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.

PPARγ-Induced Global H3K27 Acetylation Maintains Osteo/Cementogenic Abilities of Periodontal Ligament Fibroblasts

“…Hypermethylation at the CpG island of the promoter region in ECM-related genes was induced by the long-term stimulation of PDLF with LPS [50]. Sodium acetate is immediately converted to acetyl-CoA by ACSS2 and used as an acetyl group for histone acetylation by HATs [51][52][53]. In the present study, the supplementation of acetyl-CoA, but not intermediate products, restored the si-PPARγ-dependent inhibition of osteo/cementogenesis (Figure 7).…”

Dietary intervention improves health metrics and life expectancy of the genetically obese DU6 (Titan) mouse

“…Interestingly, the liver of Titan mice showed overall decreased H4 acetylation at the 4-17 motif, specifically histone acetylation motifs such as H4K16 and H4K12K16 acetylation, which is in correlation with a reduction in the expression of acetyl-CoA synthases (Accs2 and pdhx) which may imply reduced acetyl-CoA availability. This may underlie the general alteration in histone acetylation levels 39,66 and might also link this epigenetics phenotype to lifespan regulation 67 .…”

Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review

“…Of interest is that SIRT-1, SIRT-2, SIRT-3, SIRT-6 and SIRT-7 are involved in recombinational and base excision DNA repair and maintenance of genomic stability, all important functions related to longevity [110] (Figure 2). It is well known that the inhibitions of other classes of histone deacetylases (HDAC) (i.e., class I, II, and IV) may delay ageing and promote longevity in experimental systems by, i.a., contributing to the maintenance of histone acetylation and genome stability [111]. As some natural organic selenium compounds can be biotransformed to keto acid HDAC inhibitors [112,113], this might also be a mechanism by which selenium could promote longevity.…”

“…A recent observational study indicated that dietary Se intake was related to longer telomeres in middle-aged and older adults in America [118]. These results were in accordance with observations by Wu et al, who showed that dietary Se deprivation induced telomere shortening in colonocytes of mice carrying humanized telomeres (G3 It is well known that the inhibitions of other classes of histone deacetylases (HDAC) (i.e., class I, II, and IV) may delay ageing and promote longevity in experimental systems by, i.a., contributing to the maintenance of histone acetylation and genome stability [111]. As some natural organic selenium compounds can be biotransformed to keto acid HDAC inhibitors [112,113], this might also be a mechanism by which selenium could promote longevity.…”