In the aging process, metabolic and cellular changes occur. In this thesis, we investigated alterations in metabolism and mitochondrial function in different aging models. First, we analyzed the timing of age-related metabolic alterations in C57BL/6NRj mice that exhibit intact reactive oxygen species (ROS) homeostasis and glucose metabolism. Using NMR spectroscopy, we analyzed five tissues from male and female mice aged 3, 6, 12, and 24 months. Age-specific metabolite profiles were distinct across all tissues, with early metabolic changes emerging already by 6 months. Notably, we observed sex-specific differences in the liver, a biphasic metabolite pattern in brain, heart, liver, and lung, and a linear amino acid decline in muscle. These findings suggest early-onset metabolic shifts during aging, influenced by sex and genetic background. Furthermore, we investigated the role of mitochondrial calcium (Ca²⁺) in Caenorhabditis elegans (C. elegans) and human fibroblasts as a regulator of aging. Genetic and pharmacological inhibition of the mitochondrial Ca2+ uniporter (MCU) in C. elegans extended lifespan, preserved motility, mitochondrial structure, and function through a transient increase in ROS. This mitohormetic response activated conserved stress response pathways involving PMK-1, DAF-16, and SKN-1, promoting antioxidant defenses and mitochondrial health. Similar effects were observed in human fibroblasts following short-term treatment with mitoxantrone, a MCU inhibitor, underscoring the potential translational relevance of findings from nematodes to human cells. Our findings emphasize that specific modulation of mitochondrial Ca²⁺ uptake improves longevity and healthspan in nematodes, with possible implications for healthy aging in human cells.
Interrelations between Ca²⁺ and ROS homeostasis during aging
Bresilla, D. (Author). 2025
Student thesis: Doctoral thesis