Understanding how ageing mechanisms cause alterations to tissues and understanding the consequences of those alterations brings us one step closer to developing new therapeutic ways of treating and, more importantly, preventing the appearance of age-related impairment and disease. In regard to cellular senescence, an in-depth understanding of the senescent phenotype of all mitotic cell-types is required so we can better assess the potential consequences of their appearance.
To combat the problem of senescent cells in tissues, ongoing and future research should concentrate on the following three strategies: (1) prevention, (2) removal and (3) replacement.
Telomerase therapy is aimed at preventing the appearance of senescent cells by elongating the telomeres of somatic cells (Shawi and Autexier 2008
). The idea is to develop strategies for transiently turning on telomerase in cells. This results in longer telomeres, a higher replicative capacity and a reduced chance of a cell becoming senescent through replication. However, not all cells appear to senesce as a result of telomere shortening. Some cells have been shown to senesce independently of telomere shortening (Itahana et al. 2003
,) and as such would be unaffected by the elongation of telomeres by telomerase (Kiyono et al. 1998
). Also, cells can become senescent as a result of DNA damage (Robles and Adami, 1998
, Chen et al. 1998
), meaning even those cells with elongated telomeres can become senescent. It is not known to what degree DNA damage plays in the formation of senescent cells in vivo.
Even if telomerase therapy is made possible, there will still be a fraction of senescent cells present in tissues. As such, strategies should also focus on direct removal of senescent cells from tissues. Two potential approaches include the development of drugs which specifically target and destroy senescent cells, and the use of the body’s own immune system to target and remove senescent cells.
At present, a drug which specifically targets senescent cells is unavailable. However, drugs which are currently being developed (Gillies and Frechet 2005
; Alexis et al. 2008
) to target specific cancer cells could one day be adapted to target senescent cells. They would recognise senescent specific cell-surface markers, bind to them and induce apoptosis, thus removing the cell.
If senescent cells appear in tissues as a result of failure of an aged immune system to remove them, then rejuvenation of the aged immune system would be greatly beneficial. An understanding of the biology which leads to the functional decline in the immune system is thus essential for the development of rejuvenation medicine. One area of focus should be on age-related changes associated with tumour-antigen capture and presentation. In brief, dendritic cells capture and process tumour-specific antigens, they begin to mature and migrate to the lymph nodes where they interact with cytotoxic T-lymphocytes (CTLs), presenting the tumour information and causing the CTLs to become activated and proliferate, targeting tumour cell removal (Chan and Housseau 2008
). If senescent cells are indeed removed by the immune system, the mechanism is probably similar to that of tumour cell removal. Although not discussed in detail here, there are a number of stages during antigen capture and presentation that could become altered with age and thus in need of further investigation (Shurin et al. 2007
- Dendritic cells did not recognise the target cell
- The dendritic cell did not display the target cell specific marker
- Lymphocytes were not activated in response to dendritic cells
Finally, the third strategy is the replacement of cells. If telomerase therapy is not possible, the removal of senescent cells from tissues will only stimulate the proliferation of surrounding cells for its replacement, reducing the replicative capacity of that tissue and increasing the appearance of more senescent cells. However, tissues may also consist of a population of stem cells involved in cell replacement (Li and Neaves 2006
), but it is not known to what extent these stem cells or the surrounding somatic cell population plays in tissue regeneration. Stem cells may also be affected by ageing mechanisms and as a result may become functionally impaired (Sharpless and DePinho 2007
). As such, the addition of stem cell populations into tissues (Smart and Riley 2008
) after the removal of senescent cells is thus another strategy in need of research.
Strategies involving the prevention, removal and replacement of senescent cells is at its infancy. It is only through a deeper understanding of the biology of ageing and the ability to translate such knowledge into practical therapeutic applications that we will begin to see inevitable benefits in regenerative medicine.