Genetic and epigenetic mechanisms for the limited lifespan and ageing of normal, diploid cells.

Abstract

The genetic basis of the limited lifespan and apparently programmed number of divisions in normal, diploid cells is discussed. Two different mechanisms may underlie a programmed inhibition of cell divisions before they age and die: 1. A genetic mechanism involving the CpG sequence in promotor regions of genes. Inactive, but gradually activated basic function genes such as ribosomal and energy metabolism genes, when inactive have their CpG promotor sequences methylated. During each cell division a proportion of 5-methyl cytosines will be oxidatively deaminated leading to C to T transitions. After a certain number of divisions all methylated CpG islands will be mutated with consequent loss of viability and cell death. 2. An epigenetic mechanism involving the methylated promotor sequences of silent growth control genes. After a certain number of divisions with incomplete maintenance methylation, the growth control genes will be derepressed with consequent cessation of proliferation, decline of metabolic activity, ageing, and death.