May critical molecular cross-talk between indoleamine 2,3-dioxygenase (IDO) and arginase during human aging be targets for immunosenescence control?

Ismael Dale Cotrim Guerreiro da Silva,Dirce Maria Lobo Marchioni,Antonio Augusto Ferreira Carioca,Gisele Wally Braga Colleoni,Valquiria Bueno

doi:10.1186/s12979-021-00244-x

Abstract

BackgroundThis study aimed to identify novel plasma metabolic signatures with possible clinical relevance during the aging process. A biochemical quantitative phenotyping platform, based on targeted electrospray ionization tandem mass spectrometry technology, was used for the identification of any eventual perturbed biochemical pathway by the aging process in prospectively collected peripheral blood plasma from 166 individuals representing the population of São Paulo city, Brazil.ResultsIndoleamine 2,3-dioxygenase (IDO) activity (Kyn/Trp) was significantly elevated with age, and among metabolites most associated with elevations in IDO, one of the strongest correlations was with arginase (Orn/Arg), which could also facilitate the senescence process of the immune system. Hyperactivity of IDO was also found to correlate with increased blood concentrations of medium-chain acylcarnitines, suggesting that deficiencies in beta-oxidation may also be involved in the immunosenescence process. Finally, our study provided evidence that the systemic methylation status was significantly increased and positively correlated to IDO activity.ConclusionsIn the present article, besides identifying elevated IDO activity exhibiting striking parallel association with the aging process, we additionally identified increased arginase activity as an underlying biochemical disturbance closely following elevations in IDO. Our findings support interventions to reduce IDO or arginase activities in an attempt to preserve the functionality of the immune system, including modulation of myeloid-derived suppressor cells (MDSCs), T cells, macrophages, and dendritic cells’ function, in old individuals/patients.

Highlights

Immunosenescence is the name of a group of complex alterations in both innate and adaptive arms of the immune system associated with the aging process, leading to a progressive loss in the ability to respond to infections and poor immunity after vaccination [1], both associated with a higher mortality rate in old individuals
The indoloxigenase activity, as evaluated by the proportions between kynurenine to the essential amino acid tryptophan (Kyn/Trp), depicted the highest positive correlation with aging (Fig. 1A) (Correl. = 0.38, p = 2.50e-7, False discovery rates (FDR) = 1.48e-5), suggesting that the aging process seems to be driven by deficiencies in auxotrophic-related mechanisms, involving essential amino acids like tryptophan
In agreement with this hypothesis, the molar sum of the 9 essential amino acids (Val, Trp, Thr, Phe, Ile, Leu, Met, Lys, and His) exhibited an opposite and significant correlation with IDO activity (Correl. = − 0.36, p = 1.22e6, FDR = 2.62e-5), showing that nutritional aspects seem to matter in this group of individuals (Fig. 1B)

Summary

Introduction

Immunosenescence is the name of a group of complex alterations in both innate and adaptive arms of the immune system associated with the aging process, leading to a progressive loss in the ability to respond to infections and poor immunity after vaccination [1], both associated with a higher mortality rate in old individuals. Numerous studies on the mechanisms underlying agerelated immune decline became the basis for some interventions such as the reduction of the latent/lytic viral load, by vaccination and/or antiviral drugs, to diminish CMV-related immunosenescence [1, 4]. Supporting this theory, evidence suggests that infections and frailty repeatedly cross each other pathophysiological ways and accelerate the aging process in a vicious circle [5]. A biochemical quantitative phenotyping platform, based on targeted electrospray ionization tandem mass spectrometry technology, was used for the identification of any eventual perturbed biochemical pathway by the aging process in prospectively collected peripheral blood plasma from 166 individuals representing the population of São Paulo city, Brazil

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