Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts
| العنوان: | Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts |
|---|---|
| المؤلفون: | Margarita Gerou, Benjamin A. Hall, Scott P. Allen, Kathrin Meyer, Pamela J. Shaw, Ryan Woof, Jessica Allsop, Stephen J. Kolb |
| المصدر: | Neurobiology of Aging |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Aging, AGEs, advanced glycation end products, SOD1, superoxide dismutase 1, DHAP, dihydroxyacetone phosphate, chemistry.chemical_compound, 0302 clinical medicine, FALS, familial amyotrophic lateral sclerosis, PGM, phosphoglucomutase, Glycolysis, Amyotrophic lateral sclerosis, SALS, sporadic amyotrophic lateral sclerosis, Glycogen, General Neuroscience, Middle Aged, ALS, amyotrophic lateral sclerosis, Aging, ALS, iNPC, induced neuronal progenitor cell, Disease Progression, Ketoglutaric Acids, Female, medicine.drug, Adult, medicine.medical_specialty, C9ORF72, chromosome 9 open reading frame 72, ETC, electron transport chain, Citric Acid Cycle, TCA, tricarboxylic acid, Context (language use), Biology, Article, 03 medical and health sciences, iPSC, induced pluripotent stem cells, ROS, reactive oxygen species, Internal medicine, medicine, Humans, LDHA, lactate dehydrogenase A, Progenitor cell, Inosine, Aged, G3P, glyceraldehyde 3-phosphate, GP, glycogen phosphorylase, NADH, nicotinamide adenine dinucleotide, reduced form, Amyotrophic Lateral Sclerosis, ChREBP, carbohydrate response element binding protein, Metabolism, Fibroblasts, iAstrocytes, induced astrocytes, medicine.disease, NAD, mtDNA, mitochondrial DNA, AMPK, AMP-activated protein kinase, 030104 developmental biology, Endocrinology, chemistry, Neurology (clinical), Geriatrics and Gerontology, Age of onset, TDP-43, TAR DNA-binding protein 43, Energy Metabolism, 030217 neurology & neurosurgery, Developmental Biology |
| الوصف: | Highlights • Aging affects the metabolic profile of fibroblasts derived from ALS cases • Increased NADH metabolism with age is observed in the presence of a specific set of catabolic energy substrates in healthy individuals • Reduced NADH metabolism with age is observed in the presence of glycogen in the ALS cohort • Disease progression rates in ALS cases correlate with fibroblast NADH production in the presence of a number of energy substrates including inosine Aging is a major risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). As metabolic alterations are a hallmark of aging and have previously been observed in ALS, it is important to examine the effect of aging in the context of ALS metabolic function. Here, using a newly established phenotypic metabolic approach, we examined the effect of aging on the metabolic profile of fibroblasts derived from ALS cases compared to controls. We found that ALS fibroblasts have an altered metabolic profile, which is influenced by age. In control cases, we found significant increases with age in NADH metabolism in the presence of several metabolites including lactic acid, trehalose, uridine and fructose, which was not recapitulated in ALS cases. Conversely, we found a reduction of NADH metabolism with age of biopsy, age of onset and age of death in the presence of glycogen in the ALS cohort. Furthermore, we found that NADH production correlated with disease progression rates in relation to a number of metabolites including inosine and α-ketoglutaric acid. Inosine or α-ketoglutaric acid supplementation in ALS fibroblasts was bioenergetically favourable. Overall, we found aging related defects in energy substrates that feed carbon into glycolysis at various points as well as the tricarboxylic acid (TCA) cycle in ALS fibroblasts, which was validated in induced neuronal progenitor cell derived iAstrocytes. Our results suggest that supplementing those pathways may protect against age related metabolic dysfunction in ALS. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1558-1497 0197-4580 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa322bad33369b41380c3947538e1343Test http://europepmc.org/articles/PMC8346650Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fa322bad33369b41380c3947538e1343 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15581497 01974580 |
|---|