2023-05-15 16:21:00
Long Telomeres – Life. Short telomeres – death. The reality, as usual, is more complicated. Read here why immortality is not so easy after all.
Von Telomeres and the enzyme Telomerase many are fascinated. The discovery in the 1980s, which was rewarded with the Nobel Prize in 2009, not only initiated a lot of research, but also produced a whole range of metaphors. Everything was included, from the “chromosome protection package” to the “substrate of immortality”. In any case, the world of telomere metaphors is a positive world: the telomere is noble, helpful and good.
Those who have long telomeres are said to live longer – a correlation that alternative medicine promptly pounced on. Various dubious products claim to lengthen telomeres or slow down their shortening. Anything that shortens telomeres prematurely, on the other hand, is considered bad to life-threatening. Recently, this could be observed repeatedly in the discussions about the supposedly ruining effects on the immune system COVID-19 infections. They were justified, among other things, with a shortening of the telomeres of immune cells. That the manufacturers of supposedly telomere-lengthening alternative medicine promptly jumped on this bandwagon and used their products as silver bullets against Long Covid positioned, who can repay them?
Telomeres: what they are and what drives them
Telomeres are repeated DNA sequences at the ends of chromosomes. At cell divisions copies of the chromosomes are known to be made. However, this does not work 100% at the ends of the chromosomes: the last section of the telomere cannot be duplicated, which means that the telomeres in most cells become shorter with each replication. It is this generational shortening that has earned telomeres their reputation as age equivalents. At some point, when the telomeres become too short, cell division stops. A mechanism is triggered that prevents further mitoses, and after some time the cell then goes into programmed cell death.
Long Telomeres – Life. Short telomeres – death. The reality, as usual, is more complicated. Telomeres interact with a protein complex called – the world of telomeres is a positive world – called shelterin. This protein complex protects the precious telomeres; it prevents them from being broken down or tampered with by DNA repair enzymes. One of the proteins in the shelterin complex is POT1. Along with other proteins, it can attract an enzyme complex called telomerase. This telomerase contains a specialized reverse transcriptase – a rather unusual enzyme for a human. She can lengthen telomeres and thus confer a certain form of immortality on a cellular level. The organism uses this in all those cells that should not stop dividing at some point, namely in germ cells and at the stem cells proliferative tissues such as (mucous)skin and blood.
How desirable are long telomeres really?
Different types of mutations can affect telomeres and telomerase. There are some mutations in the telomerase complex that are associated with shortened telomeres. The corresponding diseases are Short-Telomer-Syndrome called. They are all rare. One of the better known is the Congenital dyskeratosisa very serious condition associated with bone marrow failure and pulmonary fibrosis and premature aging of the skin, nails and hair.
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In a now im New England Journal of Medicine published study In a way, it is about the opposite of this group of diseases, namely diseases caused by mutations that are associated with longer telomeres. Long telomeres result, among other things, from a number of mutations in the POT1 protein already mentioned. In line with the positive image of long telomeres, these mutations should actually be a good thing, a cellular switch for longevity. But the scientists led by Emily DeBoy and Mary Armanios from Johns Hopkins University are now showing that this is not true. They can show from affected families that POT1 mutation carriers have a significantly increased risk of a number of neoplasms, both benign and malignant, including B- and T-Zell-Lymphomeblood cancers as well as epithelial, mesenchymal and neuronal tumors.
The connection between POT1 mutations and the so-called CHIP syndrome was particularly clear. Two-thirds of POT1 mutation carriers had CHIP syndrome; there was evidence of an autosomal dominant inheritance and increasing penetrance with increasing age. CHIP stands for clonal hematopoiesis of undetermined potential. It has long been known that this syndrome is associated with a significantly increased risk of cancer. The US study now links the CHIP syndrome with the POT1 mutations and with a slowed down or eliminated telomere shortening and underpins this connection with various analyses.
The cellular fountain of youth as a cause of cancer
The result is an interesting new explanation for the tumor tendency in CHIP patients as well as a new mechanism for the development of cancer: the alleged cellular fountain of youth of a missing telomere shortening could lead to the resulting longer-lived cells (or cell lines) accumulating mutations because they not die in time. And that in turn increases the risk of cancer, especially in the longer course of life. The US researchers were able to definitively show this using the hematopoietic cells of the affected people: they actually showed an above-average number of somatic mutations, including known driver mutations for hematological neoplasia.
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The hypothesis – as yet unproven – is that this also applies in a similar way to other tissues and that this common cellular mechanism could underlie the association of CHIP with solid tumors of different types: “All in all, our data reveal a mechanism for hereditary cancer predisposition , which differs from mutations in tumor suppressor genes and oncogenes: an extension of the cellular lifespan that drives age-dependent clonal evolution,” the scientists conclude.
Image source: Maxime Bouffard, unsplash
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