Tricarboxylic Acid Cycle Genes are Downregulated with Age
The tricarboxylic acid (TCA) cycle is an important part of the process by which mitochondria generate chemical energy store molecules to power the cells. With age, mitochondrial function diminishes throughout the body. This produces disruption to cell and tissue function, particularly in energy-hungry tissues such as the brain and muscles. This loss of mitochondrial function is thought to be the consequence of some combination of damage to mitochondrial DNA and maladaptive changes in the expression of relevant genes, such as those coding for proteins necessary to mitochondrial energy production. For example, researchers here point out the reduced production of TCA cycle proteins in aged tissues, and note it as as a contribution to age-related mitochondrial dysfunction.
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.