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How can we overcome the problem of resistance of the senescent cells to senolytics?

Image credit: http://www.longlonglife.org/en/transhumanism-longevity/anti-aging-supplements/senolytics-the-war-on-senescence-is-on/

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Apoorva Kulkarni Sep 25, 2020
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

What ways and tools can we utilize to overcome the problem of resistance of the senescent cells to senolytics?

Drugs that selectively eliminate senescent cells are called senolytics and those that modulate their proinflammatory senescent phenotype are called senostatics. Senescent cells display resistance to most currently available senolytic drugs.

[1]Kang C. Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases. Mol Cells [Internet]. 2019 Dec 31;42(12):821–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31838837

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Targeting SCAPS

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Jamila
Jamila Sep 28, 2020
The senescent cell anti-apoptotic pathways (SCAPs) are involved in encouraging the survival of senescent cells. SCAP provides senescent cells with resistance against apoptotic signaling, the apoptotic signaling should help to eradicate the senescent cells but the senescent cells manage to persist. BCL-2 is a family of proteins that moderate cell death processes including autophagy and apoptosis. In senescent cells, various BCL-2 family proteins are upregulated. In a study, it was found that BCL-2 inhibitors were able to induce apoptosis in senescent cells. Perhaps there are other drugs that act on the SCAPs pathway that are more efficient than the current BCL-2 inhibitors. I wanted to find out if there were any more drugs/small molecules that downregulate the BCL-2 family. So I ran a search on the drug gene budger (https://maayanlab.cloud/DGB/). I found that there are many drugs/small molecules listed on there which are new and old. Here are some that came up in the search: - vorinostat - tanespimycin - phloretin - TPCA-1 - dasatinib In one study, using ABT-263 and vorinostat induced apoptosis in cell lines that were resistant to ABT-263. Vorinostat modified the expression levels of BCL-2 family proteins. Specifically, vorinostat downregulates BCL-XL and upregulates BIM and noxa.

[1]Kirkland, James L., and Tamar Tchkonia. "Senolytic drugs: from discovery to translation." Journal of internal medicine (2020).

[2]Yosef, Reut, et al. "Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL." Nature communications 7.1 (2016): 1-11.

[3]Nakajima, Wataru, et al. "Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer." Cancer biology & therapy 17.1 (2016): 27-35.

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Combinatorial drug treatment

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Shubhankar Kulkarni
Shubhankar Kulkarni Sep 25, 2020
Two different approaches have been described [1] - 1. Candidate approach: Gene-expression profiling of the resistant population will help identify the pathways that are activated to protect these cells from a particular senolytic drug. Targeting these pathways in combination with a senolytic drug will decrease resistance and increase drug efficacy. 2. Unbiased drug screen: A traditional drug screen can be used to identify drugs that display synergism with the senolytic drug of interest and the senolytic and the identified drug can be administered together. Reference: 1. Kang C. Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases. Mol Cells [Internet]. 2019 Dec 31;42(12):821–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31838837
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DNA damage-induced senescence promotes senolytic sensitivity

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Shubhankar Kulkarni
Shubhankar Kulkarni Sep 25, 2020
Researchers found that DNA damage inducers like irradiation and poly (ADP-ribose) polymerase 1 (PARP) inhibitors triggered a therapy-induced senescent state. Bcl-2 family anti-apoptotic inhibitors were lethal for therapy-induced senescent prostate cancer cells that had DNA damage. The three selected senolytics were ABT-263 (navitoclax, which inhibits both Bcl-2 anti-apoptotic family members Bcl-2 and Bcl-xL), A-1155463 (which targets selectively Bcl-xL), and piperlongumine (a natural product). [1] The group had previously showed that PARPi-therapy-induced senescent cells were sensitive to ABT-263, which triggered senolysis and improved treatment outcomes in vitro and in vivo. [2,3] This suggests that treatment for the senescent cells should be dependent on the way in which senescence is induced. Moreover, inducing DMA damage can be used as a supplementary therapy to improve the efficacy of senolytics. References: 1. Malaquin N, Vancayseele A, Gilbert S, Antenor-Habazac L, Olivier M-A, Ait Ali Brahem Z, et al. DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity. Cells [Internet]. 2020 Jul 1;9(7):1593. Available from: https://www.mdpi.com/2073-4409/9/7/1593 2. Fleury H, Malaquin N, Tu V, Gilbert S, Martinez A, Olivier M-A, et al. Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence. Nat Commun [Internet]. 2019 Dec 11;10(1):2556. Available from: http://www.nature.com/articles/s41467-019-10460-1 3. Chang J, Wang Y, Shao L, Laberge R-M, Demaria M, Campisi J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med [Internet]. 2016 Jan 14;22(1):78–83. Available from: http://www.nature.com/articles/nm.4010
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CAR T cells as Senolytics

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Antonio Carusillo
Antonio Carusillo Oct 05, 2020
Different molecules and a compound having genotypic activity are available. However, there are not always effective along with presenting possible side effects ( , ).

