Codon-restriction theory of aging and development

Abstract

This paper presents an extension of the codon modulation theory of development and aging to a number of areas that were not included in the original versions of this theory. The basic postulates of the model-that the kinds of proteins synthesized by a cell are controlled by the set of code words a cell can decode-are defined and analyzed within the context of recent findings on transfer RNA and aminoacyl-tRNA synthetase changes in various tissues during development and aging. Consistencies and inconsistencies between model and observation are considered, and it appears that early predictions of the model are borne out by recent findings. The paper then deals with a mechanism for achieving sequential gene expression through a process in which a given set of codon-reading capacities leads automatically to additions of new (and/or subtractions of old) codon usages as a result of the translatability of messages for synthetases and synthetase-repressors (chalones?) encoded in the prior language set. The investiture of new or repressed codon usages through the action of virally coded tRNA's (and/or synthetases) by oncogenic viruses is discussed as a mechanism of oncognenesis directly derived from the above concepts. The concept is also developed that each modulated synthetase permits the decoding of messages which specify repressor templates, some of which may be integral parts of structural gene products. Extension of the concepts to the problem of antibody synthesis suggests that the variable portions of the light and heavy chains are the natural repressors of a limiting synthetase, and that the constant regions represent decoded “spacer” regions between structural genes. It was shown, from an analysis of the amino acid sequence in known gamma globulins, that a complementarity exists between the initial and terminal regions of the DNA sequences which specify four out of six of the chain segments. This implies that the DNA coding for those regions exists in the form of self-complementary single-stranded loops, and that these tertiary structures may serve as binding sites for basic proteins during mitotic DNA condensation. The model is suited to explain immune tolerance and loss of tolerance provided that effective antibodies possess more than two kinds of variable regions. Clonal aging, control of regeneration, and contact inhibition are explicable as the consequences of irreversible and reversible repressor accumulation on plasma membranes. The possibility that functions lost during development and aging may be derepressed through the administration of antibodies to such autogenic repressors is discussed.