Telomere Shortening
Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that protect genetic information from degradation during cell division. In humans, telomeric sequences consist of thousands of repeats of the six-nucleotide pattern TTAGGG. During DNA replication, the enzyme DNA polymerase cannot fully copy the terminal regions of chromosomes, resulting in the loss of 50–200 base pairs of telomeric DNA with each cell division. This mechanism, known as the “end replication problem,” causes telomeres to progressively shorten over successive generations of cell division.
Cellular Aging and Senescence
Telomere shortening functions as a molecular clock that limits the replicative lifespan of somatic cells. When telomeres erode below a critical length, cells enter a state called replicative senescence, in which they cease dividing despite receiving signals to proliferate. This process is thought to serve as a tumor suppressor mechanism, preventing cells with accumulated mutations from continuing to divide indefinitely. The relationship between telomere length and cellular age has made telomere shortening a widely studied marker of biological aging, with shorter telomeres associated with various age-related diseases and reduced organismal lifespan.
Regulation and Exceptions
The enzyme telomerase can add telomeric sequences back onto chromosome ends, effectively reversing or preventing telomere shortening. Telomerase is active in germ cells, stem cells, and certain immune cells, allowing them to maintain telomere length across multiple divisions. Most somatic cells in adult organisms express little or no telomerase activity, making them subject to progressive telomere shortening. Cancer cells frequently reactivate telomerase or employ alternative lengthening mechanisms to bypass replicative senescence, a key step in malignant transformation.