Abstract
The ability to maintain systemic metabolic homeostasis through various mechanisms represents a crucial strength of kidneys in the study of metabolic syndrome or aging. Moreover, age-associated kidney failure has been widely accepted. However, efforts to demonstrate aging-dependent renal metabolic rewiring have been limited.In the present study, we investigated aging-related renal metabolic determinants by integrating metabolomic and transcriptomic data sets from kidneys of young (3 months, n = 7 and 3 for respectively) and old (24 months, n = 8 and 3 for respectively) naive C57BL/6 male mice. Metabolite profiling analysis was conducted, followed by data processing via network and pathway analyses, to identify differential metabolites. In the aged group, the levels of glutathione and oxidized glutathione were significantly increased, but the levels of gamma-glutamyl amino acids, amino acids combined with the gamma-glutamyl moiety from glutathione by membrane transpeptidases, and circulating glutathione levels were decreased. In transcriptomic analysis, differential expression of metabolic enzymes is consistent with the hypothesis of aging-dependent rewiring in renal glutathione metabolism; pathway and network analyses further revealed the increased expression of immune-related genes in the aged group.Collectively, our integrative analysis results revealed that defective renal glutathione metabolism is a signature of renal aging. Therefore, we hypothesize that restraining renal glutathione metabolism might alleviate or delay age-associated renal metabolic deterioration, and aberrant activation of the renal immune system.
Highlights
Aging accelerates multisystemic deterioration and increases the risk of developing metabolic diseases or syndromes
Since Quality control (QC) samples clustered as a group, we confirmed the reproducibility of our LC-MS-based analytical platform (Supplementary Figure 1)
Oxidized GSH were higher by 2.37- and 2.98-fold, respectively, in the old group compared with the counterpart, GSH-related metabolites such as gammaglutamyl dipeptides were lower in the old group compared with the young group
Summary
Aging accelerates multisystemic deterioration and increases the risk of developing metabolic diseases or syndromes. The ability to modulate systemic metabolite levels through various mechanisms, such as tubular secretion, glomerular filtration, and catabolism, represents a crucial strength of kidneys in the study of metabolic syndrome and aging [1]. Due to structural and functional changes, renal aging contributes to alterations in related biological processes. In aged kidneys, signaling pathways are rewired, and unhealthy mitochondria lead to the increased accumulation of oxidative stress [5]. It is widely accepted that oxidative stress contributes to tissue damage, thereby leading to pathological changes during the aging process. In both murine and human studies, researchers reported that aging was associated with increases in reactive oxygen species (ROS) generation and alterations in ROS removal ability [6]. Whether leukocyte-derived inflammatory activation is the cause or effect of aging remains unclear, increased glomerular macrophage infiltration was histologically observed in healthy aged mice [2, 11]
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