Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan

Abstract

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.

Keywords: acetyl-CoA; acetylation; aging; autophagy; calorie restriction; histone deacetylase.

Figure 1

The substrates for the synthesis of cytoplasmic or nuclear acetyl-CoA by ACLY or ACSS2 are largely mitochondrial-synthesized citrate or acetate, respectively, although the acetate released from deacetylated nucleocytoplasmic proteins can also be an important substrate for ACSS2. Abbreviations: Cit, Citrate; Isocit, Isocitrate; α kg, Alpha-ketoglutarate; Succ-CoA. Succinyl-CoA; Succ, Succinate; Fum, Fumarate; Mal, Malate; OAA, Oxaloacetate; MPC, Mitochondrial pyruvate carrier; SLC25A1, Mitochondrial citrate carrier; PDC, Pyruvate dehydrogenase complex; ACLY, ATP-citrate lyase; ACSS1, Acetyl-CoA synthetase short-chain family member 1; ACSS2, Acetyl-CoA synthetase short-chain family member 2; and HAT, Histone acetyltransferase. Proteins are shown in purple font with membrane transporters boxed, while metabolites are shown in black font, except for acetyl-CoA in green font. Pathways are shown in blue font, while subcellular localizations are labeled in red.

Figure 2

Acetyl-CoA may play different roles in the anti-aging effects of CR in different tissues. (a) CR results in decreased cytoplasmic acetyl-CoA levels in heart, skeletal muscle, and adipose tissue to stimulate autophagy to delay aging. (b) It is proposed that CR increases histone acetylation on specific promoters in some hypothalamic glial cells by activating AMP kinase (AMPK) that phosphorylates ACSS2 resulting in its nuclear translocation. ACSS2 associates with TFEB on promoters producing acetyl-CoA for PCAF and CBP-mediated histone acetylation and expression of autophagy genes. It is also proposed that the increased histone acetylation leads to increased PPAR-α expression and a shift to fatty acid oxidation. Abbreviations: SREBP-1, Sterol regulatory binding protein-1; ACLY, ATP-citrate lyase; ACSS2, acetyl-CoA synthetase short-chain family member 2; CBP, CREB binding protein; PCAF, p300/CBP-associated factor; HAT, Histone acetyltransferase; PPAR-α, Peroxisome proliferator-activated receptor-alpha; PGC-1α, PPAR gamma coactivator 1-alpha; ACC1, Acetyl-CoA carboxylase 1; and CPT1, Carnitine palmitoyltransferase 1.

Figure 3

Hypothalamic acetyl-CoA, CBP, and histone acetylation play a central role in regulating organismal energy balance and longevity pathways. Abbreviations: CBP, CREB binding protein; O-GlcNAc, O-linked N-acetyl-glucosaminylation; FOXO1, forkhead box O 1; UPR^mt, mitochondrial unfolded protein response; PDK4, pyruvate dehydrogenase kinase 4; PDC, pyruvate dehydrogenase complex; HDAC, histone deacetylase; ACC1, acetyl-CoA carboxylase 1; AMPK, adenosine monophosphate-activated protein kinase; POMC, pro-opiomelanocortin.