Bounties attract serious brainpower to the challenge.
Is it possible to devise strategies, which don't imply telomerase over-expression, to improve the life span?
Recently, a pre-print ( i.e. not peer-reviewed yet ) of a paper was published on bioRxiv
which may offer an alternative way to elongate the telomerase sequence, like using CRISPR to promote targeted re-activation of telomerase as described in a previous session.
An Italian research group has reported for the first time a process because of which the T cells lymphocytes – a key component of the human immune-system – can elongate their telomeres by acquiring the telomeric components from Antigen-Presenting-Cells (APCs) .
What does it mean?
In simple words, the T cells can recognize a target cause it presents an antigen. To mount an immune response the T cells have to interact directly with the APCs forming the so-called Immunological Synapse (IS) . To prove this they used T cells whose gene codifying for the telomerase has been inactivated, so that telomere elongation could not be accounted to it. Moreover, by inhibiting DNA polymerase activity they also ruled out that any process involving DNA synthesis was required. Therefore, the telomeric components must have been acquired somewhere.
Their discovery
Interestingly when they investigated the length of the telomeres of the APCs interacting with the T-cells, they found out that the telomeres of the APCs were reduced while one of the T-cells increased, in the same proportion, suggesting, indeed, a transfer of the telomeres from APCs to T-cells upon conjugation via IS. If this was not exciting enough, they also tried to investigate if such an event could be triggered in vivo. By marking the APCs and T cells, they could confirm in vivo transfer of the telomeres and that there was an increase in the T-cell lifespan in vivo.
This is a striking finding and some open questions are:
Is this mechanism limited to T-cells?
Is this mechanism present in humans?
Can aging – in some instances (like cell-types) - be related to the loss of “telomere-transfer-capacity” rather than loss of telomerase activity?
Do other cells feature a similar mechanism?
Can we harness such a mechanism to elongate telomeres?
[1]Intercellular telomere transfer extends T cell lifespan
Bruno Vaz, Claudia Vuotto, Salvatore Valvo, Clara D’Ambra, Francesco Maria Esposito, Valerio Chiurchiù, Oliver Devine, Massimo Sanchez, Giovanna Borsellino, Derek Gilroy, Arne N. Akbar, Michael L. Dustin, Michael Karin, Alessio Lanna
bioRxiv 2020.10.09.331918; doi: https://doi.org/10.1101/2020.10.09.331918
[2]Gaudino SJ, Kumar P. Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis. Front Immunol. 2019;10:360. Published 2019 Mar 6. doi:10.3389/fimmu.2019.00360
Can we hijack the mechanism mid-way and exploit the lipid vesicles?
Subash ChapagainNov 23, 2020
For the quest of longevity, this really seems like an interesting research. If, like you asked, the mechanism can be sustained and replicated in vivo with significant reproducibility, this can really change the face of ageing research, especially the ones focused towards telomere engineering.
After reading your session, I was really moved by the unconventional finding in the paper that was behind the session’s idea. The fact that the paper presented a unique model of addressing the issue of telomere shortening- by transferring telomeres from other cells in itself seems like a million-dollar biohack. However, for the very fact that it is still unknown if this applies for cells other than T-cells, and also whether the same mechanism could reactivate senescent T-cells, I think there is a space for a healthy skepticism.
However, I noticed one interesting thing: the involvement of the lipidic vesicles, most likely exosomes (a kind of extracellular vesicles). The Telomerase dependent elongation was excluded, evident from the observation that the TERT knockout T-cells were also able to reproduce the same results, which meant that the message for telomere elongation must have travelled via these lipidic vesicles that were secreted by the APCs. This was also confirmed by the BrdU labelling that was present in the extracellular space. Also, since DNase enzyme could only degrade the extracellular DNA upon pretreatment with detergents, this corroborated that the telomeric DNA that was transferred from APC’s and added to the T-cell is contained (en route for delivery) in these lipidic vesicles. This was later visually confirmed by transmission electron microscopy (TEM) and immunogold-based telomeric detection as well.
After reading about this critical involvement of lipid vesicles (extracellular vesicles, EVs), one thought crossed my mind. Is it imperative that APCs be present for the telomere transfer? Or could we just use these EVs (that we can administer exogenously) to contain all the markers and messages mimicking those that are released by APCs, and induce the telomeric DNA lenghthening in the target T-cells? If we could do so, we would then omit the necessity of using APCs, and could just hijack the potential of EVs (the lipidic vesicles) to induce the telomeric transfer.
This could be attained, based on the paper’s reporting, by including DNA damage proteins, especially RAD51 in the lipid vesicles that was deemed to be associated with the APC telomeres and facilitate integration of APC telomeric repeats at T-cell chromosome ends. Since it was also observed that incubation of proliferating T-cells with telomeric vesicles reduced the percentage of senescent T-cells and sustained T-cell expansion, the usage of exogenous vesicles (engineered for the suitable marker expression, containing the RAD51 enzyme) seems like a plausible approach to try.
If this feat could be achieved for T-cells, then the next step would be to see if the same lipid vesicles driven approach could be tried for other types of cells. Moreover, other questions in regard to the telomere integration- if the mechanism is homologous recombination or some other- still needs to be determined.
Antonio Carusillo Oct 12, 2020