Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
Department of Neurology, The Ohio State University Wexner Medical Centre, Columbus, OH, USA.
Neurobiol Aging. 2021 Sep;105:64-77. doi: 10.1016/j.neurobiolaging.2021.04.013. Epub 2021 Apr 27.
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.
衰老是神经退行性疾病（包括肌萎缩侧索硬化症，ALS）的一个主要危险因素。由于代谢改变是衰老的一个标志，并且之前在 ALS 中已经观察到，因此重要的是在 ALS 代谢功能的背景下检查衰老的影响。在这里，我们使用新建立的表型代谢方法，研究了衰老对来自 ALS 病例的成纤维细胞代谢特征的影响，与对照相比。我们发现 ALS 成纤维细胞具有改变的代谢特征，这受到年龄的影响。在对照病例中，我们发现随着年龄的增长，在几种代谢物（包括乳酸、海藻糖、尿苷和果糖）的存在下，NADH 代谢显著增加，而在 ALS 病例中并未重现。相反，我们发现 ALS 队列中存在糖原时，NADH 代谢随活检年龄、发病年龄和死亡年龄而减少。此外，我们发现 NADH 产生与与多种代谢物（包括肌苷和α-酮戊二酸）相关的疾病进展率相关。在 ALS 成纤维细胞中补充肌苷或α-酮戊二酸在生物能量上是有利的。总的来说，我们发现 ALS 成纤维细胞中存在与衰老相关的能量底物缺陷，这些缺陷在不同点将碳输入糖酵解以及三羧酸（TCA）循环中，在诱导神经元祖细胞衍生的 iAstrocytes 中得到了验证。我们的结果表明，补充这些途径可能有助于预防 ALS 中与年龄相关的代谢功能障碍。
