Abstract
Metallothionein (MT) is a family of low molecular weight, cysteine-rich proteins that regulate zinc homeostasis and have potential protective effects against oxidative stress and toxic metals. MT1 and MT2 gene knockout (MTKO) mice show shorter lifespans than wild-type (WT) mice. In this study, we aimed to investigate how MT gene deficiency accelerates aging. We performed comparative metabolomic analyses of plasma between MTKO and WT male mice at middle age (50-week-old) and advanced age (100-week-old) using liquid chromatography with time-of-flight mass spectrometry (LC-TOF-MS). The concentration of N6,N6,N6-trimethyl-L-lysine (TML), which is a metabolic intermediate in carnitine biosynthesis, was consistently higher in the plasma of MTKO mice compared to that of WT mice at middle and advanced age. Quantitative reverse transcription PCR (RT-PCR) analysis revealed remarkably lower mRNA levels of Tmlhe, which encodes TML dioxygenase, in the liver and kidney of male MTKO mice compared to that of WT mice. L-carnitine is essential for β-oxidation of long-chain fatty acids in mitochondria, the activity of which is closely related to aging. Our results suggest that reduced carnitine biosynthesis capacity in MTKO mice compared to WT mice led to metabolic disorders of fatty acids in mitochondria in MTKO mice, which may have caused shortened lifespans.
Highlights
Population aging is predicted to become a major global public health challenge in the decade, as the advanced age group population has been increasing [1]
Representative base peak intensity (BPI) chromatograms were obtained from plasma in electrospray ionization positive (ESI+) and negative (ESI-) modes, respectively (Supplementary Figure 1A, 1B)
All peaks in ESI+ or ESI- were merged and imported into the SIMCA-P software for multivariate statistical analysis
Summary
Population aging is predicted to become a major global public health challenge in the decade, as the advanced age group population has been increasing [1]. López-Otín C et al have characterized aging as a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death [3]. They proposed nine candidate hallmarks that contribute to the aging process and together determine the aging phenotype; 1) genomic instability, 2) telomere attrition, 3) epigenetic alterations, 4) loss of proteostasis, 5) deregulated nutrient-sensing, 6) mitochondrial dysfunction, 7) cellular senescence, 8). It is difficult to quantify and evaluate aging because the principal theories of aging are intricately intertwined. Metabolomics, using blood, serum, and plasma, has emerged as a powerful tool to characterize organism phenotypes, and identify altered metabolites, pathways, and novel biomarkers in aging and disease, which will offer wide clinical applications [4, 5]
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