Why Can a Cell Not Divide Forever? It Runs Off the End of the Instructions

Copying a strand of DNA requires the machinery to start from a short primer that is later removed, and at the very end of a linear strand there is no room to place a primer beyond the last section, so the final stretch cannot be copied. Every round of division therefore loses a small amount from each end. In a circular chromosome, which bacteria have, there is no end and no problem, but linear chromosomes face it unavoidably. The solution is to place expendable material at the ends, so that what is lost is a repeated sequence carrying no genes rather than anything that matters.

The structure is simple and does several jobs:

• •A short sequence repeated thousands of times at each chromosome end
• •The same six-letter repeat in all vertebrates
• •Bound by a protein complex that protects and organises it
• •Folded back on itself into a loop that hides the end
• •That hiding stops the cell treating the end as a break to be repaired
• •Shortened by a measurable amount at every division

Shortening is not open-ended and the cell responds when the caps become too short. At that point the protective structure fails, the end is detected as damage, and the cell stops dividing permanently and enters a state called senescence, in which it remains alive and metabolically active but will not divide again. That limit on the number of divisions was observed in cultured human cells by Leonard Hayflick in 1961, decades before the mechanism was understood, and the count is around forty to sixty divisions for many human cell types. Cells that override the stop and continue dividing accumulate serious chromosomal damage.

Length has been proposed repeatedly as a measure of biological age and using it that way runs into real problems. Length varies enormously between individuals of the same age and between different tissues in the same person, so a single measurement says little. The commonest laboratory methods measure an average across a population of cells and miss the shortest ones, which are the ones that matter. Length is strongly inherited, so a long measurement may reflect ancestry rather than health. And the direction of causation is unclear, since stress and illness shorten them and shortened ones also contribute to poor health, so a correlation supports either reading.

An enzyme exists that extends the caps and its distribution explains a great deal. It is active in germ cells and in stem cells, which must divide indefinitely, and is largely switched off in ordinary body cells, which is why those cells have a division limit at all. The great majority of cancers reactivate it, which is one of the changes that allows unlimited division and is a target for treatment. Its discovery brought a Nobel Prize in 2009. The obvious idea of switching it on to extend life runs directly into the reason it is off, since a cell able to divide without limit is a cell that has removed a major barrier to becoming a tumour.

Copying machinery cannot reach the very end of a linear strand, so chromosomes shorten each division, and expendable repeats at the ends absorb that loss instead of genes. When the repeats become too short the end reads as damage and the cell stops dividing permanently. An enzyme rebuilds them in germ and stem cells, is off in ordinary cells, and is switched back on by most cancers.