Zombie Slayers: Novel Therapeutics to Kill Senescent Cells in Disease

With Halloween right around the corner, our thoughts tend to drift toward the supernatural, with the looming shadow of witches, ghosts, and vampires in many of our minds. However, having zombies on the brain may be more literal than you think…

In this blog, we take a look at a new class of drugs, known as senolytics, that target so-called “zombie” cells and how this has the potential to treat diseases such as cancer, cardiovascular disease, and neurodegenerative disease.

Resident Evil Cells

First things first, what exactly are zombie cells? Well, scientifically speaking they are known as senescent cells — cells that have been shunted into a state of arrest where they are no longer able to proliferate yet are resistant to apoptosis. Hence, they are held in a zombie-like condition, stuck between life and death.

While cellular senescence has been described as a protective mechanism triggered in damaged cells to prevent the inheritance of potentially dangerous mutations by their ensuing progeny, the accumulation of these zombie cells can have the opposite effect. Under normal conditions, short-term senescent cells acquire a secretory phenotype, known as senescence-associated secretory phenotype or SASP, and release factors, like CXCL1, macrophage colony-stimulating factor (M-CSF), and monocyte chemotactic protein 1 (MCP-1), into their local environment which attracts immune cells and mediates their clearance. However, when the elimination of senescent cells is not efficient, these zombies gather, and their persistent secretion of factors leads to the destruction of the local environment and the spread of senescence to their neighbors, leading to tissue dysfunction and disease (von Kobbe 2019).

These zombie hordes in the body increase as we age and have been shown to promote age-related conditions, such as cardiovascular disease, cancer, and neurodegenerative diseases. In line with this, scientists have shown that removing fibroblasts from the ear of mice and inducing their senescence by irradiation before transplanting them back to the mouse shortened the animal’s lifespan. Interestingly, the cause of death was not altered by transplantation of senescent cells, indicating that survival was shortened through a general process, such as accelerated aging, rather than by induction of any particular disease (Xu et al. 2018). So, should we target zombies to prolong our lives?

The Demise of the Living Dead

A class of drugs known as senolytics have been developed for this very purpose, aiming to specifically destroy senescent cells. Zombie cells evade death via the upregulation of pro-survival pathways known as senescent cell anti-apoptotic pathways or SCAPs. Thus, senolytics often selectively target key proteins involved in these SCAPs, such as members of the Bcl-2 family, which inhibit pro-apoptotic signaling cascades (Gasek et al. 2021).

Multiple studies in animal models have supported the use of senolytics in different diseases. We all know that zombies love brains, so it may come as no surprise that they often accumulate here and have repeatedly been implicated in age-related neurodegenerative disorders. When treated with senolytics, a mouse model of Alzheimer’s disease exhibited a pronounced reduction in tau-containing neurofibrillary tangles (NFTs), neuron loss, and ventricular enlargement, which typically correlate with brain atrophy and cognitive decline (Musi et al. 2018).

In addition to this neuroprotection observed with senolytics, cardiovascular benefits have also been documented. In aged mice, or those with high cholesterol, senolytic treatment improved vasomotor function and reduced plaque calcification in the vessels, indicating a beneficial action towards reducing age-related heart disease (Roos et al. 2016).

Despite the fact that senescence can be used as a defense mechanism against cancer, by preventing the inheritance of mutations to daughter cells, chronically present zombie cells promote cancer growth by SASP-mediated suppression of the immune system and secretion of growth factors. So, while blocking the signaling cascades that induce senescence can aggravate cancer progression, attacking the fully developed senescent cells can actually ameliorate cancer development. Scientists have demonstrated that senolytics delayed the development of cancer in aged mice, as well as a separate cancer-prone mouse model (Kirkland and Tchkonia 2020).

Overall, the results look very promising in mouse models, but what about the humans who are plagued by zombies? In 2019, the first clinical trial of senolytic use in humans was published. In the study, 14 patients with idiopathic pulmonary fibrosis (IBF), a progressive, fatal lung disease affecting older patients, were treated with senolytics and showed significant improvements in physical function, as assessed by measuring parameters such as their six minute walking distance, providing preliminary evidence of their potential benefit in this disease (Justice et al. 2019). Clinical trials on the efficacy of these drugs in disorders like chronic kidney disease and premature aging associated with hematopoietic stem cell transplant are currently underway.

The Next Generation of Zombie Slayers

The zombie-killing capacity of senolytics offers huge therapeutic potential for a variety of diseases, so it’s no surprise that focus is being placed on the development of novel and effective senolytic therapies.

Recently, Al-Mansour et al. (2023) proposed that CUDC-907, a drug currently being tested in clinical trials for its antitumor effects, could have senolytic properties. CUDC-907 is a dual function histone deacetylase (HDAC) inhibitor and a phosphoinositide 3-kinase (PI3K) inhibitor. Histone acetylation has been shown to decline in relation to age, while the PI3K/Akt pathway is a common SCAP, therefore inhibiting these factors offered a potentially promising result. Indeed, the drug was able to selectively induce death of zombie cells in various models of stress-induced senescence in vitro. While initial results are promising, further research into whether this effect holds up in vivo is required (Al-Mansour et al. 2023).

Overall, the targeting of senescent cells to avoid age-related diseases appears to be a very hopeful area of research. Therefore, it may be time to consider getting apocalypse-ready, since slaying zombies could be the key to eternal youth!