A chromosome is a long strand of DNA and associated proteins that carry and transmit genetic traits. At the end of a chromosome is a section of nucleotides called the telomere. Telomeres keep chromosomes “protected” and prevent them from combining into rings or linking with other DNA strands. Telomeres play an important role in cell division. Each time a cell divides, the DNA information is copied. However, this process does not copy all of the DNA information as the telomeres are not replicated. During this process the telomeres lose some of their length. Replicative DNA polymerase, has as its major function the replication of the genome and thus to allow transmission of genetic information. As well as replicating DNA, polymerases help to maintain the integrity of the genome by participating in various modes of DNA repair. DNA polymerase does not replicate the telomere end of the DNA and that is left to a specialized enzyme known as telomerase. Not all somatic cells contain detectable telomerase levels and and as a result those cells continue to experience shortening of the telomeres to ultimate senescence as one ages.
Telomeres themselves are sequestered within a protein complex known as shelterin. The main function of this complex with telomeres is to prevent DNA repair mechanisms from repairing the telomere after DNA replication. This may seem self-defeating but if the repair activity was allowed to occur then the section remediated would act as a DNA repair point that then could lead to ultimate chromosome fusion or ring formation. So, as this process of telomere shortening cycles with DNA replication the potential is then for cell senescence and ultimate apoptosis (1)
It appears that some limited genetic alterations in genome expression patterns, including increased telomerase expression, can result in a significantly longer lifespan and a reduction in age-associated diseases. But there may be trade-offs if the exquisite balance of telomerase activity (replenishing telomere length) and telomere attrition is disturbed. We know that although telomerase is expressed in a very limited (almost undetectable level) way in most somatic cells, over expression is found in many types of cancer cells. We see the opposite action is telomere attrition leading to senescence and apoptosis that are implicated in aging and cellular dysregulation. A recent report (2) revealed a strong relationship between short telomeres and mortality risk and several studies have linked longer telomeres with longevity. But tit is more complicated then longer is better then shorter in health and longevity as evidenced by a very recent research study indicating longer telomeres being associated with melanoma risk (3). This was a study on this one particular type of aggressive cancer but has ben implicated in many others. In addition, very short and very long telomeres are seen with cognitive impairment which may mean a link to conditions such as Alzheimer’s disease. (4). The reality is that we have a very tightly controlled way telomere length and expression balances biological benefits and liabilities. This tight control when expressed ideally is likely playing a role in optimizing lifespan and as well as healthspan. The way this is maintained is far from certain. It certainly seems that telomere attrition and telomerase dysregulation and control may prove pivotal in optimizing how long we live and also how we may avoid many disease states recognized as we age.
The role of glycation in all of this is still being elucidated but a few important bits of important information are known. One recent study indicates that the glycolysis of carbohydrates that generates reactive carbonyl species such, as methylglyxal (MG) and glyoxal GO), can cause reduced telomerase activity. These very reactive species have already been mentioned in damaging the DNA. In a recent article by Larson et al (5) using a telomerase-immortalized stem cell line which possess an unlimited replicative potential due to active telomerase showed that GO causes damage to DNA not unlike that of MG, albeit MG is more reactive and leads to less proliferation then control. In this case there was detected reduced telomerase activity and cell reduced proliferation. Whether or not MG, with its greater reactivity, would enhance these effects is not known but would be reasonable to expect.
On the other side of the coin there is growing evidence that advanced glycation end products (AGEs) can stimulation overproduction of telomerase and thus be involved in proliferative disease states such as cancer. We know that AGEs play a significant role in the up-regulation of endoplasmic reticulum(ER) stress response in humans with resultant stimulation of the ER stress-induced NF-ĸB pathway. ER stress has also been shown to activate telomerase up-regulation. (6)
Telomerase activation is a prerequisite for tumorigenesis and malignant transformation.(7) Both telomerase and NF-κB are hyperactivated in large number of cancers and the interaction of telomerase and NF-κB may suggest a link that mediates the effects of telomerase in cancer cells. This NF-κB and telomerase interaction would then suggest an early event that promotes cancer progression.
The exact nature of AGEs and associated precursors such as MG and GO have with telomere and telomerase related processes is yet to be fully determined. However, even at the most superficial levels it is obvious there is a connection that links glycation and telomere/telomerase molecular chemistries and as such it is not a great leap to suggests it has a role in telomere/telomerase dysregulation.
Next: Halmarks of Aging – Role of Gltcation Part 4: Epigenetic Alterations
- Fumagalli, M., Telomeric SNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 2012, 14, 355-365
- Boonekamp, JJ., et al, Telomere length behaves as biomarker of somatic redundancy rather then biological age. Aging Cell 2013 12, 330-352
- Llorca-Cardenosa, MJ et al, Long telomer length and TERT-CLPTM1 locus polymorphism associated with melanoma risk. Eur J Cancer 2014 31-68-77
- Roberts RO et al, Short and long telomers increase risk of amnesic cognitive impairment, Mech Aging Dev, 2014 141-142
- Larsen, SA, Glucose metabolite glyoxal induces aenscence in telomerase-immortalized human mesenchymal stem cells. Chemistry Central Journal 2013, 6:18
- Zhou, J. et al, Endoplasmic reticulum stress activates telomerase. Aging Cell, 2014, 13, 197-200
- Hanahan D., Weinberg R. A. The hallmarks of cancer. Cell. (2000);100:57–70.