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.