I find myself saying the same thing over and over again and I still see the same baseless assumptions all over the internet. So, with my usual cut-through-the-BS attitude, I feel compelled to do what is necessary to protect the truth – YET AGAIN!
There are several misconceptions that continue to float around in the lay press/public about telomerase and cancer. One is the mistaken assumption that telomerase somehow causes cancer, which arises from several seemingly viable sources, but fails under scrutiny. This is the danger of the internet. Someone who states something authoritatively becomes an authoritative expert and the misconceptions spread.
Simply, cancer makes telomerase, not vice versa. It makes it by gene amplification, mutation over promotion and all kinds of unnatural ways that are germane only to the process that creates cancerous transformation in the first place. There are at least 3 cellular check points that have to be overcome, including the DDR (DNA damage response) P53/21 system and several others as well. Once that happens, in the presence of critically short telomeres, or processes that critically shorten the telomere, which are similar to the processes that cause cancer – mutations, oxidation, inflammation, etc. from all the various sources, telomerase can be massively over induced to sustain the already damaged genome of the cancer cell and allow it to divide far more rapidly than noncancerous cells. Studies on villous adenoma have suggested that telomerase induction is the very last step in cancerous transformation. Inhibiting Telomerase will always fail as an anti-cancer measure, because in removing the telomerase positive cancer cell population, you either unmask or induce ALT telomere lengthening and the cancer comes back worse than ever. Imetelstat and other telomerase inhibitors have failed, probably because of that reason.
This must be the 1000th time I have said it, but telomerase is not oncogenic, unless it is constitutively massively over expressed. In 2002, Jerry Shay’s group created an immortal cell line with the worst possible vector – a RAS oncogene promoter. The cell line doubled over 500X (normal cells quit after 70) with no evidence of cancer. The cells died a quite death when the lab assistants got tired of feeding them – since they had effectively proved a point. Maria Blasco’s lab extended mammalian lifespan (mouse model) by 24% with the AAV9 non-integrating vector. No increase in cancer. She also used the nutraceutical TA-65 in a different study for only 3 months and improved multiple measures of healthspan in a similar mouse model. No increases in cancer. Ron DePinho did a similar experiment reversing the phenotype of aging in his mouse model, using a tamoxifen trigger to express telomerase. No increases in cancer. A JAMA study in late 2010, showed an association of short telomeres with more and worse cancers, and most of us feel that canonical activation of telomerase in cancer patients is a good thing, since things like TA-65 have been shown to improve the immune system, by restoring naïve active CD 28+ helper cells which fight viral infections and cancer to normal levels, reverse bone density abnormalities, reduce the markers of inflammation, restore collagen and elastin balance to the skin and many other biomarkers of aging. In a cancer patient especially, the immune function benefits would be huge, since this would be the way to fight off the ALT-based cancers and the amount of “extra telomerase”, expressed in the normal fashion pales in comparison to what the cancer is already doing without driving the cancer forward.
Now, here is the study I hope to fund soon. We have extended mammalian lifespan as noted above. It is not rocket science to imagine that in doing so you must improve cellular repair processes, including mitochondrial function, proteasome regulation, mTor, Sirtuins, intracellular junk, glycation, ubiquitination and so on and so forth – all the “theories of aging” or the organism could not possibly survive longer with all that dysfunction. Telomerase must reverse some of it, for at least a while. No one has done that particular study yet, but I am working on it.
You don’t need to genetically re-engineer the telomere to do this, unless you have a telomeropathy like IPF, one of the Progeriod syndromes (Lamellin has now been shown to critically damage or shorten telomeres) or aplastic anemia to begin with. To reduce the aging process and improve healthspan and lifespan, you need to genetically or pharmacologically improve the telomerase enzyme. It remains to be seen whether you can pass the Hayflick limit in humans this way, but it should be possible, since it has been done in mice, although no one has interviewed every mouse on the planet to see which one is the oldest!
Telomere erosion is based on two main things – cellular division and loss of telomere length (telomerase responsive) and toxicity to the telomere from lifestyle, environment, etc. (also telomerase responsive). The inherent damage to the genome via defective repair from the DDR is always a concern, but as long as the cellular checkpoints are intact (also, you guessed it, telomere/telomerase dependent) those cells will be removed by your effective intracellular check points and your far more effective immune system. That is the current thinking, which is more than speculative, but not yet proven. Honestly, I think we should be glad we are alive now, because it is pretty promising.
Next: Resveratrol’s action on SIRT1 is via adipokines – not direct action. The SIRT 1 protein is located in the mitochondria and its action is there – thus anything that depends directly or indirectly on SIRT1 effects mitochondrial function. The main regulators of mitochondrial function are the PPAR Co Factors, specifically PCR1 alpha. As was shown by both Passos and DePinho independently, these co factors are regulated by the P53/21 systems, which are in turn directly regulated by telomere length. Subsequently, they showed this regulation included the following mitochondrial behaviors: biogenesis, mtMutation rates, and ECT function, all of which “got worse” as the telomere shortened and apoptotic/senescent signals accrued. Ultimately, this was extended to include senstatic activation, now referred to as SASP (senescent activated secretory phenotype) resulting from mitochondrial dysfunction and ROS/NOS leakage with subsequent immune response.
Sirtuin expression has also been shown to be directly related to telomere length, so stop looking at resveratrol for longevity. It is a good antioxidant that has promise in treating -based disorders like diabetes, metabolic syndrome and obesity, all important. But, in spite of reports of telomerase activation, which cannot be reproduced by the best lab in the world for that sort of thing – Bill Andrews’ Sierra Sciences – it is not a telomerase activator and therefore not a longevity drug.
But if you are fat, by all means take it! Just don’t expect to live longer because of it.