Note the abbreviation “kb” means kilobases as in thousands of base pairs. So 3 kb = 3000 base pairs.
At a conference I spoke at recently, I was asked why telomerase does not replicate the “full DNA duplex of telomeres”. I was not sure if they were asking why telomeres shorten, if there is an enzyme that can lengthen them, or why does telomerase leave a single stranded end known as the “T loop”. I decided to answer both questions, since there are a lot of good instructional points here.
First, the full DNA duplex of telomeres is just a weird way to phrase something. DNA is usually coiled in a compressed 2 stranded structure known as a duplex (two strands). To me the “full DNA duplex” means the whole kit ‘n caboodle of the whole bloody chromosome. Technically, the telomere is no longer double stranded at the end, so that confuses things more to me. Don’t you just love how science can get complicated way beyond what is necessary, because of the word choices!
So, speaking of choices, I had no choice but to launch into a “double stranded duplex answer”—in other words, I gave two answers.
Let’s start with the shortening issue first. In normal DNA, there is what is known as the end replication problem. DNA polymerase may be physically too large, or functionally “kicked off”, as it approaches the telomere strand, as DNA polymerase is unable to complete the replication of the telomere. Instead, the enzyme “Telomerase”, which is an RNA reverse transcriptase, is active in some cell lines, primarily germ, stem and some rapidly replicating somatic lines. The degree of activation determines the degree of telomere shortening, maintenance, or lengthening.
In most cases, telomerase activity is not sufficient to add length to the total telomere mass, nor does it attempt to. In most cases, any telomerase activity that does occur, appears to be focused on the short telomeres (variously defined as less than 3-5kb) only. In some early stage progenitor lines, there does appear to be enough telomerase activity to prevent loss of the mean telomere length as well, so the trigger for telomerase binding/unbinding may be different or set at a different point. Telomerase over expression has recently been used to extend mouse life span (Blasco 4/2012), with no evidence of increasing cancer, or loss of cell cycle checkpoints. In most cases however, there is simply not enough expression, as the enzyme is repressed and telomeres don’t lengthen – they shorten and induce cell cycle checkpoints, leading to senescence or apoptosis. This is probably part of the function of the single strand end known as the T loop, since this appears to be where telomere erosion appears first. Which brings us to:
Why telomerase leaves a single strand end unpaired, that ultimately curls over on itself and binds to a displaced double strand of DNA, that loops out to “catch” the free end and form the “D loop”, which is technically triple stranded. No one knows, but from a design standpoint, with reference to the above cell cycle check points, it looks like this structure is part of the “time clock” function of the telomere. Having the free end tied up, prevents the DNA Damage Response (DDR) from treating the telomere end like a double stranded DNA break, which would incite senescence or apoptosis, even with a long telomere. As the telomere erodes and shortens, the D loop and T loop structures are eroded and at some point (again variously described as 3-5kp) the telomere is short enough to cause a DDR and stop replication. At this point, someone usually starts talking about “telomerase causing cancer”. It should be noted that this is not a satisfactory explanation, since telomerase does not cause cancer. Cancerous changes occur and it appears like the last step is the immortalization of the cancerous cell line, by massive over expression of telomerase. But the changes occur first and cause the telomerase over expression, not vice versa. The sad failure of Imetelstat is but one example of the fallacy in the “cancer causes telomerase” theory. You may inhibit telomerase, but you then select out the remaining cancer cells that use the other way to lengthen telomeres, ALT and you get a recurrence that is worse and less treatable than the original cancer. If telomerase was a cause of cancer, telomerase inhibition would cure it. More and more, it looks like having a lower percentage of short telomeres and a longer mean telomere length, stabilizes the genome and prevents DNA damage. Thus, telomerase expression may actually protect from cancer.
In the long run, there are two simple (meaning I am simplifying this greatly) reasons telomeres shorten and they are causally mutually exclusive of each other – which means the “treatment” is also mutually exclusive.
First, telomeres shorten naturally with each replication of the cell, unless telomerase is around to prevent that by adding more base pairs. The only way to do this safely in humans is TA-65. This is the only telomerase activator with real human data. Rumor is, some “other” telomerase activators are undergoing human trials, but I am willing to bet the results will be reported in the presence of several other compounds made by this MLM company, not solely. Especially if it turns out, as another rumor has it, that this compound is inferior in telomerase activation to TA-65. They will want to get something for their money, so count on other “biomarkers of disease” being used, if the telomerase activation doesn’t look good, or they might simply leave out the comparison to TA-65 and not mention it at all. That should be a clue!
Next, and independent of cellular reproduction, is the ongoing damage to the telomere that happens as a result of oxidative damage. This can be from oxygen or nitrogen free radicals and some other less common forms of free radicals. The telomere has a DNA molecule in it called Guanine, which is extremely sensitive to oxidative damage. In this case, there are many good antioxidants on the market that may help. My personal favorite are my own purpose-designed Telomere Edge Packs, naturally.
We covered a lot here today and I hope it helps broaden your understanding of what is surely the most important discovery in human health and longevity so far.
Doc