Takayuki Teruya’s research while affiliated with Okinawa Institute of Science and Technology Graduate University and other places

Definitive differences in blood metabolite profiles between obese and non-obese Type 2 diabetes (T2D) have not been established. We performed an LC–MS-based non-targeted metabolomic analysis of whole blood samples collected from subjects classified into 4 types, based on the presence or absence of obesity and T2D. Of the 125 compounds identified, 20, comprising mainly nucleobases and glucose metabolites, showed significant increases or decreases in the T2D group. These included cytidine, UDP-glucuronate, UMP, 6-phosphogluconate, and pentose-phosphate. Among those 20 compounds, 11 enriched in red blood cells (RBCs) have rarely been studied in the context of diabetes, indicating that RBC metabolism is more extensively disrupted than previously known. Correlation analysis revealed that these T2D markers include 15 HbA1c-associated and 5 irrelevant compounds that may reflect diabetic conditions by a different mechanism than that of HbA1c. In the obese group, enhanced protein and fatty acid catabolism causes increases in 13 compounds, including methylated or acetylated amino acids and short-chain carnitines. Our study, which may be considered a pilot investigation, suggests that changes in blood metabolism due to obesity and diabetes are large, but essentially independent.

Ergothioneine is a well-known anti-oxidant that is abundant in both human red blood cells and in fission yeast responding to nutritional stress. In frail elderly people, whose aging organs undergo functional decline, there is a correlation between ergothioneine levels and cognitive, but not skeletal muscle decline. In patients suffering from dementia, including Alzheimer's disease with hippocampal atrophy, deteriorating cognitive ability is correlated with declining ergothioneine levels. S-methyl-ergothioneine, trimethyl-histidine, and three other trimethyl-ammonium compounds also decrease sharply in dementia, whereas compounds such as indoxyl-sulfate and quinolinic acid increase, possibly exacerbating the disease. Using these opposing dementia markers, not only diagnosis, but also therapeutic interventions to mitigate cognitive decline may now become possible.

Significance Dementia is a slowly progressing, chronic, and usually irreversible decline in cognitive function. Mechanistic causes and definitive treatments remain elusive. Using comprehensive metabolomics, we identified five groups of 33 metabolites (A to E), 13 of them previously reported, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimer’s disease. Seven A compounds may act as neurotoxins, whereas B to E compounds may protect the nervous system against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Five metabolites, ergothioneine, S -methyl-ergothioneine, trimethyl-histidine, methionine, and tryptophan, overlap with those reported for frailty. Interventions for cognitive diseases involving these dementia metabolomic markers may be accomplished either by inhibiting A compounds or by supplementing B to E compounds in patients.

Metabolites in human biofluids reflect individual physiological states influenced by various factors. Using liquid chromatography-mass spectrometry (LC–MS), we conducted non-targeted, non-invasive metabolomics using saliva of 27 healthy volunteers in Okinawa, comprising 13 young (30 ± 3 year) and 14 elderly (76 ± 4 year) subjects. Few studies have comprehensively identified age-dependent changes in salivary metabolites. Among 99 salivary metabolites, 21 were statistically age-related. All of the latter decline in abundance with advancing age, except ATP, which increased 1.96-fold in the elderly, possibly due to reduced ATP consumption. Fourteen age-linked and highly correlated compounds function in a metabolic network involving the pentose-phosphate pathway, glycolysis/gluconeogenesis, amino acids, and purines/pyrimidines nucleobases. The remaining seven less strongly correlated metabolites, include ATP, anti-oxidation-related glutathione disulfide, muscle-related acetyl-carnosine, N -methyl-histidine, creatinine, RNA-related dimethyl-xanthine and N -methyl-adenosine. In addition, glutamate and N -methyl-histidine are related to taste, so their decline suggests that the elderly lose some ability to taste. Reduced redox metabolism and muscle activity are suggested by changes in glutathione and acetyl-carnosine. These age-linked salivary metabolites together illuminate a metabolic network that reflects a decline of oral functions during human aging.

Due to global aging, frailty and sarcopenia are increasing. Sarcopenia is defined as loss of volume and strength of skeletal muscle in elderlies, while frailty involves multiple domains of aging-related dysfunction, impaired cognition, hypomobility, and decreased social activity. However, little is known about the metabolic basis of sarcopenia, either shared with or discrete from frailty. Here we analyzed comprehensive metabolomic data of human blood in relation to sarcopenia, previously collected from 19 elderly participants in our frailty study. Among 131 metabolites, we identified 22 sarcopenia markers, distinct from 15 frailty markers, mainly including antioxidants, although sarcopenia overlaps clinically with physical frailty. Notably, 21 metabolites that decline in sarcopenia or low SMI are uremic compounds that increase in kidney dysfunction. These comprise TCA cycle, urea cycle, nitrogen, and methylated metabolites. Sarcopenia markers imply a close link between muscle and kidney function, while frailty markers define a state vulnerable to oxidative stress.

