Half a century ago, a scientist named Leonard Hayflick discovered that the number of times a normal, non-cancerous human cell can divide is limited. Beyond this point, Hayflick noted that cells would stop dividing and that there is a maximum number of times a cell can divide. This hypothetical maximum number of cell divisions came to be known as the “Hayflick Limit”, and the phenomenon itself is now known as cellular senescence.

Cellular senescence is a process in which cells at risk of becoming cancerous adopt a state of permanent growth arrest. While this process prevents tumor formation (a cell that does not divide cannot become a tumor), senescent cells may also cause or contribute to aging and age-related conditions.

Hallmarks of senescence. The senescent phenotype is complex, and consists of many changes to the nature of the cell, those discovered thus far include:

Above: Human skin cells are spindle-shaped. Below: Senescent skin cells are flatter and activate the enzyme beta-galactosidase which is stained in blue.

Above: Human skin cells are spindle-shaped. Below: Senescent skin cells are flatter and activate the enzyme beta-galactosidase which is stained in blue.

Permanent arrest of cell division – This is the key characteristic that defines senescence. Upon assuming the senescent phenotype, that cell will never divide again. This prevents it from ever becoming a cancer cell, and most cancers feature mutations that prevent those cells from becoming senescent.

Morphological changes – in a dish, senescent cells assume a large, flattened shape.

Beta galactosidase – in 1996, the Campisi lab (now at the Buck Institute) identified activation of the enzyme beta-galactosidase as a marker of senescent cells, and it is still the most commonly used means of detecting senescence. This marker allows researchers to stain senescent cells blue.

Epigenetic changes – Senescent cells fundamentally change the way that their genes are expressed by altering the structure of their nuclei and chromatin. Following induction of senescence, cells undergo a complex change in nuclear structure, including release high mobility box group protein 1 (HMGB1), and senescence-associated heterochromatin foci (SAHF). Senescent cells also lose lamin B1, a key component of the nuclear envelope, which results in a distortion known as “nuclear blebbing”. In this way, senescent cells resemble those of children that suffer from the premature aging disease known as Hutchinson-Guilford Progeria Syndrome (HGPS).

The SASP – In 2008, the Campisi lab demonstrated that senescent cells secrete a myriad of factors with potent biological activities. This senescence-associated secretory phenotype, or SASP, is the most potentially damaging effect of senescent cells. While senescent cells account for less than 10% of total cells in aged tissues, the SASP allows these cells to play a much larger role than their relatively small numbers would otherwise suggest. It is hypothesized that this aspect of senescent cells is what drives aging or age-related conditions.

Inducers of senescence. Many different triggers can induce senescence. Depending on intensity and cell type, these can include:

Telomere erosion – each time a cell divides, it loses a bit from the ends of its chromosomes, called telomeres. If telomeres become sufficiently short, they send a signal to the cell to stop dividing. This prevents the cells of the body from growing unchecked and therefore prevents tumors.

Genotoxic stress – if a cell’s DNA is sufficiently damaged, it can lead to mutations that might ultimately result in cancer. To combat this, a cell’s DNA damage response can trigger senescence to prevent the cell from becoming cancerous. DNA damage can also activate pro-cancer genes, called “oncogenes”. Activation of many of these genes can also trigger a senescence response, assuring that the cell will never become cancerous.

Drugs and chemotherapy – Some drugs can target pathways that ultimately drive the senescent response. In fact, many chemotherapy drugs, designed to target rapidly dividing cells (such as those in tumors), can result in off-target senescence. It is possible that these off-target effects drive some of the deleterious side effects that many cancer patients can experience years after their cancers have gone into remission.

Senescence as a therapeutic target for aging. If senescent cells are so bad, why not get rid of the genes that cause the formation of senescent cells in the first place? Evidence from humans and animals indicates this is not an effective strategy. For example, mutations in the retinoblastoma or P53 genes, the two most essential pathways for senescence, result in strong predisposition to cancer. Therefore, the loss of the cells’ ability to undergo senescence would cause a person to die of cancer long before they would grow old enough to worry about the effects of senescent cells.

What about killing the senescent cells that have already formed in the body? This could allow cells to senesce and prevent cancer, but could then eliminate them from the body before they produce harmful effects. In 2011, a group of researchers at the Mayo Clinic decided to test this idea using a mouse engineered to kill senescent cells when the mice were given a drug. The results were astonishing: the mice were prevented from developing a host of issues including cataracts and loss of fat, hair, and muscle. They proved to be healthier in most ways than untreated mice. This new therapeutic option, termed “senolysis” (lysis or breaking down of senescent cells), is currently being tested by several aging researchers for its effectiveness in treating the conditions of old age.

Now that senescent cells have been demonstrated to cause many of the conditions of old age, the field of senescence research is primed for a renaissance that could result in a host of new strategies for the therapeutic treatment of aging.