Researchers at the Spanish National Cancer Research Centre (CNIO) have shown that it is possible to extend the life of mice, without using any gene modifying technologies. The finding is the result of a study launched some years ago that aimed to investigate mice with hyper-long telomeres.
Image Credit: Crevis / Shutterstock.com
Given the relationship between telomeres and aging (telomeres become shorter with age), Maria Blasco and colleagues decided to create mice at CNIO that had hyper-long telomeres in 100% of their cells.
The researchers reported their findings in the journal Nature Communications and demonstrate only positive outcomes; the mice live for longer and in better health than would be expected for their species, while also being free from age-related conditions such as cancer and obesity.
No need for genetic modification
The most important finding for the team was that the increased lifespan and health benefits have been achieved for the first time without genetic modification being needed.
"This finding supports the idea that, when it comes to determining longevity, genes are not the only thing to consider", says Blasco… "There is margin for extending life without altering the genes.”
Telomeres form the end of chromosomes in the nucleus of cells and protect the genetic integrity of DNA. Each time a cell divides, the telomeres shorten a little, so one characteristic of aging is shortened telomeres in cells.
The author's state:
Telomere shortening is considered to be one of the primary causes of ageing, given that short telomeres cause ageing of the organism and reduce longevity.”
Telomerase extends longevity
The Telomeres and Telomerase Group at CNIO has already shown in various studies that stopping telomere shortening by activating the enzyme telomerase, which lengthens telomeres, extends longevity without causing any adverse health effects.
Until now, these experiments have been based on techniques that altered gene expression. For example, some years ago, the group developed a gene therapy that promotes the synthesis of telomerase and used it to generate mice that live 24% longer than usual, without developing cancer or other age-related illnesses.
This time, however, the team has not needed to use any gene-altering technologies.
Telomere length medical concept and telomeres located on the end caps of a chromosome resulting in aging by damaging DNA or protection resulting in living longer or longevity as a 3D illustration. Image Credit: Lightspring
Generating telomeres twice as long as usual
In 2009, the researchers experimented with induced pluripotent stem (IPS) cells, which are stem cells taken from adult organisms that have had their pluripotency (ability to differentiate into other cell types) restored. The researchers found that once the cells had divided in culture a certain number of times, they acquired telomeres that were twice the usual length.
Intrigued by the findings, they investigated whether the same could be achieved in normal embryonic stem cells that had been cultivated after being extracted from blastocytes.
The team discovered that during the pluripotency phase, certain epigenetic marks on the telomeric chromatin aid the lengthening by telomerase. This enabled the generation of embryonic cells with telomeres that were twice as long as normal.
Next, the team wanted to find out whether these embryonic cells with extended telomeres could generate live mice, which the group demonstrated they could indeed do some years ago. That study was also published in Nature Communications.
However, the mice used were chimeras, with only 30 to 70% of the cells in their bodies made up of ones with extended telomeres. The mice were in good health, but the team could not rule out that the good health could be attributed to the proper functioning of the unaltered cells that had normal telomeres.
In the new study, the researchers have managed to generate mice that have hyper-long telomeres in every single cell of their bodies.
The mice live longer, are less likely to develop cancer and are slimmer
According to the authors:
These mice have less cancer and live longer. An important fact is that they are slimmer than normal because they accumulate less fat. They also show lower metabolic aging, with lower levels of cholesterol and LDL (bad cholesterol), and increased tolerance to insulin and glucose.”
Age also does not damage their DNA as much as it usually would and their mitochondria function better.
"These unprecedented results show that longer than normal telomeres in a given species are not harmful but quite the contrary: they have beneficial effects, such as increased longevity, delayed metabolic age and less cancer,” concludes the team.
More specifically the average lifespan among the mice with extended telomeres is 13% longer than usual. The metabolic changes that were seen are also important because this is the first time that a clear relationship between telomere length and metabolism has been observed.
No need for genetic modification
However, the most striking finding for the researchers is that longevity was extended without any alterations to gene expression being required.
Epigenetic marks on the telomeric chromatin facilitate telomere lengthening in the pluripotency phase by modifying the work of genes, but without altering them.
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. We present a new model of mouse in which aging has been delayed without any genetic manipulation.”
- Muñoz-Lorente, M. A., et al. (2019). Mice with hyper-long telomeres show less metabolic aging and longer lifespans. Nature Communications. https://www.nature.com/articles/s41467-019-12664-x
- Varela, E., et al. (2019). Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations. Nature Communications. https://www.nature.com/articles/ncomms11739