“Zombie cells,” also known as senescent cells, are cells that have stopped dividing but do not die off. Instead, they accumulate within tissues. This accumulation is linked to aging and age-related diseases, making them a target for emerging therapeutic strategies.
Understanding Senescent Cells
Senescent cells are a cellular state characterized by irreversible growth arrest. This state can be triggered by cellular stress, including DNA damage, telomere shortening, or oncogenic stress. While initially considered a protective mechanism against cancer, their persistence can become detrimental.
Senescent cells secrete molecules known as the Senescence-Associated Secretory Phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors, and proteases. These factors promote chronic inflammation, damage neighboring healthy cells, and disrupt normal tissue function. The accumulation of these cells and their SASP is implicated in numerous age-related conditions, such as atherosclerosis, osteoarthritis, and Alzheimer’s disease.
Targeting Senescent Cells: Senolytics
Senolytics are compounds designed to selectively eliminate senescent cells by inducing apoptosis. These drugs work by targeting specific survival pathways that senescent cells rely on for survival. By disabling these pathways, senolytics cause these cells to undergo apoptosis while sparing healthy cells.
Examples of senolytic compounds include dasatinib and quercetin, as well as fisetin. Dasatinib is a tyrosine kinase inhibitor which targets specific enzymes involved in these survival pathways. Quercetin, a natural flavonoid, also acts on these pathways. Fisetin, another natural flavonoid, functions similarly by disrupting senescent cell survival mechanisms. These compounds are often administered in a “hit-and-run” fashion, given for a short period, allowing them to eliminate senescent cells without lingering effects.
Modulating Senescent Cells: Senomorphics
In contrast to senolytics, senomorphics do not aim to kill senescent cells. Their goal is to modify the behavior of these cells by suppressing the detrimental molecules they secrete as part of the SASP. This neutralizes harmful effects without removing the cells.
Senomorphics often interfere with signaling pathways that regulate SASP production. Some inhibit pathways involved in inflammatory factor secretion. Metformin, a widely used drug for type 2 diabetes, has demonstrated senomorphic properties by suppressing SASP secretion. Certain anti-inflammatory drugs and other natural compounds are also being investigated to reduce the inflammatory burden from senescent cells. This helps alleviate chronic inflammation and improve tissue function, offering a distinct strategy compared to the direct clearance achieved by senolytics.
Current Research and Therapeutic Potential
Research into “zombie cell” treatments is rapidly advancing, with many senolytic and senomorphic compounds in preclinical and early-phase clinical trials. These investigations explore a broad range of diseases that could potentially benefit from targeting senescent cells.
Potential targets include:
- Idiopathic pulmonary fibrosis
- Osteoarthritis
- Cardiovascular disease
- Neurodegenerative disorders
- Certain cancers
- Metabolic dysfunction
- Frailty
- Chronic kidney disease
Early human pilot trials using senolytics like dasatinib and quercetin have shown promise in reducing senescent cell burden and SASP factors. These treatments are still experimental and not widely available or approved for general use. Ongoing clinical trials are validating their safety and efficacy across patient populations.