Could Telomere Length and Lifespan be Enhanced with CRISPR?
Image credit: Thomas Ried/NCI Center for Cancer Research
Jamila Jul 28, 2020
Could CRISPR editing be used to improve lifespan by enhancing telomere length?
Previous research suggests that maintaining telomere length can reverse age-related diseases and may improve lifespan, as TERToverexpression in mice delayed aging and enhanced life expectancy. Furthermore, a vector containing TERT improved the lifespan of one-year old and two-year old mice by 24% and 13% respectively. The use of CRISPR-Cas in telomeres for aging research is a largely unexplored area. In one study, the TERTpromoter was targeted by CRISPR-Cas to vary the gene expression of TERT, some mutations had increased telomerase levels similar to that seen in the immortalised cells. In the future, studies using CRISPR editing to modify the TERT, TERC, or TRF1 genes should be conducted to assess the effect on lifespan.
Interestingly, DNA methyltransferase 2 deficient cells have shortened telomeres and decreased telomerase activity. Therefore, exploring the use of epigenome editing could be ground-breaking in the anti-aging field. Specifically, epigenetic editing of the TERT gene could be conducted to observe its effect on lifespan.
Tomás-Loba, Antonia, et al. "Telomerase reverse transcriptase delays aging in cancer-resistant mice." Cell, 135.4, 2008, pp. 609-622.
de Jesus, Bruno Bernardes, et al. "Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer." EMBO molecular medicine, 4.8, 2012, pp. 691-704.
Chiba, Kunitoshi, et al. "Cancer-associated TERT promoter mutations abrogate telomerase silencing." Elife, 4, 2015, pp. e07918.
Lewinska, Anna, et al. "Downregulation of methyltransferase Dnmt2 results in condition‐dependent telomere shortening and senescence or apoptosis in mouse fibroblasts." Journal of cellular physiology, 232.12, 2017, pp. 3714-3726.
Epigenetic editing to increase Telomerase reverse transcriptase levels: possibilities and concerns
Antonio CarusilloAug 26, 2020
The human telomerase comprises Telomerase reverse transcriptase (hTERT) which embodies the catalytic activity of the enzyme Telomerase and the Telomerase RNA component (TERC) that provides the template for telomerase elongation ( https://jme.bioscientifica.com/view/journals/jme/58/2/R129.xml ). The role of human telomerase is to elongate the telomeres which are hexameric repeats of a 5′-TTAGGG-3′ sequence ending in a 3′ single-stranded overhang. The telomeres are necessary for genome stability and integrity since they mask the ends of the DNA strand which otherwise would be mistaken for a DNA lesion – a DNA double-stranded break (DSB) – and activate the DNA damage response (DDR) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717580/). This latter in the attempt to “repair” the lesion may create gross rearrangements like translocation and head to head chromosomic fusions (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458522/). The telomerase by adding tandem repetitions of TTAGGG at the ends of the telomeres keeps their length costant. In somatic cells, the telomerase expression is low or absent. This results in a irreversible shortening of the telomeres. When this happens, the DNA ends are no masked anymore, the DDR is activated . This is detected by a surveillance system led by p53 which commits the cell to senescence or apoptosis ( https://pubmed.ncbi.nlm.nih.gov/15865944/ ) while in case of a p53 dysfunctional such cells may survive, accumulate genomic aberrantions and acquire cancer behavior ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233470/). CRISPR as described in a previous post ( https://brainstorming.com/sessions/enhancer-dysregulation-in-aging-and-disease/60 ) can be used to modulate gene expression, such approach has been defined as Epigenetic Editing. Over-expressing TERT via viral vector delivery could increase the lifespan in mice(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494070/ ). It is important to note what the paper title is “
Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer “. The part highlighted in bold is very important. The reason behind this is because even if higher level of TERT may ameliorate aging, we don´t have to forget the fact that high TERT levels are also found in cancer (https://jme.bioscientifica.com/view/journals/jme/58/2/R129.xml) although it has to be said that not all cancers have TERT over-expression. Still, it´s importance in promoting cancer on-set and progression should not be underestimated.
So how we may address this- at least in an experimental setting - with CRISPR? We may for example combine epigenetic editing with synthetic biology concepts like molecular circuits and feedback loops ( https://pubmed.ncbi.nlm.nih.gov/29524134/ ) which may allow for temporal control of CRISPR expression. So that we may imagine to build a system where CRISPR is fused for example to transcriptional activator like VP64 and that it may be used to increase TERT expression. When TERT expression rises it activates an off-switch that turns off CRISPR-VP64 expression. When TERT expression decreases, the off-switch is disabled and CRISPR-V64 is active again. This is just an example and a person may - for example - engineer more complex circuits perhaps based on more than one layer. For instance, the switch may be triggered by changes in the pH of the cells that may indicate that the cells are over-proliferating like a cancer cell would do. The possibilities are many, what it is important would be to achieve a situation in which the TERT levels are not “over-doing” leading to uncontrollable cell growth and proliferation with the risk to induce cancer.