Sinclair et al. using the eye as a model CNS tissue, showed that ectopic expression of Oct4, Sox2 and Klf4 genes in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2.
TET enzymes are iron and 2-oxoglutarate dependent dioxyegenases. Fixing TET enzymes could be a key part of the treatment of a range of chronic illness and would be a lot simpler and safer than systematic ectopic expression of OCT4, KLF4 and SOX2 in humans. A lot of methylation changes acquired during aging must be beneficial. Systematically turning back the clock to 18 or so would not be desirable .’Just’ fixing TET enzymes would allow desirable methylations to occur but would allow DNA demethylations of undesirable DNA methyations. Clearly fixing TET enzymes would be a required first step prior to any genetic engineering of humans to restore youthfulness given that such genetic engineering was feasible and desirable.
Research indicates that 2-oxoglutarate by affecting TET and Jmjc domain-containing proteins can have epigenetic effects reversing epigenetic changes arising from dysregulation of the tricarboxylic acid (TCA) cycle. The TCA cycle synthesizes 2-oxoglutarate.
I have been stressing in this blog that with a dysregulation of iron-sulfur cluster formation there is a dysregulation of aconitase which is an iron-sulfur protein early in the TCA cycle With aconitase dysregulated the TCA cycle is dysregulated. Another enzyme in the TCA cycle, succinate dehydrogenase, also has iron-sulfur clusters.
Could deleterious epigenetic changes in humans, due to dysregulation of the TCA cycle, be reversed by supplemental alpha-ketoglutarate? That has not yet been established.
2-oxoglutarate-dependent dioxygenases are involved in aging, 2-oxoglutarate could be a longevity supplement. A rule of thumb in regards to longevity supplements is never take a longevity supplement for longevity that does not have immediate positive benefits as absent immediate positive benefits knowing whether one is going in the correct direction is unknowable . If 2-oxoglutarate proves to be useful in the treatment of various neurological illnesses but also increases longevity so much the better.
Taurine lowers blood pressure in humans by increasing synthesis of hydrogen sulfide, which is a vasodilator, through increasing activities of cystathionine beta-synthase and cystathionine gamma-lyase, the two enzymes in the transsulfuration pathway. Cystathionine beta-synthase and cystathionine gamma-lyase synthesize hydrogen sulfide. A meta-analysisindicates that taurine lowers blood pressure in clinically relevant amounts. Taurine also decreases homocysteine levels in humans. There is also lots of evidence fromanimalsthan taurine lowers total cholesterol. Research points to taurine as being the factor for Japanese longevity which could be due to taurine lowering various cardiovascular risk factors. The actions of taurine are more pronounced when taurine is taken on an empty stomach.
Pyruvate dehydrogenase and the 2-oxoglutarate dehydrogenase are rate limiting enzymes of the pyruvate dehydrogenase complex and the 2-oxoglutarate complex respectively. NADH activates pyruvate dehydrogenase kinase which inhibits pyruvate dehydrogenase and inhibits 2-oxoglutarate dehydrogenase. Increasing levels of NAD+ via supplemental nicotinamide mononucleotide, which is marketed as an anti-aging and longevity supplement, would increase levels of NADH which would inhibit pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase which would decrease activity of the pyruvate dehydrogenase complex and the 2-oxoglutarate complex which could be a large misstep in terms of increased longevity. Decreased activity of the pyruvate dehydrogenase complex and the 2-oxoglutarate complex enzymes are present in brains of individuals who had Alzheimer’s disease. Supplementing with nicotinamide mononucleotide must be avoided.