A Component of Grape Seed Extract Eliminates Zombie Cells to Support Aging and Longevity in Mice

Zombies have captured the imagination of filmmakers and musicians, featuring in chart-topping hits like the eponymous 90s song by the Cranberries and monumental tv shows like The Walking Dead, to name a few. So, perhaps it is not surprising that the concept of the undead also has made its way into the world of biomedical science. Around the same time that zombies were making a cinematic splash in the 60s with the horror film Night of the Living Dead, scientists were beginning to document seemingly undead cells. These so-called senescent cells have received substantial attention, as they represent a druggable process that prevents or delays aging.

Now, new research points to a compound in grape seed extract that could be the kryptonite for these zombie cells, much like garlic is to vampires. In an article published in Nature Aging, Xu and colleagues show that procyanidin C1 (PCC1) increases the healthspan and lifespan of mice through its action on senescent cells. At high concentrations, PCC1 works as a senolytic, meaning the plant-derived compound eliminates senescent cells. When the researchers administered PCC1 intermittently to naturally aged old mice, the senolytic alleviated physical dysfunction and prolonged survival.

“Altogether, our study opens a new avenue for extending healthspan and prolonging lifespan … with a [senolytic], which is derived from natural sources and possesses pronounced efficacy,” said Xu and colleagues. “The potential anti-aging effects of PCC1 demonstrated in our preclinical assays provide good support for further translational and clinical development of PCC1, with the overall aim of achieving a longer and healthier life.”

How to Kill a Zombie Cell

Cellular senescence refers to a state involving essentially irreversible replicative arrest and resistance to cell death (apoptosis) — in other words, undead and zombie-like. These cells also overproduce pro-inflammatory signaling molecules, a feature termed the senescence-associated secretory phenotype (SASP). These characteristics are likely what make senescent cells not just linked to aging but causal drivers. Genetically removing senescent cells mitigates tissue degeneration and extends animal healthspan, supporting the contention that senescent cells play a causative role in organismal aging.

Since the first discovery in 2015, researchers have revealed a handful of synthetic or small-molecule senolytic agents. Intermittent administration of senolytics holds the potential to reduce the risk of patients developing adverse conditions, minimize off-target effects of drugs, and prevent the development of drug resistance of senescent cells, which do not divide.

However, most reported senolytics are dependent on cell lineage or cell type or, alternatively, exhibit substantial cytotoxicity in organisms, thus limiting their potential use for clinical purposes. Furthermore, senolytics often have low solubility and oral bioavailability as well as marked side effects of some senolytic compounds. Therefore, there is a need to identify new compounds with senolytic activity but reduced cytotoxicity.

Procyanidin 1 Is Senolytic and Improves Aging in Mice

In this study, Xu and colleagues screened a natural product medicinal library composed of anti-aging agents and identified several candidates, including grape seed extract. Further analysis revealed that PCC1 could act both as a senomorphic agent — meaning it plays a major role in inhibiting SASP — at low concentrations and a senolytic at higher concentrations, the latter through inducing apoptosis. Xu and colleagues found that PCC1 exerts an apoptosis-inducing effect on senescent cells in a dish and living organisms like mice.

Cellular senescence is a highly heterogeneous process that depends on different cell origins and environmental stimuli. One of the key features of PCC1 is its ability to efficiently clear senescent cells in a broad spectrum of cell types and stressors. PCC1 has a superior senolytic activity with high specificity and efficiency for a broader range of cell types than many reported senolytics — such as ABT-263, dasatinib, quercetin, and fisetin — and can target senescent cells generated by several significant types of senescence inducers.

In this study, Xu and colleagues also treated naturally aged mice with PCC1 and tested its effects on senescent cells, immune responses, and physical function. PCC1 could suppress levels of SASP-associated genes in aged livers and kidneys and support healthy immune responses in the blood. In aged mice, the senolytic and senomorphic agent supported motor function (movement), balance, exercise, muscle strength, and spontaneous exploration — an indicator of physical and mental well-being. 

Collectively, these findings show that the plant-based compound PCC1 selectively targets senescent cells in the tissue microenvironment and generates remarkable biological effects in naturally aged mice. The authors propose that PCC1 represents a new class of plant-based senolytics isolated from natural sources that support healthy aging and warrant further exploration as a potential geroprotective agent in clinical medicine.

What’s Next for Procyanidin C1?

This study demonstrates the superiority and relative safety of a geroprotective strategy that selectively targets senescent cells in aged tissues across a broad spectrum of cell types. However, effective PCC1 concentrations may vary between organs. A thorough evaluation of the toxic effects of PCC1 and fine tuning of the dosing regimen is necessary before being evaluated for its effectiveness in supporting healthy aging and longevity in people.

Story source:

​​Xu Q, Fu Q, Li Z, Liu H, Wang Y, Lin X, He R, Zhang X, Ju Z, Campisi J, Kirkland JL, Sun Y. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab. 2021 Dec;3(12):1706-1726. doi: 10.1038/s42255-021-00491-8. Epub 2021 Dec 6. PMID: 34873338.