Mitotic cells

Mitotic tissues consist of cells which have the ability to divide when stimulated. Most mitotic cells (i.e. fibroblasts, endothelial cells, smooth muscle cells, glial cells, astrocytes etc) within tissues are found in a reversible growth arrest known as quiescence. These cells remain quiescent until stimulated to proliferate, usually for the purpose of cellular replacement. How often these cells proliferate is dependent upon how frequent cells become damaged or lost, and this may be connected to the function of the tissues in which they reside. For example, fibroblasts exposed to environmental UV radiation or endothelial cell in blood vessels exposed to high turbulence in blood flow may be more likely to proliferate to replace cell loss than less damage prone tissues.

Overview of cellular senescence

The predominant ageing mechanism of mitotic tissue is thought to be due to the gradual accumulation of senescent cells. Senescent cells have undergone an irreversible cell cycle arrest, and display a radically altered phenotype: genetically, morphologically and behaviourally distinct from its growth-competent counterparts. The accumulation of these dysfunctional cells is thought to result in a gradual decline in tissue function and the manifestation of age-related disease.

One of the mechanisms for triggering cellular senescence is thought to be due to the presence of a critically short telomere. Telomeres are regions of highly repetitive DNA at the end of linear chromosomes, which are bound by a number of proteins which are thought to protect the telomere from being processed as DNA double strand-breaks. Every time a cell divides the telomeres become progressively shorter due to the inability to replicate DNA at the ends of chromosomes (Joosten et al, 2003). This would eventually result in the appearance of a short telomere, which can no longer be protected by telomeric proteins. This may lead to the exposure of DNA ends, resulting in a DNA damage response. This response is thought to cause the cell to enter what is known as “replicative senescence”.

If replicative senescence is essentially the result of the exposure of DNA ends, oxidative stress causing DNA damage such as DNA double strand breaks may also be a mechanism for triggering cellular senescence (Von Zglinicki et al, 1998). This idea is supported by data demonstrating that the signalling pathways connecting telomere shortening and cellular senescence is similar to the one that is activated by DNA damage (Von Zglinicki et al, 2005). The mechanism (ROS or replicative senescence) thought to be predominantly responsible for cellular senescence in tissues is currently unknown. The appearance of senescent cells within mitotic tissues is going to be dependent upon three main factors:

1) The rate of cell turnover.
2) The replicative lifespan of the cells.
3) The survival time of senescent cells in vivo.

The rate of cell turnover is dependent upon the rate of cell loss. Cells divide to replace lost cells. Tissues with a high cell turnover rate are much more likely to exhaust their replicative capacity and consequently increasing the likelihood of cells entering senescence. Different cells have different replicative capacities, some cell types may be able to divide a maximum of 100 cumulative population doublings (cPD) (Poiley et al, 1978) before entering senescence while other cell types a maximum of only 20-30 (cPD) (Kalashnik et al, 2000). Therefore, if the rate of cell turnover for all cell types was constant, some tissues are still more likely to enter senescence than others. There are at present no studies that have looked at the survival time of senescent cells in vivo. However, it has been demonstrated that senescent fibroblasts can be maintained in culture medium for years. If the survival time of senescent cells was short, then the loss of such cells would result in further cell turnover and further reduction in the proliferative capacity of the tissue. Research has suggested that senescent cells tend to be more resistant to apoptosis (and thus more likely to persist in tissues), at least in fibroblasts where most of the research has been conducted (Wang et al, 1994, 2004, Marcotte et al, 2004, Hampel and Wagner, 2005). However, experimental evidence measuring the fraction of apoptotic human vascular endothelial cells also demonstrated no difference between the apoptotic potential of senescent cells compared with their mitotic counterparts (Kalashnik et al, 2000). If there is no increase in the apoptotic potential of senescent cells, it is likely that these cells persist in tissues for long periods of time, thus causing damage.

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The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.