Priority Clearance

We previously discussed the clearance of senescent cells as a plausible treatment for multiple diseases of aging. The theory goes that senescent cells drive systemic inflammation, and that this inflammation underlies aging pathology. In August 2017 the latter part of this theory was underscored by results from the CANTOS study. These showed the addition of the anti-inflammatory ACZ885 reduced major adverse cardiovascular events by 15% above the best available standard care, and also appeared to bring a 50% reduction in cancer mortality for patients on the higher dose. However, suppressing inflammation with ACZ885 carried a stark downside: a significant increase in the risk of fatal infections that broadly eliminated any all-cause mortality benefit. This study will therefore only strengthen interest in other means of reducing systemic inflammation.

The lure of senescent-cell clearance as a one-target treatment for many diseases has attracted multiple bio-tech startups. One company, Unity Biotechnology, founded by researchers Judith Campisi and Jan van Deursen reportedly attracted one of the largest private fundings in biotechnology history towards the end of last year, following publication of their research linking senescent cells to atherosclerosis. Certain aspects of senescent-cell research might therefore be considered something of a gold rush. If cellular senescence drives multiple diseases, effective treatments in this area would likely prove commercially valuable on a traditional basis. However, low-risk interventions might create an entirely new target market: people without symptoms of any disease.

Senescence is principally a mechanism for tumour suppression, arresting cell division by virtue of specific protein pathways. Many treatment approaches will target these pathways to selectively induce apoptosis (cell death). One proof-of-concept approach combined the costly cancer drug Dasatinib with the flavanoid quercetin, and had measurable success. However, proposing cancer chemotherapy with significant toxicity as a treatment to people without life-threatening illness is unrealistic.

Another approach trialled in mice and published in March 2017 seems potentially far more promising. Here it was noted that the DNA damage within senescent cells should result in cell-death save for the interference of the protein FOX04. A peptide created to prevent this interference left healthy cells unharmed, while senescent cells died. The intervention had the visible effect of restoring fitness, fur density and kidney function in the mice. The group plans to commence safety trials in humans with the brain cancer Glioblastoma, since that condition exhibits biomarkers that suggest the treatment may be of use. If this peptide proves safe, a broader range of trials will undoubtedly follow.

To illustrate the breadth of activity in this area, work published in October 2017 by researchers from the Universities of Exeter and Brighton targets not the removal of senescent cells, but their reversal and restoration to healthy function. We previously covered a debate on aging where Professor Richard Faragher, a member of this same research team discussed his focus on near-term interventions to ameliorate aging disease. Whilst there are multiple approaches in that race, there are strong signs of convergence upon cellular senescence as a target of choice.

References

Campisi, J., D'Adda, F. (2007) Cellular senescence: when bad things happen to good cells. Nature Reviews Molecular Cell Biology 8, 729-740 doi:10.1038/nrm2233

Kirkland, J.L. et al (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell Volume 14, Issue 4, pages 644–658, August 2015 DOI: 10.1111/acel.12344

De Keizer, P.L.J et al. (2017) Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell Volume 169, Issue 1. doi:10.1016/j.cell.2017.02.031

Nagpal, J. et al. Revisiting the role of p53 in primary and secondary glioblastomas. Anticancer Res. 2006 Nov-Dec;26(6C):4633-9.

Ridker, P. M. et al. (2017) Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. The Lancet Aug 2017 DOI: http://dx.doi.org/10.1016/S0140-6736(17)32247-X

Harries, L.W. et al. (2017) Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biology Volume 18, Number 1. doi:https://doi.org/10.1186/s12860-017-0147-7

 

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Gavin Ritchie
Gavin Ritchie is the IT Director of Longevitas