Posted on 8 January 2021
Senescent cells are damaged cells that have permanently stopped dividing. In an ideal situation, all of these cells should be removed by the body’s immune system and by apoptosis (cell suicide). However, as we grow older, senescent cells begin to build up faster than they can be removed. This is a problem because despite sometimes being described as ‘dormant’, senescent cells are far from inactive. These cells can secrete harmful signalling molecules such as inflammatory mediators, and thereby contribute to many diseases of ageing including cancer.
It is hoped that drugs aimed at removing senescent cells, called senolytics, may give us a new and powerful tool with which to combat age-related diseases. Senolytic drugs have already shown success in clearing senescent cells and thereby delaying age-associated disorders in animal models. Given what we know of the mechanisms behind senescence and some of the early evidence from human trials, there is reason to be optimistic that senolytics will work in humans, though exactly how effective they will be is still uncertain.
The first generation of senolytics currently being trialled in humans are primarily repurposed small molecules. Dasatinib, for example is a leukemia drug that has been approved for over a decade, while quercetin and fisetin (both flavonoids found in plants) are widely used dietary supplements that have senolytic properties when appropriately dosed.
Despite some uncertainty surrounding the eventual effectiveness of senolytics in humans, we are already thinking ahead to the second generation of senolytics. The goal of senolytics is to clear senescent cells only, and so to minimise side effects, an ideal senolytic should have no effects on cells that are not senescent. Our best bet for achieving this may be the use of nanoparticles to deliver senolytic drugs in a more targeted manner.
Nanoparticles are tiny particles that are 100nm wide or smaller (that’s about one 70th the width of a red blood cell) that can be made to contain drug molecules. Nanoparticles hold great potential for targeted senolytic drug delivery, as they can be engineered to release their contents in the presence of enzymes that are primarily present in the target cells. For example, nanoparticles can (and have) been engineered with protein coats that can be removed by β-galactosidase, an enzyme that is overexpressed in senescent cells.
Another possible application of nanoparticles is the monitoring of senescent cell populations. Chemotherapy treatments can induce scenescence in cells surrounding the tumour which, in turn, secrete molecules that promote the growth of the very tumour that the chemotherapy is aimed at treating. Nanoparticles loaded with a reporter molecule could be used to ‘label’ these senescent cells, thus allowing us to monitor the development of senescence around the tumour and adjust treatment accordingly, perhaps with drugs aimed at eliminating those cells.
Some hurdles still need to be overcome for these treatments to see clinical application. For a start, our understanding of the treatability of age-related diseases in humans using senolytics is still incomplete. There are also many different types of nanoparticle that could be used to deliver senolytic therapies, and research will be required to determine which of these produces optimal results. The ideal nanoparticle for this task would be well absorbed, metabolised, and excreted from the body, with minimal uptake by non-senescent cells.
Nano-Based Theranostic Tools for the Detection and Elimination of Senescent Cells: https://doi.org/10.3390/cells9122659
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders: https://doi.org/10.1038/nature10600
Targeted cargo delivery in senescent cells using capped mesoporous silica nanoparticles: https://doi.org/10.1002/anie.201204663