Length matters
Researchers at the Spanish National Cancer Research Center (CNIO) have for the first time proved the connection between telomere length and the metabolism of insulin and glucose, which have a strong effect on aging.
This discovery suggests that genes are not the only reason for species' longevity. Researchers have shown that it is possible to increase the lifespan of mice by epigenetically changing the length of telomeres in the absence of genetic modifications.
Ten years ago, a random find led to the appearance of the first mice born with much longer telomeres than usual. Given the relationship between them and aging – telomeres shorten during life, and they are shorter in older organisms – scientists have created mice whose 100% of cells had extra-long telomeres. The results show only positive consequences: animals live longer and get sick less, they are protected from cancer and obesity.
Telomeres form the ends of chromosomes in the nucleus of every cell in the body. Their function is to protect the integrity of genetic information in DNA. Whenever cells divide, telomeres shorten slightly, so one of the main characteristics of aging is the accumulation of short telomeres in cells. Therefore, telomere shortening is considered one of the main causes of aging.
A group from CNIO has already shown in various studies that maintaining telomere length by activating the telomerase enzyme increases life expectancy without any side effects. However, until now, all interventions have been based on changing gene expression using one technique or another. In fact, a few years ago, the group developed a gene therapy that promotes telomerase synthesis, and obtained mouse models that live 24% longer without developing cancer of other age-related diseases.
13% longer, slimmer and healthier
What is new is that mice born with extra-long telomeres had no genetic changes. In 2009, researchers worked with induced pluripotent stem cells – cells of an adult organism that had been restored the ability to generate a full-fledged organism. They found that after a certain number of divisions, these cells acquired telomeres that are twice as long as normal ones. The same thing was repeated in normal embryonic cells.
Investigating this phenomenon, the group found that at the pluripotency stage, there are certain biochemical (epigenetic) marks on telomeric chromatin that contribute to their elongation by the enzyme telomerase. For this reason, the telomeres of pluripotent cells during cultivation doubled in comparison with the normal length.
The question was whether embryonic cells with extra-long telomeres could produce live mice. A few years ago, the group demonstrated that this is possible. However, the first modified animals were chimeric, that is, only a part of their cells (30-70%) originated from embryonic cells with extra-long telomeres. Their good health could be related to the functioning of the remaining cells with normal telomeres.
In a new study, the authors managed to obtain super-long telomeres in 100% of mouse cells and prove that all the features are associated with this phenomenon. To do this, the researchers isolated cells with only long telomeres from chimeric embryos and obtained embryos only from this cell population.
Unprecedented results
Mice obtained as a result of double selection of embryonic cells suffer less cancer and live longer. An important fact is that they accumulate less fat in their body. They also show slower metabolic aging, have low cholesterol and LDL levels, and increased glucose tolerance. Age-related damage to their DNA is less, and mitochondria, another Achilles heel of aging, function better.
In conclusion, these results show that longer telomeres in this species do not have a negative effect, rather the opposite: they have beneficial effects, such as increased life expectancy, slower metabolic age and fewer cancers.
Adipose tissue, liver and skin of adult mice with normal (left) and extra-long (right) telomeres. Nuclei are marked in blue, telomeres are marked in red. Cells that are derived from animals with extra-long telomeres are brighter, indicating longer telomeres in adulthood.
The average life expectancy of mice with extra-long telomeres is 13% longer than that of normal mice. The observed metabolic changes are also relevant, since for the first time a clear relationship between telomere length and metabolism has been discovered. The genetic pathway of insulin and glucose metabolism has been identified as one of the most important in relation to aging.
However, the most striking thing for researchers is that it has been proven that it is possible to increase life expectancy without changing the body's genes. Biochemical changes in telomeric chromatin that contribute to telomere elongation in the pluripotency phase are epigenetic, in other words, they change the work of genes, preserving their essence.
Article by M. A. Muñoz-Lorente et al. Mice with hyper-long telomeres show less metabolic aging and longer lifespans is published in the journal Nature Communications.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on CNIO materials: CNIO researchers acquire the first mice born with hyper-long telomeres and show that it is possible to extend life without any genetic modification.