Chimeric Antigen Receptor (CAR) T cells are engineered T cells whose activity can be re-wired against a specific target and used to mount a potent immune response. They have been successfully used in the clinics to treat in particular B cell malignancies and currently, two CAR T cells based therapeutics (YESCarta and Kymeriah) are approved both in the USA and in Europe on the market . CAR T cells action is based on the interaction between the receptor installed on the T cells and the antigen which is presented by the target cells. When the two elements come together, the Immuneresponse is triggered.

A recent approach to target senescent cells has exploited the targetability of the CART cells against a defined antigen. In this case, an antigen marking senescent cells .

To identify the antigen, the researches took three different well-established senescence models and analyzed the expression of the genes, looking in particular for the ones that were highly expressed and whose product (the protein) was exposed on the cell membrane of the cells. The reason is simple: to identify a possible antigen. From the lot they obtained, they picked the gene whose protein was expressed on the cell membrane of the senescent cells only (or at least expressed in very few other cell types). The reason is clear, whatever cell will present that antigen will be a target of the CAR T Cells. By choosing an antigen present only on the desired cell, you will avoid “attacking” healthy cells.

The gene, in this case - the PLAUR gene, was a possible target. In particular, its product, known as uPAR receptor, is expressed in senescent cells both in vitro and in vivo. Also, a portion of the uPAR, upon binding with its natural ligand, is released as a “soluble form” known as suPAR. This is secreted by the senescent cells as a part of the Senescent-Associated-Secretory-Phenotype (SASP). This event is also linked to the possible challenges to achieve limb regeneration. Overall, this confirmed that the uPAR was an attractive target for the approach. Thus, they generated CAR T cells engineered with a receptor able to recognize the uPAR antigen. They did the first test in a model presenting senescent hepatocytes (liver cells) and could prove that the uPAR-CAR T cells could eliminate the senescent cells and were able to reduce liver fibrosis (due to senescent cell accumulation). The efficacy of the approach was, hence, proved. Moreover, no side effects were observed at this stage.

This approach proves the flexibility of the CAR T cells and even if a better safety profile has to be established we can see how they may constitute a potential approach to combat aging-related conditions by working as senolytic agents. Besides, based on the “-omics” technologies (transcriptomic, proteomics, and epigenomics), we may also envision CAR-T cells engineered to recognize only a specific type of senescent cell (good vs bad).

[1]Grezella C, Fernandez-Rebollo E, Franzen J, Ventura Ferreira MS, Beier F, Wagner W. Effects of senolytic drugs on human mesenchymal stromal cells. Stem Cell Res Ther. 2018;9(1):108. Published 2018 Apr 18. doi:10.1186/s13287-018-0857-6

[2]Cardiac Glycosides as Senolytic Compounds, Martin, Nadine et al.Trends in Molecular Medicine, Volume 26, Issue 3, 243 – 245

[3]Halim L, Maher J. CAR T-cell immunotherapy of B-cell malignancy: the story so far. Therapeutic Advances in Vaccines and Immunotherapy. January 2020. doi:10.1177/2515135520927164

[4]Amor, C., Feucht, J., Leibold, J. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020). https://doi.org/10.1038/s41586-020-2403-9

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Targeting BCL-XL with CRISPR

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Jamila
Jamila Oct 06, 2020
The BCL-2 family of proteins include BCL-XL, a transmembrane protein found in mitochondria. BCL-XL is encoded by the BCL2-like 1 gene. BCL-XL inhibits apoptosis; it works by stopping cytochrome c from being released by the mitochondria, ultimately blocking apoptosis. Many senolytics work by inducing apoptosis in senescent cells. Specifically, Navitoclax, A1331852, and A1155463 are senolytic drugs that inhibit the action of BCL-XL, leading to apoptosis of senescent cells.

In the case that senescent cells become resistant against senolytic drugs, alternative senolytic drugs could be used instead (as mentioned above). However, it would be interesting to develop a novel senolytic therapy that can target genes instead of proteins. What if we could use CRISPR technology to induce apoptosis in senescent cells instead! Specifically, we could try to target the BCL2-like 1 gene or other SCAPs or SASPs related genes for senolytic therapy.

To find out more about the idea, click here.



[1]Yosef, Reut, et al. "Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL." Nature communications 7.1 (2016): 1-11.

[2]Zhu, Yi, et al. "New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463." Aging (Albany NY) 9.3 (2017): 955.

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