In humans (and other mammals) telomeres are repeating sequences of nonsense DNA (TTAGGG) bound to special proteins at the ends of chromosomes. They protect the ends of chromosomes from being recognized as double strand breaks by the DNA repair machinery and thus ensure the integrity of DNA. If there were no telomeres, the ends of chromosomes would be joined together resulting in incapability to divide, because our cell division machinery cannot handle this sort of situation. Telomeres also shorten with each cell division because our DNA replication machinery cannot start from the very tip of the chromosome, so parts of the ends are not replicated. This is known as the “end-replication problem” and prevents the cell from dividing indefinitely because at one point the telomeres would completely erode away.
In cells that can divide indefinitely, such as stem cells, telomeres must be maintained somehow. In humans there are two ways to maintain telomere length. One is the enzyme telomerase. It consists of a template providing RNA subunit and a catalytic subunit that extends the telomeres. Telomerase is suppressed as an anti-cancer defense in cells that do not need to divide at all (e.g. neurons) or do not normally divide but are capable of dividing, call these mitotically competent cells (e.g. liver cells). The other way is ALT or alternative lengthening of telomeres, which has a yet unknown mechanism and is expressed in some cancers.
A common answer to the question “what causes aging?” is telomere shortening and the eventual tissue degeneration due to the tissue’s inability to keep dividing once the telomeres have been completely eroded, this is known as replicative senescence. From there follows the simple cure for aging: have telomerase in every cell so that telomeres do not shorten. It is a persistent view and you stumble upon it in every conversation about the causes of aging. The persistence, I believe, comes from the simplicity of the theory and straight forwardness of the proposed solution giving people a sense of control over aging and thus comfort. However, if we wish to abolish aging we must forget our biases and look at the facts.
This review (de Magalhaes and Toussaint, 2004) explores the relationship between aging and telomere length.
There exists a great disparity between in vivo observations of aging and the telomere length:
“No connection exists between mean telomere length and mammalian ageing. Of all studied primates, humans appear to have the shortest telomeres and the longest lifespan.[61]”
“Telomerase overexpression does not alter ageing in mice.[76]”
“There is no correlation between the number of CPDs [cumulative population doublings] cells can endure and the age of the donor.[45]”
Telomeres certainly do seem to shorten in some tissues, but the connection between aging and telomere shortening is on thin ice due to the disparities.
“As with replicative potential, telomere length in vivo is very heterogeneous.[87] Telomere shortening in vivo has been reported in skin cells,[31] blood,[68] and colon mucosa.[30] Other studies found weak correlations between donor age and telomere length,[32] while some studies found no correlation[47,87,88] Moreover, long telomeres have been found in cells from centenarians.[89] Taken as a whole, these results indicate that telomere length varies widely amongst individuals and between different tissues. Although telomere shortening appears to occur in some tissues in vivo, there is little evidence linking telomere shortening to ageing.”
While telomeres do shorten in some tissues, it is unclear whether the cells in vivo let their telomeres completely erode away through divisions and let themselves descend into replicative senescence. In vitro cell cultures of mitotically competent cells seem to have a certain limit to the amount of doublings they can perform (around 50), this is famously called the Hayflick limit. It was thought that this limit also applies to cells in vivo, but newer evidence contradicts this view. Toussaint and de Magalhaes touch upon this in their review:
“In addition, they raised doubts on whether telomere shortening occurs in vivo and whether senescence-associated genes in vitro are also differentially expressed in vivo.[47] In fact, gene expression patterns show differences between in vitro senescent cells and cells from old donors.[48]”
“some evidence suggests that hTERT transient expression can occur in human cell lines when necessary for regeneration,[91] and there is little evidence to suggest that further hTERT expression is necessary in human tissues.[92,93]”
Another article (Rubin, 2002) also speaks about this. The author points out that more careful observations show that healthy cells in vivocan express telomerase when necessary and thus renew their telomeres.
“More careful study, however, has revealed telomerase activity in stem cells and some dividing transit cells of many renewing tissues and even in dividing myocytes of repairing cardiac muscle. It now seems likely that telomerase is active in vivo where and when it is needed to maintain tissue integrity.”
Senescent cells, those that have ceased dividing and exhibit eroded telomeres, however, do appear in mammalian tissues (Herbig et al., 2006). How can this be explained? One theory (von Zglinicki, 2002) tries to explain this. It is argued that oxidative damage which causes DNA damage also shortens telomeres, because any damage in the telomeres is not well repaired by DNA repair machinery. This could act as an anti-cancer mechanism, because as more DNA damage accumulates and the cell becomes more unstable, the telomeres also shorten and prevent the cell from going rogue. This means that DNA damage is the underlying cause of senescent cells in vivo.
If we actually overexpressed telomerase in normal cells the side-effects might be quite bad. I have mentioned before that monkeying around with the pathways of our metabolism is a bad idea. But what would happen? Well de Magalhaes and Toussaint point out that telomerase actually alters the functions of cells and this would probably disrupt the functions of tissues that suppressed telomerase.
“Previously, experimental evidence raised questions on whether telomerase could help tumorigenesis.[77,78] Namely, telomerase stabilizes the telomeres which promotes tumorigenesis.[21,22,79] In addition, some reports suggest telomerase favors tumorigenesis by a telomere length-independent mechanism.[80] For example, a recent study found that hTERT expression in HDFs leads to an up regulation of epiregulin, a potent growth factor involved in tumorigenesis.[81] Another recent study found that telomerase modulates the expression of growth-controlling genes to enhance cellular proliferation,[82] and thus hTERT-immortalized cells may not be functionally equivalent to normal cells. In addition, recent results demonstrate that hTERT-immortalized cell cultures accumulate changes as they proliferate, suggesting caution in the use of such cell lines for tissue engineering.[83] Taken together, these results suggest that telomerase activity promotes tumorigenesis and so using hTERT for therapeutic purposes must be approached with great caution.”
In a previous post I also talked about how telomerase has many extratelomeric functions many of which could promote tumorigenesis, especially if overexpressed. In fact, the mice that overexpressed telomerase had higher rates of cancer than controls.
So it seems that telomere shortening May Not the cause of aging at all, and we may not have to worry about it when coming up with new anti-aging therapies.
