Abstract
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.
Highlights
Aging is considered one of the major risk factors for several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and as a natural process is affected by several key mechanisms including metabolic alterations (Lopez-Otin et al, 2016)
When we eliminated age from the analysis, we found all cases clustered at a single point indicating that age may play a significant role in defining the metabolic profile of the fibroblast cohort
This Principle component analysis (PCA) analysis indicated that in fibroblasts, ALS results in an altered metabolic profile, which is influenced by age
Summary
Aging is considered one of the major risk factors for several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and as a natural process is affected by several key mechanisms including metabolic alterations (Lopez-Otin et al, 2016). Mitochondria undergo significant damage during the aging process leading to progressive dysfunction and, together with alterations in intercellular communication; these factors play a crucial role in aging (Gonzalez-Freire et al, 2015). Age-related mitochondrial damage has been linked to increased reactive oxygen species (ROS) production (Ferrucci and Fabbri, 2018). Woof et al / Neurobiology of Aging 105 (2021) 64–77 increase of the electron transport chain (ETC) redox state, which contributes to ROS overproduction (Golpich et al, 2017; Stefanatos and Sanz, 2018)
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