Researchers here report on the generation of a mouse lineage with much longer telomeres than is normally the case. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes; a little is lost with each cell division, and cells self-destruct or become senescent when telomeres become too short. This acts as a limit on the ability to replicate for most cells in the body. Stem cells use telomerase to maintain long telomeres, however, allowing them an indefinite number of cell divisions, used to deliver daughter somatic cells with long telomeres into tissues. Thus average telomere length in a tissue is some function of the pace of cell division and the pace at which stem cells generate replacement cells.
This division of cells into a privileged minority and a restricted majority is the way in which all higher forms of animal life control the risk of mutation and the unfettered replication of cancer to a sufficient degree to allow evolutionary success. Over the past decade or more, researchers have been exploring ways to alter the balance of telomere length and telomerase activity in mice, and have found that enhanced telomerase activity extends life, reduces cancer risk, and improves health. As a consequence a number of groups are working on delivery of telomerase gene therapies to human patients, though there remains the question of whether the balance of cancer risk is the same in humans as in mice. The two species have quite radically different telomere dynamics.
In this study, the enhanced mice live somewhat longer than their unmodified peers, though not as much longer as is the case for the application of telomerase gene therapy. The mice do also exhibit reduced cancer risk, however. The scientists here class telomere shortening as a cause of aging, which is not a point universally agreed upon. Reductions in average telomere length in tissues looks much more like a downstream consequence of reduced stem cell activity than an independent mechanism.
Given the relationship between telomeres and ageing - telomeres shorten throughout life, so older organisms have shorter telomeres - scientists launched a study generating mice in which 100% of their cells had hyper-long telomeres. The findings show only positive consequences: the animals with hyper-long telomeres live longer in better health, free from cancer and obesity. "This finding supports the idea that, when it comes to determining longevity, genes are not the only thing to consider. There is margin for extending life without altering the genes".
Telomeres form the end of chromosomes, in the nucleus of each cell in the body. Their function is to protect the integrity of the genetic information in DNA. Whenever the cells divide the telomeres, they are shortened a little, so one of the main characteristics of ageing is the accumulation of short telomeres in cells. Up to now, all interventions on the length of telomeres have been based on altering the expression of genes, through one technique or another. In fact, researchers developed a gene therapy that fosters the synthesis of telomerase, obtaining mice that live 24% longer without developing cancer of other illnesses associated with age.
In 2009, researchers worked with the so-called induced pluripotent stem cells - cells from an adult organism which have been given back pluripotency or the capacity to generate a full organism - and they observed that after a certain number of divisions in culture plates, these cells acquired telomeres twice as long as normal. Intrigued, they confirmed that the same occurred in normal embryonic cells - also pluripotent - as they are kept in cultivation after being removed from the blastocyst. The team found that during the pluripotency stage, there are certain epigenetic marks on the telomeric chromatin that facilitate their lengthening by the telomerase enzyme. For this reason, the telomeres of pluripotency cells in cultivation were extended to twice the normal length.
The question was whether the embryonic cells with hyper-long telomeres could produce live mice? Some years ago, the group demonstrated that they could, and have now managed to obtain mice with hyper-long telomeres in 100% of their cells. The mice are slimmer than normal because they accumulate less fat. They also show lower metabolic ageing, with lower levels of cholesterol and LDL, and an increased tolerance to insulin and glucose. Damage to their DNA as they age is less and their mitochondria, another Achilles heel of ageing, function better. The average longevity of mice with hyper-long telomeres is 13% higher than usual. The metabolic alterations observed are also relevant as this is the first time that a clear relationship between the length of telomeres and metabolism has been found. The genetic route of insulin and glucose metabolism is identified as one of the most important in relation to ageing.
Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.