Metabolomic profiling of plasma from middle-aged and advanced-age male mice reveals the metabolic abnormalities of carnitine biosynthesis in metallothionein gene knockout mice

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 N 6, N 6, N 6-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.

Oxidative Stress and Cellular Senescence Are Involved in the Aging Kidney

“…Despite this, the precise extent of senescent cell accumulation in aged animals, and a deeper characterization of age-related senescence in the kidney and its functional outcome remain unclear. Most of senescence-related experimental studies have been done in very old mice [ 27 , 28 ]. However, in a recent preclinical study we demonstrated an age-related increased susceptibility to develop more severe AKI in 12-month-old mice through exacerbation of senescence-related mechanisms [ 29 ].…”

Senescent cell accumulation & Research-based undergraduate education

“…Despite this, the precise extent of senescent cell accumulation in aged animals, and a deeper characterization of age-related senescence in the kidney and its functional outcome remain unclear. Most of senescence-related experimental studies have been done in very old mice (Kadota et al, 2021;Kim et al, 2021). However, in a recent preclinical study we demonstrated an age-related increased susceptibility to develop more severe AKI in mice by the age of 12 months through exacerbation of senescence-related mechanisms .…”