38. Senescence

The average cell will proliferate and divide happily and without problem, however eventually the telomers on the end of the chromosomes will be so short that the cell cannot divide anymore without damaging the genome. At this point, the cell will enter a senescent (aged) state where they will no longer divide and eventually die.

Not only telomer shortening can cause cells to become senescent. DNA damage, oxidative stress, oncogene activation or some other problem with the chromosomes will also cause the cell to enter senescence.

This figure shows the different fates a cell can have. The normal pathway is the upper arrow, where the cell enters senescence when the telomers are shortened.

The cell enters this stage by overactivation of a protein called p16, which is a CDK inhibitor. When p16 is overactivated, the cell cycle of the cell stops. This is a defense-mechanism against tumor formation, because if the cell continued to replicate even when there is something wrong with the DNA or the DNA would be damaged during replication, the cell could become cancerous.

Because p16 works to prevent cells from becoming cancerous, it’s a tumor suppressor protein. If p16 should be defect or inactivated, the cell could become cancerous.

The effect of the tumor suppressors p53 and p21 on the cell cycle (proliferation)

Other tumor suppressors are also involved in this process. Ras, Her2 and PTEN are all oncogenes or tumor suppressors. If one of them are mutated and cancerogenous, the tumor suppressor protein p53 will step in and inhibit CDK and thereby the cell cycle and proliferation. If the p53 protein is defective or mutated, there will be nothing to stop the cell from becoming cancerous.

Senescent cells

Senescent cells do not replicate. The differences between senescent cells and normal cells is shown in the table below.

Phenomenon	Replicative cell	Senescent cell (non-replicative)
Telomer length	Decreasing	Constant
Number of nuclear mutations	Many, increasing	Fewer, constant
Number of mutant mitochondria	Few	High, increasing
Deformed proteins	Few	Many, increasing
Lipofuscin	Few	Many
Protein degradation	Intensive	Slow
Antioxidant capacity	High	Low

Sirtuins

A protein type called sirtuins, known as SIRT1, SIRT2 and so on. They are all protein deacetylases, so they remove acetyl-groups from proteins. When activated, they mediate many beneficial functions in the cell, like repairing DNA, stress resistance and genomic stability.

Notably, SIRT1 activates FOXO transcription factors.