Written by Joyce Smith, BS. Without the use of genetic manipulations, molecular biologist Maria Blasco and team from the Spanish National Cancer Research Centre developed in a mouse model a generation of mice with hyper-long telomeres and significantly delayed aging.
Telomeres are nucleoprotein structures that essentially form the protective caps at the ends of the chromosomes in the nucleus of each cell in the body 1,2. They protect chromosome ends from DNA degradation and DNA repair activities and promote chromosome stability 3,4. They consist of tandem repeats of the TTAGGG DNA sequence and are bound by a protein complex 2,5; furthermore, they don’t remain the same length throughout life, and at each cell division, telomeres become progressively slightly shorter. This telomere shortening is thought to be one of the hallmarks of aging, in that after reaching a critically short length telomeres can trigger a number of secondary pro-aging phenomena such as increased DNA damage and genomic instability, cellular senescence and/or apoptosis, and impaired ability of stem cells to regenerate tissues 4,6,7. Telomere length is determined genetically and both telomere length and rate of shortening varies between species, thus while we are born with shorter telomeres than mice, their telomeres shorten 100-times faster than human telomeres 8,9.
Most studies involving the manipulation of telomere length have required some sort of alteration of gene expression. However, molecular biologist Maria Blasco and colleagues, from the Spanish National Cancer Research Centre (CNIO) group 10 were able to develop a gene therapy that harnesses the synthesis of telomerase, the enzyme that is responsible for at least partially rebuilding telomeres in pluripotent cells (stem cells capable of giving rise to several different cell types), to generate mice that lived 24% longer without developing cancer or other illnesses associated with age. The work builds on past research, where biologists discovered that when induced pluripotent stem cells are left to divide in a petri dish, they end up with telomeres twice as long as normal. They subsequently found that the same phenomenon occurred in normal blastocyst-derived embryonic cells (ES) that are cultivated in a lab. Blasco’s team found that during the pluripotency stage, epigenetic marks (nongenetic influences on gene expression) on the telomeric chromatin facilitate their lengthening by the telomerase enzyme. The same telomere lengthening happened to self-replicating embryonic stem cells cultivated in this way, thus in a new study Blasco and team generated chimeric mice in which 100% of their cells were derived from hyper-long telomere ES cells. To address whether hyper-long telomeres have deleterious effects, the Blasco team closely observed these mice throughout their entire lifetime.
In the past, researchers generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulation. To address whether hyper-long telomeres have deleterious effects, the Blasco team generated mice in which 100% of their cells are derived from hyper-long telomere ES cells and observed them for their entire lifetime.
Researchers found that rather than having any adverse effects, hyper-long telomeres were linked with numerous health benefits. Compared with control animals that had normal length telomeres, the animals with hyper-long telomeres were leaner, accumulated significantly less body fat than control mice, and had lower levels of cholesterol, in particular, low-density lipoproteins (LDL). The hyper-long telomere mice also demonstrated improved metabolic health, with improved glucose metabolism and insulin sensitivity, developed significantly less DNA damage as they aged, and retained better mitochondrial function. In addition, the mice with hyper-long telomeres had a significant increase of 12.75% in median longevity as well as an increase in maximum longevity of 8.4% compared to the normal telomere length control mice. Normal cognitive capabilities, such as normal coordination, balance and smell and less spontaneous cancer were also positive observations. These findings demonstrate that longer telomeres than normal in a given species may not be harmful or damaging, but instead, may demonstrate beneficial effects.
Source: Muñoz-Lorente, Miguel A., Alba C. Cano-Martin, and Maria A. Blasco. “Mice with hyper-long telomeres show less metabolic aging and longer lifespans.” Nature Communications 10, no. 1 (2019): 1-14.
© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/
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Posted November 12, 2019.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
References:
- Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569-573.
- de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes & development. 2005;19(18):2100-2110.
- Chan SW, Blackburn EH. New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene. 2002;21(4):553-563.
- Blasco MA. Telomeres and human disease: ageing, cancer and beyond. Nature reviews Genetics. 2005;6(8):611-622.
- Martinez P, Blasco MA. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nature reviews Cancer. 2011;11(3):161-176.
- Flores I, Cayuela ML, Blasco MA. Effects of telomerase and telomere length on epidermal stem cell behavior. Science. 2005;309(5738):1253-1256.
- Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nature reviews Cancer. 2008;8(6):450-458.
- Gomes NM, Ryder OA, Houck ML, et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell. 2011;10(5):761-768.
- Vera E, Bernardes de Jesus B, Foronda M, Flores JM, Blasco MA. The rate of increase of short telomeres predicts longevity in mammals. Cell reports. 2012;2(4):732-737.
