Physical exercise impact on aging-related pathways across generations in C. elegans

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 2023. Tutor/a: Christian Griñán FerréAging has been defined as a gradual functional decline with a progressive physiological integrity loss, increasing the organism’s vulnerability to death. Otherwise, this described deterioration is the major risk factor for most current human pathologies, including neurodegenerative diseases, cancer, cardiovascular disorders, and diabetes. However, in the last decades, non-pharmacological treatments like physical exercise have provided general health benefits against aging decline. In this study, we aim to analyze how lifestyle factors such as physical exercise can modify the molecular expression of aging-related pathways and observe if this gene expression modification pattern is inherited transgenerationally throughout the following generations. Among all hallmarks of aging process, in this study we highlight epigenetic alterations. Even though extensive studies of transgenerational epigenetic inheritance have been reported in Caenorhabditis elegans, there is still a gap regarding how physical exercise might benefit organisms through epigenetic pathways. Then, we implement a physical exercise treatment in the first C. elegans generation, and we analyze the subsequent generations to study transgenerational heritable changes in gene expression involved in aging-related pathways. We emphasized on CREB transcription factor pathway, early growth response 1 (EGR1) transcription factor, superoxide dismutase 1 (Sod1) as a powerful antioxidant, and disintegrin and metalloproteinase domain-containing protein (ADAM10) pathway since its role in correct neurological development. Key words: exercise, C. elegans, aging, transgenerational epigeneti

Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks.

Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy,cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, weanalyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders suchas Alzheimer’s Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a−/−)mice to evaluate AD progression. Behavioral tests showed that Gadd45a−/− mice presented lowerworking and spatial memory, pointing out an apparent cognitive impairment compared with WTanimals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involvedin its phosphorylation in the hippocampus. Moreover, Gadd45a−/− animals significantly increased thebrain’s pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins andthe dendritic spine length of the neurons were reduced in Gadd45a−/− mice, which could contributeto the cognitive alterations observed in these animals. Overall, these findings demonstrate that thelack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting thatpromoting this protein’s expression or function might be a promising therapeutic strategy to slowdown AD progression.</p

Deletion of <i>Gadd45a</i> Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks

Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy, cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such as Alzheimer’s Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a−/−) mice to evaluate AD progression. Behavioral tests showed that Gadd45a−/− mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, Gadd45a−/− animals significantly increased the brain’s pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in Gadd45a−/− mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein’s expression or function might be a promising therapeutic strategy to slow down AD progression