Elsevier

Medical Hypotheses

Volume 60, Issue 4, April 2003, Pages 578-583
Medical Hypotheses

Gene silencing – a new theory of aging

https://doi.org/10.1016/S0306-9877(03)00050-1Get rights and content

Abstract

The aging process involves silencing of the genes through methylation of promoter sequences and the acetylation of histones. This process contributes not only to aging, but also cancer when silencing affects tumor suppressor genes. Antineoplastons work as molecular switches, turning inactive tumor suppressor genes back on through demethylation of the DNA and acetylation of the histones. While they activate tumor suppressor genes, antineoplastons also activate some additional genes silenced during the aging process. Evidence of activation of silenced genes can be pursued by documenting the relationship between ‘molecular switches’ – DNA-demethylating agents and histone deacetylation inhibitors, genes which are turned on by them, and clinical anti-aging changes.

Introduction

Theories about the mechanism of human aging have been proposed many times over the last 2000 years. And yet we still do not have a generally accepted and well-proven explanation for this universal phenomenon of life. Because aging consists of multiple events with a variety of causes, no one has been able to single out one predominant cause. Numerous theories have risen and then been cast aside as scientific knowledge increased. Some current theories center on a purported ‘master clock’ of aging. We do know that telomeres govern much of the aging program of individual cells (1). In addition, humans appear to possess another program for aging, one which includes methylation of promoter sequences of the genes and deacetylation of histones.

Section snippets

Silencing of genes during development and aging

Adult cells in the human body have an established methylation pattern in their DNA that is central to the aging program. But in the very first day of life the methylation pattern is erased. Most of the genes, which are silences later, are active during initial embryonal development. Then they begin to be blocked through methylation and deacetylation as their expression is no longer needed. Many genes are silenced after birth, including the genes for hemoglobin F. This trend accelerates

Supporting data and discussion

Differences in gene expression in various age groups were documented approximately 10 years ago [18], [19]. However, a number of studies in this area provided disappointing results, possibly due to lack of adequate technology. Introduction of DNA microarrays permitted determination of the levels of transcriptions of thousands of genes simultaneously and confirmed different patterns of gene expression during development and aging (20). A new DNA methylation technology allowed detection of

Future prospects and conclusion

Research done by others indicates many genes are silenced during aging and development. Additional evidence comes from observation of the silencing of genes for hemoglobin F. This is the primary hemoglobin in the developing fetus after the first 10 weeks of fetal life. Adult hemoglobin A becomes the main hemoglobin within 18–24 weeks after birth. Hemoglobin F production falls dramatically after birth and practically stops within 1 year. During this process the hemoglobin F genes are silenced

References (65)

  • K. Georgopoulos

    Haematopoietic cell-fate decisions, chromatin regulation and ikaros

    Nat. Rev., Immunol.

    (2002)
  • H. Ogawa et al.

    A Complex with chromatin modifiers that occupies E2F-and myc-responsive genes in G0 cells

    Science

    (2002)
  • Burzynski SR, Musial L. Synthesis of 4-phenylbutyric acid. US Patent No....
  • V.M. Richon et al.

    Histone deacetylase inhibitors: a new class of potential therapeutic agents for cancer treatment

    Clin. Cancer Res.

    (2002)
  • M. Fournel et al.

    Sulfonamide anilides, a novel class of histone deacetylase inhibitors, are antiproliferative against human tumors

    Cancer Res

    (2002)
  • P.A. Jones et al.

    The role of DNA methylation in mammalian epigenetics

    Science

    (2001)
  • J.M. Ordway et al.

    Methylation matters: modeling a manageable genome

    Cell Growth Differ.

    (2002)
  • M.C. Liau et al.

    Altered methylation complex isozyme as selective targets for cancer chemotherapy

    Drugs Exp. Clin. Res.

    (1986)
  • Liau M. C., Luong Y., Liau C. P. et al. Prevention of drug-induced DNA hypermethylation by antineoplastons. In: D. Adam...
  • S.C. Riley et al.

    Altered Vh gene segment utilization in the response to phosphorylcholine of aged mice

    J. Immunol.

    (1989)
  • L.A. Bangs et al.

    Comparison of D, Jh, and junctional diversity in the fetal, adult, and aged B cell repertories

    J Immunol

    (1991)
  • M.N. Arbeitman et al.

    Gene expression during the life cycle of Drosophila melanogaster

    Science

    (2002)
  • G.S. Roth et al.

    Biomarkers of caloric restriction may predict longevity in humans

    Science

    (2002)
  • S.A. Belinsky et al.

    Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers

    Cancer Res.

    (2002)
  • M. Esteller et al.

    A gene hypermethylation profile of human cancer

    Cancer Res.

    (2001)
  • H. Shi et al.

    Expressed CpG island sequence tag microarray for dual screening of DNA hypermethylation and gene silencing in cancer cells

    Cancer Res.

    (2002)
  • D.M. Berman et al.

    Medulloblastoma growth inhibition by Hedgehog pathway blockade

    Science

    (2002)
  • V. Santini et al.

    Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications

    Ann Intern Med

    (2001)
  • M. Gorospe et al.

    Up-regulation and functional role of p21WAF1/Cip1 during growth arrest of human breast carcinoma MCF-7 cells by phenylacetate

    Cell Growth Differ.

    (1996)
  • Wolffe AP. The cancer-chromatin connection. Sci. Med.:...
  • B.N. Kampalath et al.

    Chemoprevention by antineoplaston A10 of benzo[a]pyrene-induced pulmonary neoplasia

    Drugs Exp. Clin. Res.

    (1987)
  • B.N. Kampalath et al.

    Protective effect of antineoplaston A10 in hepatocarcinogenesis induced by aflatoxin B1

    Int. J. Tissue React.

    (1990)
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