A fortuitous discovery ten years ago led to the creation, by researchers at the Spain’s National Cancer Research Center (CNIO), of the first mice born with telomeres much longer than normal in their species. Given the relationship between telomeres and aging – telomeres shorten throughout life, so older organisms have shorter telomeres – scientists have set out to study how having hyperlong telomeres affects mice. The results are published in Nature Communications and show only positive consequences: animals live longer in better health, without cancer or obesity. The most important thing, for the authors, is that for the first time longevity is significantly increased without any genetic modification.

Munoz and Blasco at CNIO
Miguel Ángel Muñoz, first author of the work, and Maria Blasco, main author. /CNIO

This result supports the idea that, when determining longevity, genes are not the most important thing,” says Maria Blasco, head of CNIO’s Telomeres and Telomerase Group and intellectual author of the work. “There is scope for extending life without altering genetic material.

Telomeres form the end of the chromosomes, in the nucleus of each cell of the body. Their function is to protect the integrity of the genetic information contained in DNA. Every time cells divide, the telomeres shorten a little, so one of the main characteristics of aging is the accumulation of short telomeres in the cells. “The shortening of telomeres is considered one of the indicators of aging, since short telomeres are enough to cause the body to age and reduce the duration of life,” explains at Nature Communications.

The Telomeres and Telomerase Group of CNIO has already demonstrated in various works that avoiding the shortening of telomeres through the activation of the telomere extension enzyme, telomerase, prolongs longevity without side effects.

But until now all interventions on the length of telomeres have been based on altering the expression of genes, using one technique or another. In fact, the CNIO group developed a few years ago a gene therapy that promotes the synthesis of telomerase, with which it obtained mice that live 24% longer without developing cancer or other diseases associated with age.

13% longer-lived, thinner and cancer-free

The novelty is that in mice born with hyperlong telomeres there has been no genetic alteration. In 2009, researchers were working with so-called IPS cells – cells from an adult organism to which pluripotency or the ability to generate a complete organism has been restored – 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 occurred in normal embryonic cells – also pluripotent – when kept in culture after extracting them from the blastocyst.

Hyper-long telomeres
Fat, liver and skin images of adult mice with normal telomeres and hyperlong telomeres. Cell telomeres from animals with so-called hyperlong telomeres are more intense, indicating greater telomeric length from embryo to adulthood. /CNIO

When investigating the phenomenon, they found that during the pluripotency stage there are certain biochemical marks in the telomeres that facilitate their elongation by the telomerase enzyme. That is why in pluripotent cells in culture, the telomeres were elongated up to twice as much as normal.

The question was: could embryonic cells with hyperlong telomeres give rise to living mice? A few years ago the group proved – with a publication also in Nature Communications- that they could. But these first animals were chimerical, that is to say, only part of their cells – between 30% and 70% – came from embryonic cells with hyperlong telomeres. Their good health could be attributed to the correct functioning of the rest of the cells, with normal telomeres.

In the work now published the authors have achieved that 100% of mouse cells have hyperlong telomeres, so that any peculiar trait is attributable to this phenomenon. And there are, in fact, many peculiarities.

“Unprecedented results”

“These mice have less cancer and are more long-lived,” the authors describe. “An important fact is that they are thinner than normal because they accumulate less fat. They also show less metabolic aging, with lower levels of cholesterol and LDL (bad fat), and better insulin and glucose tolerance. The damage to their DNA as they age is less and they have a better function of their mitochondria, another Achilles heel of aging.

Telomeres elongation
Scheme representing the telomeric elongation process associated with the cell division of pluripotent cells and the generation of animals with hyperlong telomeres. Mouse embryonic stem cells are obtained and cultured during a few cell divisions to allow telomeric elongation without any genetic manipulation. After this process, pluripotent cells with hyperlong telomeres are introduced into a recipient embryo with normal cells, thus generating a chimera with two different cell types. These chimeric embryos are reimplanted into mice for the generation of mice in which 100% of their cells are derived from embryonic cells with hyperlong telomeres. /CNIO

In conclusion, “these unprecedented results demonstrate that telomeres longer than normal in a given species are not harmful, but rather the opposite: they have beneficial effects, such as increased longevity, metabolic age delay and less cancer.”

Specifically, the average longevity of mice with hyperlong telomeres is 13% higher than usual. The metabolic alterations observed are also relevant, because this is the first time that a clear relationship between telomere length and metabolism has been found. The genetic pathway of insulin and glucose metabolism is one of the most important identified 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 elongation of telomeres in the pluripotency phase is epigenetic in nature, that is, it acts as a chemical annotation that modifies the work of genes, but does not alter their essence. It has been enough “to lengthen the time in which embryonic cells remain in pluripotency to generate mice with longer telomeres, protected from cancer and obesity, and more longevity”, the authors point out. “We present a new mouse model that has been delayed in aging without any genetic manipulation.

Reference article: Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Miguel A. Muñoz-Lorente, Alba C. Cano-Martin, Maria A. Blasco (Nature Communications, 2019). DOI: 10.1038/s41467-019-12664-x

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