Dementia is caused by factors that damage neurons. We quantified small molecular markers in whole blood of dementia patients, using non-targeted liquid chromatography-mass spectroscopy (LC-MS). Thirty-three metabolites, classified into 5 groups (A-E), differed significantly in dementia patients, compared with healthy elderly subjects. Seven Group 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 (Groups B-E) decreased, possibly causing a loss of support or protection of the brain in dementia. Six Group B metabolites, normally enriched in red blood cells (RBCs) of healthy subjects, all contain trimethylated ammonium moieties. These metabolites include ergothioneine and structurally related compounds have scarcely been investigated as dementia markers, validating the examination of RBC metabolites. Ergothioneine, a potent anti-oxidant, is significantly decreased in various cognition-related disorders, such as mild cognitive impairment and frailty. Group C compounds, also include some oxidoreductants and are normally abundant in RBCs (NADP ⁺ , glutathione, ATP, pantothenate, S-adenosyl-methionine, and gluconate). Their decreased levels in dementia patients may also contribute to depressed brain function. Groups D (12) contains plasma compounds, such as amino acids, glycerophosphocholine, dodecanoyl-carnitine, 2-hydroxybutyrate, which normally protect the brain, but their diminution in dementia may reduce that protection. Seven Group D compounds have been identified previously as dementia markers. Group B-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 so significantly in dementia remain to be determined. Significance Statement Dementia is a slowly progressing, chronic, and usually irreversible decline in cognitive function. Mechanistic causes and definitive treatments remain elusive. Using comprehensive metabolomics, we identified 5 groups of metabolites (A-E), 21 of which are novel, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimer’s disease. Seven Group A compounds may act as neurotoxins, whereas Group B-E compounds may protect the CNS against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Five metabolites, ergothioneine, S -methyl-ergothioneine, trimethyl-histidine, methionine, and tryptophan identified in this study overlap with those reported for frailty. Interventions for cognitive diseases involving these dementia metabolomic markers may be accomplished either by inhibiting Group A compounds or by supplementing Group B-E compounds in patients.

Metabolites in human biofluids document the physiological status of individuals. We conducted comprehensive, non‐targeted, non‐invasive metabolomic analysis of urine from 27 healthy human subjects, comprising 13 young adults (30 ± 3 years) and 14 seniors (76 ± 4 years). Quantitative analysis of 99 metabolites revealed 55 that displayed significant differences in abundance between the two groups. Forty‐four did not show a statistically significant relationship with age. These include 13 standard amino acids, 5 methylated, 4 acetylated, and 9 other amino acids, 6 nucleosides, nucleobases, and derivatives, 4 sugar derivatives, 5 sugar phosphates, 4 carnitines, 2 hydroxybutyrates, 1 choline, and 1 ethanolamine derivative, and glutathione disulfide. Abundances of 53 compounds decreased, while 2 (glutathione disulfide, myo‐inositol) increased in elderly people. The great majority of age‐linked markers were highly correlated with creatinine. In contrast, 44 other urinary metabolites, including urate, carnitine, hippurate, and betaine, were not age‐linked, neither declining nor increasing in elderly subjects. As metabolite profiles of urine and blood are quite different, age‐related information in urine offers additional valuable insights into aging mechanisms of endocrine system. Correlation analysis of urinary metabolites revealed distinctly inter‐related groups of compounds.

Since ancient days, human fasting has been performed for religious or political reasons. More recently, fasting has been employed as an effective therapy for weight reduction by obese people, and numerous studies have investigated the physiology of fasting by obese subjects. Well-established fasting markers (butyrates, BCAAs and carnitines) were considered essential energy substitutes after glycogen storage depletion. However, a recently developed metabolomic approach has unravelled previously unappreciated aspects of fasting. Surprisingly, one-third (44) of 120 metabolites investigated increase during 58 h of fasting, including antioxidative metabolites (carnosine, ophthalmic acid, ergothioneine and urates) and metabolites of entire pathways, such as the pentose phosphate pathway. Signalling metabolites (3-hydroxybutyrate and 2-oxoglutarate) and purines/pyrimidines may also serve as transcriptional modulators. Thus, prolonged fasting activates both global catabolism and anabolism, reprogramming metabolic homeostasis.