Spices and Senescence: Compound in Ginger Identified as Novel Senolytic to Clear Senescent Cells and Inflammation

Although you may associate the term ‘walking dead’ with a popular zombie apocalypse TV show, it can also apply to a regular occurrence inside the human body. Also known as senescent cells, aging adults accumulate dysfunctional zombie-like cells that undergo irreversible growth arrest but remain in the body, leaving a trail of inflammatory cellular debris behind.

As cellular senescence accelerates aging, inflammation, and disease, targeting the removal of these zombie cells is at the top of many researchers' minds. In a recent study, scientists out of the National Institute on Aging with the National Institute of Health (NIH) screened various plants as a natural way to fight senescence, zeroing in on ginger extract. In this study published in PLoS One, Moaddel and colleagues find that one compound of ginger, gingerenone A, produces potent senescence-clearing effects, representing a promising natural compound for fighting this aspect of cellular aging. 

The Biology of Aging: Cellular Senescence 101

Simply put, senescence is when cells stop dividing and lose their function. This growth arrest occurs with increasing age or in response to various stressors, including inflammation or an accumulation of reactive oxygen species — unstable compounds that cause oxidative stress, damaging cells and DNA.

However, while these senescent cells lose function, they don’t die. Instead of undergoing the routine and programmed cell death called apoptosis, senescent cells enter a zombie-like state that perpetuates damage to neighboring tissues and cells. This damage occurs through the senescence-associated secretory phenotype (SASP), which secretes a cascade of destructive compounds, including cytokines, chemokines, and growth factors. As a result, this inflammatory damage that comes with cellular senescence is thought to contribute to age-related tissue and organ dysfunction and various chronic diseases. 

Researchers have started testing and implementing the use of senolytics — drugs or chemicals that remove senescent cells from the body. However, these compounds tend not to have specific targets, leading to accidental clearance of non-senescent cells and increasing the risk of toxic side effects. One commonly used senolytic is a combination referred to as DQ — the chemotherapy drug dasatinib plus quercetin, an antioxidant compound found in many fruits and vegetables. 

Another group of senescence-fighting compounds is called senomorphics, which suppress SASP and its inflammatory features without inducing cell death. Put together, a compound that is both a selective senolytic and a senomorphic could be referred to as a senotherapeutic, which is what Moaddel and colleagues aimed to find.

Ginger Grasps the Gold for Slashing Senescence 

The NIH team first screened four plant compounds that have exhibited anti-inflammatory properties in past research: ginger, devil’s claw, cat’s claw, and Canadian goldenrod. They took connective tissue cells called fibroblasts and rendered them senescent by exposing them to a type of X-ray. Then, Moaddel and colleagues added various plant extracts to the senescent cells to see which acted as senotherapeutics — and ginger extract turned out to be the winner.

Native to Southeast Asia, ginger (Zingiber officinale Roscoe) is a flowering plant, but the commonly consumed part of ginger is its root. Although there are hundreds of bioactive compounds in ginger, the most prominent are gingerols, shogaols, paradols, and zingerone, contributing to ginger’s anti-inflammatory and antioxidant properties. 

Of the various compounds in ginger, the researchers found gingerenone A to be the most potent senotherapeutic, with 6-shogaol coming in second place. Gingerenone A induced senescent cell death, effectively clearing out the zombie cells lurking around. This ginger compound also reduced levels of most of the measured pro-inflammatory cytokines and other detrimental molecules involved in SASP. However, 6-shogaol did not regulate these inflammatory markers, indicating that gingerenone A has more promise as a senotherapeutic. 

Both gingerenone A and 6-shogaol exhibited senescence-clearing effects. The two ginger compounds enhanced caspase-3 activity, a marker of the programmed cell death called apoptosis, while inhibiting levels of Bcl-XL, an anti-apoptotic compound. The research team then compared gingerenone A to DQ, the commonly used senolytic cocktail. After DQ treatment, there was a significant decrease in senescent cells, but there was also a moderate toxic effect on proliferating cells. Conversely, gingerenone A also cleared senescent cells but with higher selectivity than DQ, meaning that non-senescent cells didn’t also get killed off. 

The Perks of Plant-Based Senolytics 

These results indicate that ginger extract — especially gingerenone A — could be a promising new therapeutic target for clearing senescent cells and mitigating the inflammatory damage that comes with senescence. The benefits of using a natural plant compound like ginger extract are wide-reaching, including its ability to selectively kill off senescent cells without causing toxic harm to normal, proliferating cells — a common drawback of other senolytic drugs like DQ. Further, senolytic drug cocktails tend to produce undesirable side effects, including respiratory and gastrointestinal symptoms. 

As Moaddel and colleagues conclude, “Together, our findings suggest that gingerenone A suppresses several senescence traits and promotes senolysis [destroying senescent cells], thus representing a promising natural senolytic compound.” However, this research is in its infancy, and studies with animals and humans will need to be done to determine the efficacy of gingerenone A in larger species.

References: 

Moaddel R, Rossi M, Rodriguez S, et al. Identification of gingerenone A as a novel senolytic compound. PLoS One. 2022;17(3):e0266135. Published 2022 Mar 29. doi:10.1371/journal.pone.0266135