Reduced expressions of TCA cycle genes during aging in humans and mice.

Abstract

Aging is associated with a decline in physiological functions and an increased risk of metabolic disorders. The liver, a key organ in metabolism, undergoes significant changes during aging that can contribute to systemic metabolic dysfunction. This study investigates the expression of genes involved in the tricarboxylic acid (TCA) cycle, a critical pathway for energy production, in the aging liver. We analyzed RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to assess age-related changes in gene expression in the human liver. To validate our findings, we conducted complementary studies in young and old mice, examining the expression of key TCA cycle genes using quantitative real-time PCR. Our analysis of the GTEx dataset revealed a significant reduction in the expression of many genes that are critical for metabolism, including fat mass and obesity associated (FTO) and adiponectin receptor 1 (ADIPOR1). The most overrepresented pathway among the statistically enriched ones was the TCA cycle, with multiple genes exhibiting downregulation in older humans. This reduction was consistent with findings in aging mice, which also showed decreased expression of several TCA cycle genes. These results suggest a conserved pattern of age-related downregulation of TCA cycle, potentially leading to diminished mitochondrial function and energy production in the liver. The reduced expression of TCA cycle genes in the aging liver may contribute to metabolic dysfunction and increased susceptibility to age-related diseases. Understanding the molecular basis of these changes provides new insights into the aging process and highlights potential targets for interventions aimed at promoting healthy aging and preventing metabolic disorders.