by Alex Yule, PhD, Associate, Alacrita Consulting
The saying that “old age doesn’t come alone” holds true right down to the cellular level. Ageing cells differ from their younger counterparts in being locked into the zombie state of cell cycle arrest: neither replicating nor being naturally snuffed out through programmed cell death (apoptosis).
Along with alterations in genetic stability, energy production and cell to cell communication, ageing cells secrete a variety of pro-inflammatory cytokines, growth factors, proteases and extracellular matrix components- collectively “senescence-associated secretory components” (SASPs). SASPs usefully trigger tissue repair and remodelling but persistent signalling can promote chronic inflammation, a possible contributor to age-related dysfunction[1].
While the relationship between cellular senescence and specific disease states is unclear and awaits practical means of quantifying the abundance of ageing cells in human tissues, mechanistic links have been drawn to cardiovascular disease, diabetes, Alzheimer’s disease and other neurodegenerative conditions, osteoarthritis and age-related retinopathies.
Might the selective removal of ageing cells be of benefit? Using a model system involving transplantation of an artificially aged form of stem cell into young mice, Xu and colleagues were able to demonstrate improvements in physical performance and lifespan following treatment with a combination of two well-characterised drugs, dasatinib (better known as Sprycel®, used in the treatment of several forms of adult leukaemia), and quercetin, a widely-available dietary supplement. Naturally old mice treated with the combination also showed a modest improvement in physical function and lifespan compared with untreated animals[2].
Xu and colleagues selected the test drugs from a panel of 46 agents predicted through bioinformatics to have pro-apoptotic properties in senescent cells[3]. Several other agents, including navitoclax, an investigational cancer drug which targets several Bcl proteins, and bafilomycin A, a macrolide antibiotic, appear to be capable of selectively triggering apoptosis in senescent cells[4]. Bioinformatics trawling could conceivably turn up a number of other selective, pro-apoptotic “senolytic” agents with known pharmacokinetics and safety profiles, allowing relatively early establishment of clinical proof of concept with repurposed drugs.
Several small biopharmas are leading the charge into clinical development. Unity Biotechnology is focused on the elimination of ageing cells in selected disease states. UBX0101 targets the interaction between the MDM4 and p53, key regulators of cell-cycle arrest and apoptosis. A Phase I study (NCT03513016[5]) is currently recruiting subjects with osteoarthritis, who will each receive a single intra-articular injection into the knee. A preclinical candidate, UBX1967, which targets the pro-apoptotic protein Bcl-2, is intended for the treatment of age-related ophthalmological conditions.
Other novel candidate senolytics in preclinical evaluation include FOX04-DRI, a pro-apoptotic peptide developed by Cleara Biotech, and an undisclosed pro-apoptotic small molecule developed by Antoxerene. Oisin Biotechnologies is pursuing a plasmid-based gene therapy to selectively ablate senescent cells.
Establishing whether senolytics can achieve a degree of selectivity necessary to safely and usefully deplete aged cells and be active against the variety of cell types associated with different age-related conditions is still several years away but, mindful of the increasing healthcare burden ageing imposes on all economies, success in even a handful of disease states would be of significant value.
Senescent cells interact with both the innate and adaptive immune system and ageing immune systems may have a reduced ability to naturally remove senescent cells. This opens up the intriguing possibility that passive or active immunotherapies might eventually be developed to provide continual elimination of ageing cells[6].
[1] Therapeutic interventions for aging: the case of cellular senescence. Abel Soto-Gamez, A & Demaria, M. Drug Discovery Today May 2017; 22(5): 787-795.
[2] Senolytics improve physical function and increase lifespan in old age. Xu, M et al. Nature Medicine 2018. Published online 9th July 2018. https://doi.org/10.1038/s41591-018-0092-9
[3] The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Zhu, Y et al. Aging Cell (2015) 14, pp644–658.
[4] Hallmarks of cellular senescence. Hernandez-Segura, A et al. Trends in Cell Biology,June 2018; 28(6): 436-453.
[5] A safety and tolerability study of UBX0101 in patients with osteoarthritis of the knee. http://tinyurl.com/ybmldguq
[6] Cellular senescence: Immunosurveillance and future immunotherapy. Burton, DGA & Stolzing, A. Ageing Research Reviews 2018; 43:17–25.