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Treating Osteoarthritis by Removing Senescent Cells

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The removal of senescent cells has shown further potential for the treatment of osteoarthritis in a recent publication, in which the researchers reduce the impact of post-injury osteoarthritis by clearing senescent cells [1].

So, senescent cells are bad news, right?

It has been suggested that because the amount of senescent cells increase with aging, cellular senescence contributes to aging. However, this is not quite as simple as it first appears and downplays what the likely primary purpose of cellular senescence is. Senescence is a safety measure built into cells to prevent the propagation of damaged cells, allowing them to enter apoptosis (programmed cell death) and have the immune system dispose of them.

So, actually, senescence is generally speaking a good thing, as it keeps us safe from damaged cells causing cancer and promotes healthy tissue repair.



However, there is a tipping point in this safety checkpoint: clearing away unwanted senescent cells is the job of the immune system, and replacing the lost cells requires stem cells to repopulate the tissue. As we age the ability of the immune system to clear these cells begins to fail and they begin to accumulate, this in turn then increases inflammation reducing the ability of stem cells to replace loses, thus begins the downward spiral.

At this point, cellular senescence ceases to be a safety checkpoint and switches to becoming an active driver of the aging process. Senescent cells are also involved in the wound healing process, but only a very small number of cells is required to achieve this [4].

Clearing senescent cells

The researchers of this new study have used local clearance of senescent cells to reduce the development of post-traumatic osteoarthritis and encourage tissue regeneration. They tested the hypothesis that senescent cells play a causative role in osteoarthritis by using a transgenic mouse, modified in a way that allowed them to selectively follow and remove senescent cells using a compound that triggers the cells to die.

The research team discovered that senescent cells accumulated in the articular cartilage and synovium after they induced anterior cruciate ligament injury. Anterior cruciate ligament (ACL) tears are a common injury, particularly among athletic and younger populations.



There is a well-established association between ACL injury and subsequent development of osteoarthritis, and the researchers believed senescent cells might play a key role in that.

They discovered that not only do senescent cells accumulate at the site of injury, but they also found that the selective elimination of these cells reduced the development of osteoarthritis post injury, reduced pain, and encouraged cartilage development.

The delivery of a senolytic agent (a compound that can induce apoptosis in senescent cells) caused these problem cells to be destroyed. The researchers used a compound called UBX0101, a senolytic drug created by Unity Biotechnology.

Perhaps best of all, the research team validated these results in transgenic, non-transgenic, and aged mice. They saw similar positive results in all three, meaning that there is a good chance this might directly translate to humans.

The selective removal of senescent cells from in vitro cell cultures of chondrocytes isolated from people with osteoarthritis also showed a reduction of pro-inflammatory biomarkers, and in addition an increase in the expression of pro-regenerative proteins indicating enhanced tissue repair.



Conclusion

Collectively, this research supports the use of senescent cells as a therapeutic target for treating degenerative joint disease. This is yet another example of the validity of clearing senescent cells to treat age-related diseases. In the last year or so, the interest in senescent cell clearing senolytic therapies has exploded, and will almost certainly make this the first of the true rejuvenation therapies in the SENS repair approach to aging.

We have now reached the tipping point where the theories proposed long ago by Aubrey de Grey are now producing tangible results that are impossible to refute. Indeed, senescent cell clearance is set to enter human clinical trials this year with Unity Biotechnology.

The tide has truly turned, and whilst there is much work to be done, at last the results are starting to arrive as is the validation that we can do something about the aging processes, for healthier, independent, and disease-free lives.

Literature



[1] Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., … & Baker, D. J. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature Medicine.

[2] Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010). The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annual Review of Pathology, 5, 99–118.

[3] Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010). Inflammatory Networks during Cellular Senescence: Causes and Consequences. Trends in Molecular Medicine, 16(5), 238–246. [4] Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., … & Hoeijmakers, J. H. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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