This article shows two changes from normal in autism.
1. Reduced antioxidant capacity. Sulforaphane an Nrf2 agonist increases antioxidant capacity and improved behavior in autistic children.
2. Hypomethylation of gene promoter sites which also occurs in aging and is associated with methylation of histone gene promoter sites. I suspect that gene specific methylation of histone production dysregulates normal epigenetic control of acetylation deacetylatoon of genes. Without adequate histones production, methylated CpG gene promoter sites cannot lay down histone to fully block gene transcription, therefore control of gene expression is haphazard and incomplete. Melatonin through its HDAC INHIBITIONS and ANTIOXIDANT functions might demethylate the histone gene promoter site and restore histone gene function and thereby return command and control for non impaired epigenetic control of cellular functions. It should be stated that methylation is a dimmer not a light switch because of redundancy of gene copies to express certain products. HIIE and fasting produced beta hydroxybutyrate is also an HDAC INHIBITOR.
CONJECTURE:. HRW, sulforaphane, spermidine, melatonin and lifestyle changes could ameliorate autism through epigenetic change and return to normal command and control of gene expression.
It also follows that hypomethylation secondary to aging related methylation or acetylation of histone CpG gene promoter site would be more and better regulated! This is the reason that heterochromic parabiosis results in a plasma transfer of a youthful factor to the older mouse and an aging factor to the younger mouse with conjoined circulation. The aging clock genes express a ratio of protein products that stimulate and inhibit histone expression in the elderly cell that mimics histone gene promoter site methylation in the young "autistic" cell.
The hypomethylation of aging increases exponentially and is counterintuitive to epigenetic aging measures of biological aging based on number of methylated genes in peripheral blood. I interpret this to mean that epigenetic biological aging is directly proportional to methylated gene CpG promoter sites to mortality predictions with a 96% correlation before histone gene promoter methylation that causes exponential increases in its opposite, hypomethylation.
In effect autistic children lose control of gene expression through methylation of histone gene promoter site.
Aging adults in final descent toward mortality, show clock gene related histone associated down regulation of histone production.
An old gamete cell or stem cell escapes by turning back the clock genes or increasing the ratio of histone producing/histone inhibiting gene products as highlighted by Rando in interpreting parabiosis experiments. This reverses replicative aging only. DNA damage is wear and tear aging and is the homeostasis of gene repair, cell energetics and proteostasis forces working under the histone ratio drag of replicative aging.
Metabolic Imbalance Associated with Methylation Dysregulation and Oxidative Damage in Children with Autism
Oxidative stress and abnormal DNA methylation have been implicated in the pathophysiology of autism. We investigated the dynamics of an integrated metabolic pathway essential for cellular antioxidant and methylation capacity in 68 children with autism, 54 age-matched control children and 40 unaffected siblings. The metabolic profile of unaffected siblings differed significantly from case siblings but not from controls. Oxidative protein/DNA damage and DNA hypomethylation (epigenetic alteration) were found in autistic children but not paired siblings or controls. These data indicate that the deficit in antioxidant and methylation capacity is specific for autism and may promote cellular damage and altered epigenetic gene expression. Further, these results suggest a plausible mechanism by which pro-oxidant environmental stressors may modulate genetic predisposition to autism.
No comments:
Post a Comment