It is possible to extend the life without any genetic modification: Study

In recent years, the fight against cellular aging has become an active topic of research in biology. One of the research focuses on the telomeres of chromosomes, the chromosome ends, which are shortened a little more at each cell division. However, until now, the manipulation of telomeres and the associated enzyme, telomerase, required genetic modifications in situ . Recently, a team of biologists has shown that it is possible to lengthen the telomeres, and therefore the lifespan, without genetic alteration, in mice. The results produced mice with longer lifespan, better health and more efficient metabolism.

A fortuitous discovery made ten years ago led researchers at the Spanish National Center for Cancer Research (CNIO) to create the first mice with much longer telomere than normal in their species. Given the relationship between telomeres and aging - telomeres are shorter in life, older organisms have shorter telomeres - biologists have developed mice with 100% of their cells long.

The results have been published in the journal Nature Communications and show only positive consequences: animals with hyper-long telomeres live longer and healthier, without cancer or obesity. The key point of the study, for the authors, is the fact that longevity has been greatly increased for the first time without any genetic modification.

" This discovery supports the idea that when it comes to determining longevity, genes are not the only thing to consider, " says Maria Blasco, head of the CNIO Telomeres and Telomerase group . " There is room to prolong life without altering genes ."

Length of telomeres and genetic modifications

Telomeres form the end of chromosomes, in the nucleus of each cell of the body. Their function is to protect the integrity of genetic information carried by DNA. Whenever the cells divide, the telomeres get shorter. One of the main features of aging is therefore the accumulation of short telomeres in the cells.

" The shortening of telomeres is considered one of the main causes of aging, because short telomeres cause the aging of the body and reduce its longevity " explain the authors. The CNIO Telomeres and Telomerase group has already shown in various studies that avoiding telomere shortening by activating the telomerase-extending enzyme, telomerase, increases longevity without any side effects.

However, so far all telomere length interventions have been based on the modification of gene expression. In fact, a few years ago, the CNIO group developed a gene therapy that promotes the synthesis of telomerase. The researchers obtained mice that live 24% longer without developing cancer and other age-related diseases.

Telomeres, telomerase and pluripotent stem cells

The novelty is that in this study, there was no genetic alteration in mice born with hyper-long telomeres. In 2009, researchers worked with IPS cells - pluripotent stem cells - and found that after a number of divisions on culture plates, these cells acquired telomeres twice as long as normal. Intrigued, they confirmed that it was the same in normal embryonic cells - also pluripotent - preserved in culture after being removed from the blastocyst.

Images showing mouse fat , hepatic ( liver ) and dermal ( skin ) cells , as well as their nucleus (blue) and the telomeres of their chromosomes (red). Left, adult mouse cells with normal and right telomeres, with hyper-long telomeres. These are brighter because longer. Credits: CNIO
By researching the phenomenon, the Blasco team discovered that during the pluripotency phase, certain biochemical brands (epigenetic marks) on telomeric chromatin facilitate their elongation by telomerase. For this reason, telomeres of pluripotent cells in culture were expanded to twice the normal length. The question was whether embryonic cells with hyper-long telomeres could produce viable mice?

Longer life, better health and more efficient metabolism

A few years ago, the group showed that it was possible. However, these early animals were chimeric, i.e., only a portion of their cells - between 30% and 70% - came from embryonic cells with hyper-long telomeres. Their good health could be attributed to the good functioning of the rest of the cells, with normal telomeres. In the study that has just been published, the authors have managed to obtain hyper-long telomeres in 100% of the cells of mice.

Mice with hyper-long (black) telomeres have better weight control over their lifetime. They thus have a lower weight than mice with normal telomeres (gray). Credits: Miguel A. Muñoz-Lorente et al. 2019

" These mice have fewer cancers and live longer. An important fact is that they are thinner than normal because they accumulate less fat. They also have lower metabolic aging, lower cholesterol and LDL levels, and increased tolerance to insulin and glucose. The damage caused by old age to their DNA is weaker and their mitochondria work better "explain the authors.

Mice with hyper-long (green) telomeres live longer while developing far fewer spontaneous cancers. Credits: Miguel A. Muñoz-Lorente et al. 2019

More specifically, the average longevity of mice with hyper-long telomeres is 13% higher. The observed metabolic alterations are also relevant because this is the first time that there is a clear relationship between telomere length and metabolism. The genetic pathway of insulin and glucose metabolism is identified as one of the most important in relation to aging.

Delay aging without genetic manipulation
This discovery paves the way for an extension of longevity without changing the genes of the body. The biochemical changes of telomeric chromatin that facilitate elongation of telomeres in the pluripotency phase are epigenetic. In other words, they act as a chemical annotation that modifies the work of the genes, but does not change their structure.

" Extending the time during which embryonic cells remain pluripotent to generate mice with longer telomeres, protected from cancer and obesity and with increased longevity, was enough for mice to have longer telomeres and live longer. long time. We present a new mouse model in which aging has been delayed without any genetic manipulation "conclude the researchers.


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