Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.

INTRODUCTION

Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known.

AIM

This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging.

METHODS AND RESULTS

We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, ; however, selective mtDNA genes, such as and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including and , were significantly induced, with a substantial induction of and . However, age-associated differences were not observed in the induction of mt chaperones ( and ), but significant induction of , a mitochondrial co-chaperone, was observed. The ER stress transcription factors and were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone with no change in and chaperones. However, induction of was significant, whereas and were downregulated in contrast to , suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels.

CONCLUSION

These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.