Mitotic cells

Senescent phenotype and biological impact

Senescent cells tend to adopt an extracellular matrix (ECM) degrading, proinflammatory phenotype (West et al, 1989; Kletsas et al, 2004). Senescent cells usually up-regulate matrix metalloproteinases (MMPs), enzymes capable of degrading proteins such as collagen and elastin which make up the extracellular matrix. Since the extracellular matrix (ECM) is important for providing support and anchorage for cells, separating different tissues and regulating intercellular communication, its degradation by MMPs is likely to impact all areas of ECM function. MMP activity is normally inhibited by TIMPs (tissue inhibitor of metalloproteinases), but research suggests that that these inhibitors themselves are down-regulated at senescence, thereby further contributing to matrix degradation (Hornebeck, 2003).

Senescent cells also secrete many cytokines which due to their diverse function could have multiple consequences on the ageing of tissues. These secreted proteins may not just impact on local tissue but also tissues found throughout the organism. The presence of cytokines can alter cell functions by up-regulating or down-regulating several genes and their transcription factors, resulting in the production of other cytokines and an increase in the number of surface receptors for other molecules (Gallin and Snyderman, 1999). The ability of cytokines to reach many tissues and have such diverse consequences on cell function suggests that only a small fraction of senescent cells may need to be present for there to be any significant impact on tissue impairment or disease development.

As discussed in post-mitotic ageing, the accumulation of senescent cells in some tissues is likely to reduce the number of cells which can provide support and protection to post-mitotic cells. Therefore, the appearance of senescence cells may have a direct impact on the impairment of post-mitotic tissues.

Some of the changes observed during cellular senescence are also likely to be cell type specific. Different cell types are going to have different transcriptional profiles since their functions are different and these differences may result in tissue specific impairment. For example, in senescent vascular endothelial cells, nitric oxide synthase (eNOS) activity has been found to be decreased (Matsushita et al, 2001; Minamino et al, 2002). Since nitric oxide (NO) is important in regulating vascular function, a decline in its production may have detrimental consequences. A reduction in NO production by eNOS for example has been suggested to be a significant risk factor for cardiovascular disease (Cannon, 1998). This decline in eNOS activity at senescence appears to be specific to vascular endothelial cells. Even if eNOS is produced by other cells types and a similar decline with age is observed, the consequence of such changes is going to be different, if any at all. This is due to alterations in specific structure-function relationships.

Overall, senescent cells within tissues are thought to contribute to the ageing process by:

1) Altering the behaviour of neighbouring growth-competent mitotic cells.
2) Degradation of structural components such as the extracellular matrix.
3) Reducing the pool of growth-competent mitotic cells.
4) Cellular dysfunction: inability to function properly.