an accurate and comprehensive assessment of frailty by modulating the Edmonton Frail Scale (EFS). [Participants and Methods] The EFS, covering multiple domains, is one of the major diagnostic tools for frailty. Frail and non-frail participants (n=67) were evaluated for each diagnostic item of the EFS to identify the most efficient combination of questions by evaluating its sensitivity and specificity. [Results] The Kyoto Frailty Scale (KFS) was developed as a rapid frailty scale, based on the EFS. The KFS comprises nine questions about health status, polypharmacy, hospitalization, living with a reliable caregiver, shopping, transportation, housework, money management, and forgetting to take medicine. The KFS has an excellent negative predictive value (100%) for screening frailty and a positive predictive value (97%) for screening prefrailty and frailty if we regard KFS ≥4 as a test positive. [Conclusion] The KFS permits clinician to rapidly and accurately screen for frailty and prefrailty, or exclude frailty.

Whole Blood Metabolomics in Aging Research.

Diversity is observed in the wave of global aging because it is a complex biological process exhibiting individual variability. To assess aging physiologically, markers for biological aging are required in addition to the calendar age. From a metabolic perspective, the aging hypothesis includes the mitochondrial hypothesis and the calorie restriction (CR) hypothesis. In experimental models, several compounds or metabolites exert similar lifespan-extending effects, like CR. However, little is known about whether these metabolic modulations are applicable to human longevity, as human aging is greatly affected by a variety of factors, including lifestyle, genetic or epigenetic factors, exposure to stress, diet, and social environment. A comprehensive analysis of the human blood metabolome captures complex changes with individual differences. Moreover, a non-targeted analysis of the whole blood metabolome discloses unexpected aspects of human biology. By using such approaches, markers for aging or aging-relevant conditions were identified. This information should prove valuable for future diagnosis or clinical interventions in diseases relevant to aging.

Individual variability in human blood metabolites identifies age-related differences.

Metabolites present in human blood document individual physiological states influenced by genetic, epigenetic, and lifestyle factors. Using high-resolution liquid chromatography-mass spectrometry (LC-MS), we performed nontargeted, quantitative metabolomics analysis in blood of 15 young (29 ± 4 y of age) and 15 elderly (81 ± 7 y of age) individuals. Coefficients of variation (CV = SD/mean) were obtained for 126 blood metabolites of all 30 donors. Fifty-five RBC-enriched metabolites, for which metabolomics studies have been scarce, are highlighted here. We found 14 blood compounds that show remarkable age-related increases or decreases; they include 1,5-anhydroglucitol, dimethyl-guanosine, acetyl-carnosine, carnosine, ophthalmic acid, UDP-acetyl-glucosamine,N-acetyl-arginine,N6-acetyl-lysine, pantothenate, citrulline, leucine, isoleucine, NAD(+), and NADP(+) Six of them are RBC-enriched, suggesting that RBC metabolomics is highly valuable for human aging research. Age differences are partly explained by a decrease in antioxidant production or increasing inefficiency of urea metabolism among the elderly. Pearson's coefficients demonstrated that some age-related compounds are correlated, suggesting that aging affects them concomitantly. Although our CV values are mostly consistent with those CVs previously published, we here report previously unidentified CVs of 51 blood compounds. Compounds having moderate to high CV values (0.4-2.5) are often modified. Compounds having low CV values, such as ATP and glutathione, may be related to various diseases because their concentrations are strictly controlled, and changes in them would compromise health. Thus, human blood is a rich source of information about individual metabolic differences.

Element selective oxidation on Rh-Pd bimetallic alloy surfaces.

The interactions between oxygen and Rh-Pd bimetallic alloy surfaces were investigated using surface sensitive experimental techniques and density functional theory calculations. The alloy surfaces were oxidized under 10-5 Torr and 100 mTorr oxygen upon heating above 250 °C. A thin Rh oxide layer was preferentially formed on a Rh1Pd9(100) surface, while a thin Pd oxide layer was formed on a Rh1Pd9(111) surface, though the Rh oxide is thermodynamically more stable irrespective of the surface orientation. Chemical analyses revealed that the initial Rh fraction for the (111) surface was significantly lower than that for the (100) surface, which suggests that the oxidized element on the surface is kinetically selected depending on the near surface initial composition.

In situ S-K XANES study of polymer electrolyte fuel cells: changes in the chemical states of sulfonic groups depending on humidity.

Changes in the chemical states of sulfonic groups of Nafion in polymer electrolyte fuel cells (PEFCs) under gas-flowing conditions were studied using in situ S-K XANES spectroscopy. The applied potential to the electrodes and the humidity of the cell were changed under flowing H2 gas in the anode and He gas in the cathode. While the potential shows no significant effect on the S-K XANES spectra, the humidity is found to induce reversible changes in the spectra. Comparison of the spectral changes with simulations based on the density functional theory calculations indicates that the humidity influences the chemical state of the sulfonic group; under wet conditions the sulfonic group is in the form of a sulfonate ion. By drying treatment the sulfonate ion binds to hydrogen and becomes sulfonic acid. Furthermore, a small fraction of the sulfonic acid irreversibly decomposes to atomic sulfur. The peak energy of the atomic sulfur suggests that the generated atomic sulfur is adsorbed on the Pt catalyst surfaces.

Dysregulated glycolysis as an oncogenic event.

