A fortuitous finding by researchers of the National Oncology Research Center (CNIO) ten years ago has led to the creation of the first mice born with telomeres much longer than normal in their species. The results are published in Nature Communications and show that these animals live longer with better health, without cancer or obesity. Most relevant, the average longevity of mice with hyperlarge telomeres is 13% higher than usual. Longevity is significantly increased for the first time without any genetic modification.
“This result supports the idea that, when determining longevity, genes are not the most important,” said María Blasco, head of the Telomeres and Telomerase Group of the CNIO and intellectual author of the work. “There is room to extend life without altering the genetic material.”
Our chromosomes, which contain the specific instructions that make us unique, are found in the nucleus of all our cells. Telomeres are stretches of DNA at the ends of our chromosomes, protecting our genetic information. They function similarly to the plastic tips on shoelaces; because they keep chromosome from fraying, which avoids deterioration or fusion with neighboring chromosomes, making it possible for cells to divide.
However, every time a cell divides its telomeres get shorter; and when they became too short, the DNA gets damaged and that cell can no longer divide. When this happens a cell may die or become “senescent”.
“The shortening of telomeres is considered one of the indicators of aging, given that short telomeres are enough to cause the organism to age and reduce the life span,” explains Nature Communications.
The Group of Telomeres and Telomerase of the CNIO already demonstrated in various works that avoiding the shortening of telomeres by activating the telomere extender enzyme, telomerase, prolongs longevity without side effects.
But so far all interventions on telomere length have been based on altering the expression of genes, by one technique or another. In fact, the CNIO group developed a gene therapy a few years ago that promotes the synthesis of telomerase, with which it obtained mice that live 24% longer without developing cancer or other diseases associated with age.
Living longer, thinner and without cancer
The novelty is that in mice born with hyper-large telomeres there has been no genetic alteration. In 2009 the researchers worked with induced pluripotent stem (IPS) cells —cells of an adult organism that have been reprogrammed back into an embryonic-like pluripotent state that allows reprogramming in any type of cell— and observed that after a certain number of divisions in culture plates these cells acquired telomeres twice as long as usual. Intrigued, they confirmed that the same thing happened in normal embryonic cells —also pluripotent— when kept in culture after removing them from the blastocyst.
When investigating the phenomenon they found that during the stage of pluripotence there are certain biochemical marks on the telomeres that facilitate its elongation, by the enzyme telomerase. That is why in culture the telomeres of pluripotent cells lengthened to twice as normal.
Could embryonic cells with hyper-large telomeres give rise to live mice? A few years ago the group showed yes. But these first animals were chimeric, that is, only part of their cells (between 30% and 70%) came from embryonic cells with hyperlarge telomeres. Their good health could be attributed to the proper functioning of the rest of the cells, with normal telomeres.
In the most recently published work, the authors have achieved mice with 100% cells with hyper-large telomeres, with which every peculiar feature is attributable to this phenomenon.
These mice have less cancer and live longer, the authors describe. “An important fact is that they are thinner than normal [mice] because they accumulate less fat. They also show lower metabolic aging, with lower levels of cholesterol and LDL (bad fat), and better insulin and glucose tolerance. The damage in their DNA as they age is less and they have a better function of their mitochondria, another of the Achilles’ heel of aging. ”
In conclusion, “these unprecedented results show that the longer than normal telomeres in a given species are not pernicious, but rather the opposite: they have beneficial effects, such as longer longevity, delayed metabolic age and less cancer.”
The observed metabolic alterations are also relevant, because it is the first time that a clear relationship is found between telomere length and metabolism. The genetic pathway of insulin and glucose metabolism is one of those identified as most important in relation to aging.
But what is most striking to researchers is that the finding opens the way to prolong longevity without changing the genes of the organism. The biochemical alteration that facilitates the lengthening of telomeres in the pluripotency phase is epigenetic, that is, it acts as a chemical annotation that modifies the work of genes, but does not alter them in their essence.
It was enough “to extend the time in which embryonic cells remain in pluripotency to generate mice with longer telomeres, protected from cancer and obesity, and living longer,” the authors point out. “We present a new mouse model that has delayed aging without any genetic manipulation.”