Aging: gene silencing or gene activation?

Summary

According to the author’s theory of gene silencing, the key process in aging involves reduced expression of a number of genes. Silencing of genes has a complex mechanism, which involves methylation of DNA, histone modification and chromatin remodeling. In addition to deacetylation of the histones and methylation of DNA, recently described RNAi mechanism could initiate formation of silenced chromatin. Hypermethylation of the promoter will silence the gene. Genome-wide hypomethylation will induce genomic instability, amplification of oncogenes and also silencing of the genes through RNAi mechanism. Studies by different groups, conducted in yeast, worms, flies and mice, confirmed substantial changes in gene expression in aging. Among them, the most important was silencing of tumor suppressors and other genes involved in the control of cell cycle, apoptosis, detoxification, and cholesterol metabolism. There was also increased expression of the smaller group of oncogenes and other genes which are associated with typical diseases of old age. Caloric restriction normalizes expression of a substantial percentage of these genes. Animal studies confirmed importance of caloric restriction, which decreases signaling through the IGF-1/AKT pathway and expression of gene p53. These studies, however, cannot be directly applied to human aging. It is proposed that age management therapy should attempt to normalize gene expression in the older population to the level typical for young adults. This would require activation of silenced genes and normalization of overexpressed genes. Caloric restriction and exercise are helpful in decreasing the activity of important oncogenes and activation of silenced tumor suppressors, and may have a positive impact, not only on aging, but also on prevention of cancer. Dietary supplements containing phytochemicals should normalize increased expression of oncogenes. Examples are: genistein and EGCG, which effect signaling through the IGF-1/AKT pathway and resveratrol and limonen, which do so through the RAS pathway. A group of amino acid derivatives and organic acids of animal and human origin should activate silenced tumor suppressor genes (Aminocare^® A10, Aminocare^® Extra). Among them 3-phenylacetylamino-2, 6-piperidinedione intercalates specifically with DNA and protects sequences of tumor suppressor genes, which are vulnerable to the effects of carcinogens. Phenylacetate activates p53 and p21 through inhibition of methyltransferase and farnesylation of the RAS protein. Phenylbutyrate activates tumor suppressor genes through inhibition of histone deacetylation. Phenylacetylglutamine decreases genomic instability and expression of oncogenes and promotes apoptosis. The application of DNA microarray techniques to human studies should provide more information about differences in gene expression in different age groups and help design more effective age management regimens.

Introduction

Genetic mechanisms may provide the best explanation of the aging process. Two years ago, I had the pleasure of presenting my gene silencing theory of aging [1]. After determination of the sequence of the human genome, it was found that less than 2% of the human genome codes for proteins and only 1/10 of these are active in adult life. This means that approximately 90% of our genes are silenced. The system of biochemical factors named epigenome consist of molecular switches which activate and silence the genes during our life [2]. Methylation of promoter sequences of the genes is the main mechanism for silencing both genes no longer necessary for development and genes which are gradually turned off during the aging process [3], [4]. Adult cells have an established methylation pattern in their DNA that is central to the aging program, but, in the very first day of life, that methylation pattern is erased [5]. Most of the genes, which are silenced later, are active during initial embryonal development, then they begin to be blocked through methylation and deacetylation as their expression is no longer needed [6]. The continuous silencing of genes through methylation and deacetylation is a major factor leading to progressive aging, cancer and, ultimately, death [7], [8], [9], [10].

Silencing of genes is a complex process, which involves methylation of DNA, histone modification, and chromatin remodeling. A number of excellent reviews and books have recently been written on this subject [5], [10], [11], [12]. Two biochemical processes, which I described in the previous publication, play a very important part in silencing of the genes: deacetylation of the histones and methylation of DNA [1]. Since then, additional new mechanisms of methylation have been proposed explaining two different issues of DNA methylation in aging cells: (1) site-specific hypermethylation of promoter sequences and (2) genome-wide hypomethylation. It was confirmed recently that genome-wide hypomethylation is inducing genomic instability, amplification of oncogenes and silencing of tumor suppressor genes through RNAi mechanism [13], [14], [15], [16].