Enhanced glycolysis in cancer, called the Warburg effect, is a well-known feature of cancer metabolism. Recent advances revealed that the Warburg effect is coupled to many other cancer properties, including adaptation to hypoxia and low nutrients, immortalisation, resistance to oxidative stress and apoptotic stimuli, and elevated biomass synthesis. These linkages are mediated by various oncogenic molecules and signals, such as c-Myc, p53, and the insulin/Ras pathway. Furthermore, several regulators of glycolysis have been recently identified as oncogene candidates, including the hypoxia-inducible factor pathway, sirtuins, adenosine monophosphate-activated kinase, glycolytic pyruvate kinase M2, phosphoglycerate mutase, and oncometabolites. The interplay between glycolysis and oncogenic events will be the focus of this review.

The overview for regulation of aging and the future perspective of anti-aging medicine.

Individual variability is one of the common features of aged human populations. As the popu- lation aging rate in Japan is forecasted to be over 40 % around 2050, physiological and patho- logical variability of aging is a rising big issue not only for medical scientist but also as social concerns. Such variability could be partly explained as consequences of human evolution, but decrease of death rates also facilitates it indirectly. Here we review on aging and anti- aging research in 21st century, which would play a significant role to dissolve the problems relevant to the following issues. That is, regulation of aging, epigenetics, removal of senescent cells, regeneration of the tissues, and environmental improvement.

Disruptive chemicals, senescence and immortality.

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.

Deacetylation of phosphoglycerate mutase in its distinct central region by SIRT2 down-regulates its enzymatic activity.

Substantially high rate of glycolysis, known as the Warburg effect, is a well-known feature of cancers, and emerging evidence suggests that it supports cancerous proliferation/tumor growth. Phosphoglycerate mutase (PGAM), a glycolytic enzyme, is commonly up-regulated in several cancers, and recent reports show its involvement in the Warburg effect. Here, a comprehensive analysis shows that PGAM is acetylated at lysines 100/106/113/138 in its central region, and a member of the Sirtuin family (class III deacetylase), SIRT2, is responsible for its deacetylation. Over-expression of SIRT2 or mutations at the acetylatable lysines of PGAM attenuates cancer cell proliferation with a concomitant decrease in PGAM activity. We also report that the acetyltransferase PCAF (p300/CBP-associated factor) interacts with PGAM and acetylates its C-terminus, but not the central region. As prior evidence suggests that SIRT2 functions as a tumor suppressor, our results would provide support for the mechanistic basis of this activity.

Hepatocyte nuclear factor-1ß (HNF-1ß) promotes glucose uptake and glycolytic activity in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a morphologically and biologically distinct subtype of ovarian carcinomas that often arises in ovarian endometriosis. We previously reported that a unique carcinogenic environment, especially iron-induced oxidative stress in endometriotic cysts may promote development of OCCC. We also identified a gene expression profile characteristic of OCCC (the "OCCC signature"). This 320-gene OCCC signature is enriched in genes associated with stress response and sugar metabolism. However, the biological implication of this profile is unclear. In this study, we have focused on the biological role of the HNF-1ß gene within the OCCC signature, which was previously shown to be overexpressed in OCCC. Suppression of HNF-1ß in the HNF-1ß-overexpressing human ovarian cancer cell line RMG2 using short hairpin RNA resulted in a significant increase in proliferation. It also facilitated glucose uptake, glycolytic activity, and lactate secretion along with increased expression of the glucose transporter-1 (GLUT-1) gene and several key enzymes in the glycolytic process. Conversely, forced expression of HNF-1ß in the serous ovarian cancer cell line, Hey, resulted in slowed cellular growth and repressed glycolytic activity. These data suggest that HNF-1ß represses cell growth, and at the same time, it promotes aerobic glycolysis which is known as the "Warburg effect." As the Warburg effect is regarded as a characteristic metabolic process in cancer which may contribute to cell survival under hypoxic conditions or in a stressful environment, overexpression of HNF-1ß may play an inevitable role in the occurrence of OCCC in stressful environment.

In situ observation of model catalysts under reaction conditions using X-ray core-level spectroscopy.

Chemical reactions at solid surfaces are of great importance in heterogeneous catalysis and the understanding of their reaction mechanisms has been challenged for a long time by a wide variety of approaches. In situ observation of model catalysts under reaction conditions is a promising approach to understand the mechanisms. Toward this aim we have been developing several spectroscopic techniques using synchrotron-radiation X-rays. In this Personal Account, synchrotron-radiation-based X-ray core-level spectroscopies for in situ observation are introduced and some of their applications in studying the mechanisms of catalytic reactions are highlighted. Future directions for further development of these spectroscopies are also described.

A high-pressure-induced dense CO overlayer on a Pt(111) surface: a chemical analysis using in situ near ambient pressure XPS.

We investigated the high-density CO adsorption phase formed on a Pt(111) surface when exposed to CO gas of pressure ranging from UHV to 100 mTorr using near-ambient-pressure (NAP)-XPS. Combined results from the NAP-XPS measurements and DFT calculations reveal the adsorption structure of CO molecules in the dense CO overlayer, which is stable under realistic conditions.

Metabolites in aging and aging-relevant diseases: Frailty, sarcopenia and cognitive decline.

Aging shows biologically complex features with high individual variability, which reflects the exposure to several stimuli and the adaptation to them. Among them, metabolic changes are well observed as consequences or possible causes of aging. Calorie restriction extends organismal life span in experimental models. Several metabolites; for example, resveratrol or nicotinamide mononucleotide, are reported to mimic calorie restriction effects in vivo. Metabolomic research would be useful to evaluate metabolites as biomarkers in aging-relevant events and to identify metabolic regulation of aging. We recently developed the metabolomic approach for whole blood analysis, which functions as strong tool for this purpose. We review the update findings in aging-relevant metabolites detected by this method. Geriatr Gerontol Int 2024; 24: 44-48.