The accumulation of senescent cells (cells which have undergone permanent growth arrest) in tissues is thought to contribute to the development/progression of age-related disease and disability. Why? Partly because when cells become senescent, their gene expression becomes radically altered and as a result secrete proteins that damages the body. Growth-competent cells can become senescent as a result of telomere shortening. Telomeres are a region of repetitive DNA at the end of chromosomes, important in chromosome stability. Every time a cell divides, telomeres gradually become shorter and shorter until they trigger a response which causes them to enter senescence. This is known as replicative senescence. However, an enzyme known as telomerase can lengthen telomeres and thus prevent a cell from becoming senescent.
Telomerase is an enzyme which consists of an RNA molecule and a catalytic component known as hTERT. It is a reverse transcriptase which uses its RNA component as a template to reverse transcribes DNA back to the ends of chromosomes. Telomerase activity is repressed in most somatic cells and reactivated in ~90% of human cancers (Artandi, 2006). Introduction of telomerase into normal somatic cells has been shown to extend replicative life-span (Bodnar et al, 1998) and not induce changes associated with a malignant phenotype (Jiang et al, 1999).
Since senescent cells are potentially detrimental to the tissues in which they reside, anti-ageing research has three main aims for dealing with this problem:
(1) Prevention: prevent cells from becoming senescent.
(2) Removal: remove senescent cells as they appear.
(3) Replacement: replacement of cells which have naturally or artificially been removed.
PREVENTION: Telomerase Therapy
Telomerase therapy is aimed at preventing the appearance of senescent cells in tissues by lengthening telomeres in somatic cells. At present, this is not possible. It is possible to get cells to express telomerase in culture by insertion of the hTERT gene (Bodnar et al, 1998), but there is currently no technology which can insert the hTERT gene into every cell in the body. Since every cell in the body already has the gene for hTERT (it is just not activated) a better alternative approach is the development of drugs which “turn on” the hTERT gene. This is the main focus for companies like Sierra Sciences.
Problems associated with Telomerase Therapy
Apart from the problem of turning on telomerase expression in all the cells of the body, there are a number of other issues that need to be questioned.
(1) Not all cells enter senescence as a result of telomeres shortening: Some cell types, such as keratinocytes (Darbro and Klingelhutz, 2004), and possibly astrocytes and corneal endothelial cells (unpublished) enter senescence by a mechanism independent of telomere shortening. As such, cellular senescence cannot be prevented by the addition of telomerase.
(2) Cellular senescence can be triggered as a response to DNA damage: Even if telomeres are elongated, cells can still become senescent as a result of DNA damage. It is not known what fraction of senescent cells in tissues is due to replicative senescence or the result of DNA damage.
(3) Cancer risk: The risk of cancer is likely to be great if telomerase is constantly being expressed in cells, but if telomerase expression is transiently expressed by drugs then this risk would be minimised.
REMOVAL: Therapeutic agents and/or the use of the Immune System.
All three of the above problems associated with telomerase therapy could be eliminated if senescent cells were removed as they appeared in tissues. Prevention therapies should therefore be applied along side removal strategies. Two possible approaches for removing senescent cells are:
(1) The use of therapeutic agents (drugs) to specifically target and destroy senescent cells.
(2) The use of our own immune system to remove senescent cells.
Use of Therapeutic Agents
Therapeutic agents have the potential to specifically target senescent cells and induce programmed cell death (apoptosis). At present, no such drug is available. However, drugs that are being developed to specifically target cancer cells could one day be adapted to target senescent cells. For this to be made possible, a cell surface marker specific to all senescent cells needs to be identified. A drug can then be developed which specifically identifies that marker, binds to it and induces apoptosis. A more detailed review of cell specific drug targeting will be presented at a later date.
Use of the bodies own immune system
Cancer cells (and possibly senescent cells) may persist in tissues in later life because the immune system fails to remove them (see here). Why? Because the immune system is also governed by ageing mechanisms, and as we age the immune systems ability to remove cancer and senescent cells is gradually impaired. An understanding of the mechanisms which lead to functional decline in the immune system is thus needed for the development of anti-ageing therapies. This is discussed in more detail at a later date.
The use of these two removal strategies without the use of telomerase therapy could be more harmful than good. The removal of one cell only promotes the division of another, thereby reducing the replicative capacity of cells and increasing the appearance of senescent cells. However, if cell removal strategies are used in conjunction with telomerase therapy (at least in some cell types), the negative impact normally observed with cell replacement may not be seen.
If a senescent cell is removed from tissue without the use of telomerase therapy, surrounding cells will divide to replace it, thus decreasing the replicative capacity of those cells and increasing the appearance of senescent cells. Replacement strategies focus on the use of stem cells to replace lost and damaged cells. Stem cells naturally replace lost cells in tissues but it is not known to what extent both stem cells and the surrounding somatic cells play in this process. Also, the functional ability of stem cells has been shown to decline with age in tissues (Sharpless and DePinho, 2007), so the addition of functional stem cells into tissues would be beneficial. Interestingly, it may the the presence of senescent cells that is having a detrimental impact on the functional ability of stem cells. The microenvironment of stem cell niches is important for the normal functioning of these cells (Boyle et al, 2007). Therfore, the presence of senescent cells with their altered secretome may alter the environment of the stem cell niche, thus altering their ability to function properly. The removal of senescent cells alone may therefore partly prevent the age-related decline in stem cell function, providing a stronger repair process.
Like all anti-ageing research, telomerase therapy, senescent cell removal and cell replacement are at their infancy. Only with time, money, a deeper understanding of the ageing process and a motivation to succeed, will we begin to see the inevitable benefits of anti-ageing research.