Metabolism and Aging: From Molecular Physiology to Systems Biology
نویسندگان
چکیده
Leber's Hereditary Optic Neuropathy (LHON) is a neurodegenerative mitochondrial disease characterized by retinal ganglionic cell death and eventual loss of central vision. Specific mtDNA mutations in respiratory complex I subunits (ND4/ND6/ND1) coding genes have been identified in most of LHON patients, and these mutations have been shown to cause mitochondrial dysfunctions leading to increased oxidative stress and bioenergetics failure in cell models and LHON patients. In this study, we investigated the alterations in metabolic profiling of various pathways converging to mitochondria. We aim to identify metabolic signatures of LHON associated with complex I defects. We utilized trans-mitochondrial hybrids (cybrids) of LHON carrying ND4/ND6/ND1 mutations grown in regular and mitochondrial challenged conditions. We investigated polar metabolites profiling in the cell extracts using LC-MS approach and found alterations in various metabolic intermediates of pentose phosphate pathway, amino acid metabolism, fatty acid metabolism, purine metabolism, glycolysis, and TCA cycle. Our studies indicated downregulations of some important metabolites involved in the antioxidant defense and neuro-protective mechanism, and accumulations of other metabolites involved in tryptophan degradation and protein glycation. Further investigations would provide mechanistic insights on how mtDNA mutations lead to retinal ganglionic cell death in LHON patients and may help to develop metabolic markers for disease diagnostics and to explore novel intervention approaches for treatment. use, distribution, and reproduction in any medium, provided the original work is properly cited. Circulating microRNAs profile associates with metabolites and inflammatory molecules as biomarkers of longevity and successful aging Circulating microRNAs (miRNAs) regulate a large number of genes and mediate a broad spectrum of biological processes in humans including aging and changes in metabolism. A total of 48 subjects from the Established Populations for the Epidemiologic Study of the Elderly (EPESE), aged 76Á79 at the time of the blood draw, were randomly selected into eight bins of six subjects each crossed by gender, race, and dead within 2 years vs. dead in more than 10 years post-blood draw. We profiled plasma for 179 miRNA and multiple metabolites. MiRNA were correlated with metabolites and existing cytokine and function data. High quality miRNA with good yields and highly reliable metabolite data were able to be generated from plasma samples stored for 20 years. Twelve miRNA were differentially expressed according to longevity status: four in women and men (hsa-miR-26b-5p,-374a-5p,-374b-5p,-18b-5p, and-26a-5p); five exclusive to women (hsa-miR-374b-5p,-126-3p,-500a-5p,-23a-3p, and-421); and three exclusive to men (hsa-miR-190a,-331-3p, and-30e-3p). Except for hsa-miR-500a-5p, all the miRNA positively associated …
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عنوان ژورنال:
دوره 5 شماره
صفحات -
تاریخ انتشار 2015