Induction of the anti-aging gene Klotho by a small chemical that demethylates CpG island
Klotho (KL), a gene that is thought to be anti-aging, has been described as such because mutations of the Kl gene lead to several pre-mature ageing phenotypes in mice and reduces their lifespan. Evidence is growing that an increase in KL may benefit age-related illnesses such as diabetes and arteriosclerosis. However, it is still unclear how Kl could be induced. Here we discovered novel molecular mechanism for induction of Kl expression with a small molecule ‘Compound H’, N-(2-chlorophenyl)-1 H-indole-3-caboxamide. Compound H was initially identified by a high-throughput screen of small molecules to identify Kl inducers. Compound H’s ability to induce Kl expression was never investigated. Compound H increased Kl transcription via demethylation of CpG islands in the Kl gene. Demethylation was achieved by activating the demethylases, rather than inhibiting the methylases. Compound H increased transcription factor binding to the Kl promoter due to demethylation. Pax4 and Kid3 controlled Kl promoter activities positively and negatively respectively. Our results indicate that demethylation plays a key role in Compound H’s ability to induce Kl expression. Compound H should be investigated further to determine if it demethylates Kl in vivo, and if it can act as a therapeutic for delaying or repressing age-related diseases.
Keywords: Pax4, Kid3, klotho and methylation.
The klotho mice (Kl-deficient) showed pronounced pre-mature ageing phenotypes. These mice have 10 copies of a transgene inserted in the flanking 5′ region of the Kl genes, disrupting their expression [1]. The klotho mouse dies around 2 months after birth from multiple organ failures related to aging [1]. The role of KL was later confirmed by reproducing the same aging traits in Kl homozygous mice (Kl -/-) [2]). Overexpression of KL, on the other hand extends life by 20-30%. The Kl protein can be classified into two types: membrane-integrated Kl, and non-integrated Kl including secreted Kl. The two types of proteins are produced by the two transcripts derived from a single Kl gene through alternative RNA-splicing.
Source:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564520/
