Metabolic networks in aging and age-related diseases

• Autor(a) principal: Lucas, Vasco de Almeida
• Data de Publicação: 2019
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/28463
• topic: NAD+; NAMPT; NAPRT; FK866; Aging; Aging-related diseases; Proteostasis; EGAS; Cytoscape; ClueGo; Protein Networks

Aging is a natural physiological process, but its specific causes are not entirely understood at the molecular level. During aging, the levels of the redox cofactor Nicotinamide Adenine Dinucleotide (NAD) decrease. This molecule is essential for energy production by the cell and is also a substrate to a range of enzymes that regulate gene expression and cell survival. To gain insight into the metabolic networks of age-related disorders, we took a combined bioinformatics and molecular approach. We used text-mining methods to extract protein interaction data from 1500 PubMed abstracts containing keywords related to proteostasis, aging and age-related diseases. Protein networks were obtained with Cytoscape and were submitted to parameter-based analysis. An enrichment analysis using the cytoscape plug-in ClueGo was followed. Parameter analysis revealed APP as the most central and influential protein in the network and enrichment analysis depicted a predominance of terms related to Immune system along with Cancer and Cell Cycle regulation. As a cellular model, we have used a NAD metabolism inhibitor in SH-SY5Y neuroblastoma cells to mimic the NAD decline during aging. At different time points (8h, 24h, and 48h) we measured cell viability along with the expression levels of NAMPT and NAPRT, the rate-limiting enzymes from the NAD biosynthetic nicotinamide salvage pathway and the Preiss handler pathway respectively. Our results show a 50% decrease in cell viability at 48h along with a decrease in NAPRT protein expression. No alterations in NAMPT protein levels were recorded in any measured time point. It is possible that other NAD biosynthesis pathways are activated, so further studies intended to elucidate question are required.