A New Plant-Derived Senomorphic Slows Aging in Mice

Studying grape seed extract, scientists have discovered a new senomorphic compound that enhances chemotherapy and prolongs lifespan and healthspan in mice [1].

Nature’s drugstore

Many drugs have come to us from the world of plants, including promising geroprotective molecules such as resveratrol. However, identifying specific components of plant extracts that exert positive effects can be challenging.

In this new study, the researchers started by screening a library of 46 plant-derived compounds for their senolytic potential – that is, the ability to remove senescent cells.

Why we Age: Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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The researchers treated cells in vitro with a senescence-inducing compound and then applied the chemicals from the library to ascertain their senolytic effects. They also used several known senolytics as controls. The list of compounds that had exhibited a senolytic potential included the well-known curcumin and fisetin, but the researchers decided to focus on grape seed extract (GSE) due to both the magnitude of its effects on senescent cells and its relative paucity of research.

Both senomorphic and senolytic

In a series of experiments, the researchers confirmed that GSE effectively reduces SASP secretion, but in moderate doses, this was not accompanied by senescent cells being wiped out. According to the researchers, this effect is more senomorphic in nature, which means that it preserves senescent cells but alleviates harmful aspects of their phenotype [2]. The senomorphic approach has been gaining popularity recently because senescent cells are not always bad, and their elimination might be ill-advised in certain conditions.

Still, the researchers also tested GSE’s senolytic abilities and found them to be just as impressive. At higher concentrations, GSE eliminated up to 80% of senescent cells without affecting the viability of normal cells.

GSE consists of many different molecules, so which one or ones are responsible for its senolytic action? A component called procyanidin C1 (PCC1) that belongs to the flavonoid family caught the researchers’ attention due to its known ability to induce DNA damage. The scientists repeated the experiments with only PCC1 and found that its effect was very similar to that of GSE. Other GSE components did not exhibit senolytic activity – or at least, not at the same scale as PCC1.

Senolytics and cancer

The researchers then ran a series of experiments in vivo on cancerous tumors in mice. It is known that senescent cells are instrumental in preventing cancer in its early stages but might actually team up with it in later ones [3]. For instance, they can contribute to a tumor’s resistance to chemotherapy [4]. What’s worse, radiotheraphy and chemotherapy themselves induce cellular senescence by inflicting stress on healthy cells.

The researchers induced tumors in mice and then treated them either with a chemotherapeutic known as mitoxantrone, PCC1, or with the mitoxantrone-PCC1 duo. Unsurprisingly, mitoxantrone administration led not just to an anti-tumor effect but also to the appearance of numerous senescent cells in the tumor tissue. However, PCC1 eliminated most of those cells. As a result, the combination treatment remarkably enhanced tumor regression (55.2% reduction in tumor size compared to mitoxantrone alone).

Mice who were receiving the mitoxantrone-PCCC1 combo survived 1.5 times longer than the group treated with mitoxantrone alone. To be sure, PCC1 without mitoxantrone did not have a significant effect on survivability: after all, PCC1 is just a sidekick that clears senescent cells, making the job of the chemotherapeutic agent easier.

Genuine life extension

The researchers then performed additional in vivo experiments to assess PCC1’s ability to attenuate senescence-related physical dysfunction. It is known that even a small number of senescent cells can affect organismal health, including in young organisms. The researchers implanted senescent cells into young mice, which led to a decline in their physical abilities (maximum walking speed, hanging endurance, and grip strength), but this decline was largely reversed by PCC1 treatment.

Finally, to examine the effect of PCC1 on organismal aging, the researchers tested it on a bunch of naturally aging wild type mice. By the age of two years (or around 75 in human years), cellular senescence ran rampant in those mice. Bi-weekly PCC1 treatment that lasted about four months eliminated a large percentage of senescent cells and led to an increase in physical function and longevity. Treated mice lived for almost 10% longer, and their median post-treatment lifespan increased by a whopping 64%.

Conclusion

In this study, the researchers have identified a new powerful plant-derived senolytic compound and conducted extensive experiments to learn how it helps fight cancer and prolongs lifespan and healthspan in mice. By doing so, they also provided additional support to the theory that senolytics can effectively slow aging, even when administered later in life.

Literature

[1] Xu, Q., Fu, Q., Li, Z., Liu, H., Wang, Y., Lin, X., … & Sun, Y. (2021). The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nature Metabolism, 1-21.

[2] Zhu, X. Y., & Lerman, L. O. (2022). Senomorphic, senolytic, and rejuvenation therapies. In Regenerative Nephrology (pp. 405-417). Academic Press.

[3] Wyld, L., Bellantuono, I., Tchkonia, T., Morgan, J., Turner, O., Foss, F., … & Kirkland, J. L. (2020). Senescence and cancer: A review of clinical implications of senescence and senotherapies. Cancers, 12(8), 2134.

[4] Georgilis, A., & Gil, J. (2016). Controlling secretion to limit chemoresistance. Genes & development, 30(16), 1791-1792.