Scientists at the Spanish National Cancer Research Centre (CNIO) generated the first mice that have super-long telomeres in every one of their body cells. Studies with the animals showed that in comparison with mice that have normal length telomeres, the hyper-long telomere animals lived on average nearly 13% longer, were leaner with less white fat tissue, and had better metabolic health. The researchers generated the mice from embryonic stem (ES) cells that carry the hyper-long telomeric repeats capping the ends of their chromosomes. The most relevant achievement for the scientists is that for the first time longevity was significantly increased without any genetic modification. “This finding supports the idea that, when it comes to determining longevity, genes are not the only thing to consider,” commented research lead Maria Blasco, PhD, head of the CNIO Telomeres and Telomerase Group. “There is a margin for extending life without altering the genes.”

Blasco and colleagues published their findings in Nature Communications, in a paper titled, “Mice with hyper-long telomeres show less metabolic aging and longer lifespans.”

Telomeres are nucleoprotein structures that essentially form the protective caps at the ends of the chromosomes in the nucleus of each cell in the body. “Telomeres are essential to protect chromosome ends from DNA degradation and DNA repair activities and they play an important role in chromosome stability,” the authors explained. Telomeres are composed of a repeating DNA sequence, bound by a protein complex. However, they don’t remain the same length throughout life, and at each cell division, telomeres become progressively slightly shorter. This telomere shortening is linked with cell aging. “Telomere shortening is considered to be one of the primary causes of aging, given that short telomeres cause aging of the organism and reduce longevity,” the team continued. “In turn, telomere shortening with aging can trigger a number of secondary pro-aging phenomena such as increased DNA damage and genomic instability, cellular senescence and/or apoptosis, and impaired ability of stem cells to regenerate tissues, etc., and therefore it is considered one of the primary hallmarks of organismal aging.”

Initial telomere length is determined genetically, and this, as well as the rate of telomere degradation, varies between species. For example, “humans are born with shorter telomeres than mice, but mice telomeres shorten 100-times faster than humans.” Most studies involving the manipulation of telomere length have to date required some sort of alteration of gene expression. The CNIO group developed a gene therapy that harnesses the synthesis of telomerase—the enzyme that is responsible for at least partially rebuilding telomeres in pluripotent cells—to generate mice that lived 24% longer without developing cancer of other illnesses associated with age. In 2009, researchers working with induced pluripotent stem cells derived from adult tissues, observed that after a certain number of divisions in culture plates, the cells acquired telomeres that were twice as long as normal. They subsequently confirmed that the same phenomenon occurred in normal blastocyst-derived embryonic cells that are kept in laboratory cultivation. On researching this observation, Blasco’s team found that during the pluripotency stage, epigenetic marks on the telomeric chromatin facilitate their lengthening by the telomerase enzyme. It was this that led to the telomeres of pluripotency cells in cultivation becoming extended to twice the normal length.

Scheme representing the telomeric elongation process associated with the cell division of pluripotent cells and the generation of animals with hyper-long telomeres. Mouse embryonic stem cells are obtained and cultured for a controlled number of cell divisions to allow telomeric elongation in the absence of any genetic manipulation. Upon telomere elongation, pluripotent cells with hyper-long telomeres are introduced into a recipient embryo with normal cells, thus generating a chimera with cells of different origins (normal and hyper-long telomere embryonic stem cells). These chimeric embryos are re-implanted in a mouse for the generation of mice in which 100% of their cells are derived from embryonic cells with hyper-long telomeres. [CNIO]
The team was then able, without having to resort to genetic manipulation, to generate ES cells with hyper-long telomeres, and then create healthy chimeric mice in which about 30–70% of cells came from these ES cells with the hyper-long telomeres. This work was reported back in 2016. For their newly reported studies, the investigators generated chimeric mice that were formed 100% from these hyper-long telomere ES cells. They then followed these mice throughout the animals’ lives, to see whether the hyper-long telomeres had any adverse effects. “Here, in order to address any potential long-term deleterious effects of longer telomeres than normal in the context of an organism, we generated chimeric mice that are 100% contributed from ES cells with hyper-long telomeres (hyper-long telomere mice), and followed these mice during their entire lifespan.”

They found that rather than having any adverse effects, hyper-long telomeres were linked with numerous health benefits. Compared with control animals that had normal length telomeres, the animals with hyper-long telomeres were leaner and accumulated significantly less fat than control mice, as well as showing lower levels of cholesterol and in particular low-density lipoproteins (LDL). The hyper-long telomere mice also demonstrated improved metabolic health, with improved glucose and insulin sensitivity, developed less DNA damage as they aged, and retained better mitochondrial function. The metabolic changes are particularly relevant as this is the first time that a clear relationship between the length of telomeres and metabolism has been found. The hyper-long telomere mice were also less likely to develop spontaneous tumors than control animals. “We found that hyper-long telomere mice showed a reduction of almost 50% in the number of mice that developed tumors compared to the normal telomere length control mice, although this difference did not reach statistical significance,” the investigators stated. Interestingly, having extra long telomeres was associated with a 12.75% median increase in lifespan, and an increase in maximum longevity of 8.4%. “These findings indicate that long telomeres, per se, even in the absence of telomerase overexpression, are sufficient to increase mouse longevity,” the authors stated. The hyper-long telomere mice retained longer telomeres in every tissue evaluated, throughout their lifespan. “Altogether, these results demonstrate that hyper-long telomere mice retain longer telomeres with aging, including metabolic tissues such liver, white adipose tissue, and brown adipose tissue …” the scientists wrote.

They claim that their “unprecedented results” show that rather than being harmful, longer than normal telomeres in a given species have beneficial effects, such as increased longevity, delayed metabolic age, and less cancer. “Extending the time during which embryonic cells remain in pluripotency to generate mice with longer telomeres, protected from cancer and obesity, and with increased longevity has been enough to make mice have longer telomeres and live longer.”

The findings could feasibly pave the way to the development of new approaches to extend longevity without resorting to genetic manipulation. “These results also suggest that there is not a negative selection for individuals with longer telomeres than normal in species,” the scientists concluded. “… and therefore, one can envision that natural selection processes which favor individuals with longer telomeres within a given species, could potentially increase species longevity.”

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