The removal of senescent cells has shown further potential for the treatment of osteoarthritis in this recent publication where the researchers reduce the impact of post injury osteoarthritis by clearing senescent cells[1]. As we have discussed many times in our publications, senescent cells are a key player in the aging process, if you are new to the subject and want to know what senescent cells are here is a quick primer.

What are senescent cells?

Cellular senescence is a hallmark of aging and is one of the various processes that cause you to age. As you grow older an increasing number of your cells enter into a state known as senescence. These senescent cells no longer divide or support the tissue they are part of, instead they send out a cocktail of harmful chemical signals that cause inflammation and drive the aging process. This proinflammatory collection of proteins, cytokines and signals are known as the senescence associated secretory phenotype (SASP). The SASP blocks various important cellular processes, prevents stem cells from repairing damaged tissue efficiently, and is implicated in the development of age-related diseases[2-3].

If that was not bad enough, SASP from senescent cells can also encourage other nearby healthy cells to become senescent, initiating a downward spiral of increasingly poor tissue repair. This means that a small number of these cells can have a dramatic effect.

It has been suggested that because the amount of senescent cells increase with aging that senescence contributes to aging. However, this is not quite as simple as it first appears and downplays what the likely primary purpose of cell senescence is. Senescence is a safety measure built into cells to prevent the propagation of damaged cells allowing them to enter apoptosis (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 cell 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 require a very small number of cells to achieve this[4].

Clearing Senescent cells

The researchers in 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 very high chance this will 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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