Bradshaw Patrick C
Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Antioxidants (Basel). 2021 Apr 8;10(4):572. doi: 10.3390/antiox10040572.
Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.
乙酰辅酶A是中央代谢的交汇点代谢物，也是调节基因表达的组蛋白乙酰转移酶的底物。在许多组织中，禁食或延长寿命的热量限制（CR）会降低通过ATP柠檬酸裂解酶（ACLY）的葡萄糖衍生代谢通量，以降低细胞质乙酰辅酶A水平，从而降低p300组蛋白乙酰转移酶（HAT）的活性，刺激促进长寿的自噬。因此，降低细胞质乙酰辅酶A的化合物被描述为CR模拟物。但很少有作者强调核乙酰辅酶A促进长寿的潜在作用。例如，增加核乙酰辅酶A水平会增加组蛋白乙酰化，而给予I类组蛋白去乙酰化酶（HDAC）抑制剂可通过增加组蛋白乙酰化来延长寿命。因此，增加的核乙酰辅酶A可能在促进长寿中发挥重要作用。尽管细胞质乙酰辅酶A合成酶2（ACSS2）通过降低某些外周组织中的自噬来促进衰老，但增加的胶质细胞AMPK活性或神经元分化可刺激ACSS2的核转位和染色质结合。ACSS2的核转位可导致CREB结合蛋白（CBP）、p300/CBP相关因子（PCAF）和其他HAT的活性增加，从而增加包括转录因子EB（TFEB）靶基因在内的神经保护基因启动子上的组蛋白乙酰化，导致溶酶体生物合成和自噬增加。关于乙酰辅酶A代谢与衰老的许多已知信息来自对酵母、果蝇和线虫的开创性研究。这些研究已经确定了组蛋白乙酰化在促进长寿方面的进化保守作用。未来的研究应聚焦于核乙酰辅酶A和组蛋白乙酰化在下丘脑炎症控制中的作用，下丘脑炎症是机体衰老的一个重要驱动因素。
