The new research work on senolytic drugs by Baar et al. uses a rationally designed molecule that selectively targets senescent cells in vivo, both in an accelerated aging mouse model, and in normally aged mice as well, with few if any side effects[1]. Senolytics are a new class of potential anti-aging drugs that function by specifically killing senescent cells through apoptosis.

The phenotypic changes seen in non-dividing senescent cells, such as the senescence associated secretory phenotype (SASP), can in turn aberrantly influence nearby cells, leading to chronic inflammation and other changes that are detrimental to an organism[2].

Senescent cells

Senescent cells normally destroy themselves via a programmed process called apoptosis and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.

By the time people reach old age, significant numbers of these senescent cells have accumulated in the body, and inflammation and damage to surrounding cells and tissue. These senescent cells are one of the hallmarks of aging and play a central role in the progression of aging[3-4]. Senolytics focus on the destruction of these stubborn “death resistant” cells from the body in order to reduce inflammation and improve tissue function.







It has been demonstrated that senescent cells can be cleared selectively by targeting anti-apoptotic proteins Bcl-2 and Bcl-x, using a number of different inhibitors, leading to improved tissue function in mice[5-8]. You can learn more about senescent cells in our earlier blog here and the history of senescent cell clearing senolytic drugs here.

A new pathway to trigger apoptosis

The molecule in the Baar et al study instead functions by disrupting the interaction between Foxo4 and p53, leading to p53 mediated apoptosis (cell death). The authors have shown that this interaction with Foxo4 inactivates p53 and is restricted specifically to senescent cells.

This leads to cell cycle arrest and an inhibition of apoptosis. The molecule itself consists of a small peptide of Foxo4, consisting of D-amino acids in a retro-reversed sequence, fused to an HIV- Tat domain. The D-amino acids block proteolysis of the compound while the HIV-Tat domain functions as a cell penetrating peptide, enabling the molecule to transverse plasma membranes.

Conclusion







There are of course many follow up experiments that need to be done. Are there truly no side effects? Can this or a similar drug work well in humans? Also, what are the long-term consequences of clearing senescent cells? It is known that senescent cells do play a positive role in promoting tissue repair[9]. Will stem cell replacement be required for the long-term maintenance of organ function?

All in all, however, this latest work is a truly significant step forward in the development of a feasible senolytic therapy and further validates the hypothesis that the clearance of senescent cells can promote improved organ function.

Literature

[1] Baar MP, et al. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.”Cell. 2017 Mar 23;169(1):132-147.e16.

[2] Davalos, Albert R. et al. “Senescent Cells as a Source of Inflammatory Factors for Tumor Progression.” Cancer Metastasis Reviews 29.2 (2010): 273–283. PMC. Web. 10 Jun. 2010.







[3] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[4] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.

[5] Zhu, Yi et al. “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” Aging Cell 14.4 (2015): 644–658. PMC. Web. 14 Aug. 2015.

[6] Chang, Jianhui et al. “Clearance of Senescent Cells by ABT263 Rejuvenates Aged Hematopoietic Stem Cells in Mice.” Nature medicine 22.1 (2016): 78–83. PMC. Web. Jan. 2016.

[7] Wang, Yingying et al. “Discovery of Piperlongumine as a Potential Novel Lead for the Development of Senolytic Agents.” Aging (Albany NY) 8.11 (2016): 2915–2926. PMC. Web. 19 Nov. 2016.







[8] Zhu, Yi et al. “Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl‐2 Family of Anti‐apoptotic Factors.” Aging Cell 15.3 (2016): 428–435. PMC. Web. Jun. 2016.

[9] Lujambio A. To clear or not to clear (senescent cells)? That is the question. BioEssays. 2016;38(suppl 1):S56–64.