Anti-ageing telomerase with cancer resistance tooSaturday, 15 November, 2008
Telomerase is the enzyme that elongates the ends of chromosomes, and because these telomeres become shorter every time a cell divides, this enzyme is essential to making a cell, and an organism made of cells, become immortal. Despite this, I neglected putting telomerase on my list of eight genetic modifications to live forever, because increased telomerase activity also increases the risk of cancer. For a cancer cell to proliferate into a tumour it will have to divide almost limitlessly, so cancer cells usually mutated to over-express telomerase. But if a cell is already expressing loads of telomerase, that is one less mutation that needs to occur before a cell becomes cancerous.
But, on that list I did include a study that showed mice with extra copies of the tumour supressor genes p53, p16 and Arf (so called Sp53/Sp16/SArf mice, where the S is short for ‘super’) are largely cancer-resistant (Matheu et al, 2007). This occurs because a cell must acquire mutations in all copies of these genes before it can become a tumour, and with extra copies, this requires more specific mutations.
Now, the same lab has reported, in yesterday’s edition of the journal Cell, that if they crossed transgenic mice that expressed telomerase reverse transcriptase gene Tert in many of their epithelial tissues, with those transgenic cancer-resistant mice, they end up with Tert-transgenic mice with cancer resistance (Tomas-Loba et al, 2008). The resulting mice are named Sp53/Sp16/SArf/TgTert mice. The cancer-resistance should offset the increased risk of cancer due to telomerase, leaving the telomerase to keep the telomeres on the chromosomes from getting too short, preventing at least one of the causes of ageing.
So, while the Sp53/Sp16/SArf mice lived 16% longer than wild-type (i.e. normal) mice, these Sp53/Sp16/SArf/TgTert mice lived 26% longer again. While they didn’t look at normal mice in this study, they did look at Sp53 mice (which don’t really age too differently to normal mice), and found that the Sp53/Sp16/SArf/TgTert mice lived 40.2% longer than the Sp53 mice. And, if they looked at mice lucky enough not to get cancers in these two groups (which are presumed to have died from age-related decay along, not cancer), the Sp53/Sp16/SArf/TgTert mice lived over 50% longer than the Sp53 mice. In addition to this, the older Sp53/Sp16/SArf/TgTert mice were still able to balance on a tightrope just as well as they were when they were young.
And to top it off, even the young Sp53/Sp16/SArf/TgTert mice had better glucose tolerance and gastro-intestinal tract barrier function, which suggests that telomerase can even improve regenerative capacity in young tissues. Yet these additional regulatory genes seem to slow down stem cell proliferation, but it is suggested that this may be beneficial in ensuring stem cells are still around later in life. So each stem cell is dividing less quickly, but there are more of them, even at young ages.
It is worth noting that these mice only expressed more telomerase in their epithelial cells, not their entire body. Although the telomerase seemed to have some effects on the entire body, the researchers hint strongly at their next step:
It will be of great interest to study the impact of ubiquitous TgTert expression on mouse fitness and longevity.
Given that the researchers also note that the increased lifespan of their Sp53/Sp16/SArf/TgTert mice is of similar magnitude to mice with a calorie-restricted (CR) diet, and that it may well be through a different anti-ageing pathway, these two may be combinable. If you want to win the Methuselah Mouse Prize, I suggest genetically modifying some mice with Sp53/Sp16/SArf genes as well as TgTert, and either switch them to a CR diet (or with engineered genes that mimic such a diet). And if you want to live forever, I suggest you get what these mice are having.