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Age-Associated Blood Metabolite Levels Revealed Through Mass Spec Study

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NEW YORK (GenomeWeb) – A new study has identified several blood metabolites that either increase or decrease in quantity as people age.

Using nanospray ionization followed by liquid chromatography and mass spectrometry (LC-MS), scientists from the Okinawa Institute of Science and Technology (OIST) and Kyoto University found that older individuals exhibit lower levels of antioxidants and compounds involved in high physical activity — including carnosine, UDP-acetyl-glucosamine, ophthalmic acid, 1,5-anhydroglucitol, NAD+, and leucine — while compounds associated with declining kidney and liver function — such as N-acetyl-arginine, dimethyl-guanosine, and N6-acetyl-lysine — increase with age.

"There is strong correlation between aging and age-related metabolites," senior author Mitsuhiro Yangida, a professor at OIST, told GenomeWeb in an email. "Future work will clarify the nature of the aging phenotype. We really need knowledge of the molecular phenotype" associated with aging, he said.

Yanagida and his co-authors, including first author Romanas Chaleckis, also of OIST, published their study online last week in the Proceedings of the National Academy of Sciences.

"Individual variability in blood metabolites may lead to [the identification of] candidates for markers of human aging or relevant diseases," the authors wrote. That could help solve the riddle of aging, which has been well studied but poorly understood. Because the study simply assigned a coefficient of variation for metabolites to find those associated with age, it didn't delve into why blood cell metabolites might differ in older people.

While oxidative stress has long been thought to contribute to aging and has been shown to increase drastically over the last one-third of lifespan in almost all higher-order organisms, its effects on metabolites are not well-studied, according to Rodney Levine, a subject expert from the National Heart, Lung, and Blood Institute.

The new study's results did not appear to provide any jolting insight into the tangle of factors that could cause cells to age. Though older individuals' red blood cells contained lower levels of carnosine, which is an anti-oxidant, Yanagida said glutathione, an important anti-oxidant metabolite, showed highly constant levels across age groups.

Oxidative stress might inhibit any number of enzymatic reactions, Yanagida said, "but the proteins themselves might not be destroyed." Still, one of the study's findings suggested that decreased enzyme function in the urea cycle could explain a buildup of certain metabolites.

The impetus to perform the study came from a realization that there has been little publication on metabolites in red blood cells (RBCs). "This is strange," he said, since RBCs contribute to half of blood volume. "RBC metabolites should reflect well the state of the human body's conditions."

To perform the analysis, the scientists used a Thermo Fisher Scientific LTQ Orbitrap mass spectrometer following liquid chromatography separation on a ZIC-pHILIC column from Merck SeQuant. "The HILIC column is quite useful for separating many hydrophilic blood metabolites," the authors said. Yanagida said they chose the machine for its relative ease, but noted that a similar analysis could be performed using other equipment.

He also noted that the sample preparation included rapid quenching of blood samples to -40° C.

The researchers analyzed their data with MZmine 2 software and deposited their data sets in the MetaboLights database.

They looked at 126 metabolites, confirmed by tandem MS-MS analysis. Of those, 48 showed high coefficients of variation between individuals and 14 were shown to differ significantly between groups of young and elderly subjects.

The authors pointed to a number of interesting findings that warranted further study. Carnosine was highly enriched in red blood cells, compared to plasma, and could play an important role in RBC biology. Conversely, N-acetyl-arginine and dimethyl-guanosine were enriched in plasma and are known to be related to the urea cycle. Build up of these metabolites might signal a progressive decline in kidney enzyme function as people age, the authors said.

Yanagida said that his lab will continue to pursue this line of thought in search of keys to longevity. "Healthy longevity is the real longevity that people wish to pursue, so our further studies will extend towards such directions."

That research could potentially be performed in simpler model organisms.

"It is noteworthy that 11 of these 14 age-related compounds (except for 1,5-anhydroglucitol, carnosine, and acetyl-carnosine) are also present in fission yeast," the authors wrote, adding that "in the near future, genetics of these compounds in fission yeast and other organisms may be helpful to dissect their physiological and cytological significance."

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