Can natural polyphenols hold the key to antiaging?

Senescent cells, also known as “zombie cells,” are old cells that stop dividing but never die. Found in tissues throughout the body, they can cause damage to active cells and are linked to typical aging conditions like frailty¹, cognitive impairment², inflammation³, and chronic diseases. In 2021, Matthew Yousefzadeh, PhD, found another possible correlation when he co-authored a study⁴ showing that senescent cells may exacerbate COVID-19. What does this mean for our understanding of senescent cells and potential nutraceutical solutions?

In this study, Yousefzadeh and other researchers from Mayo Clinic showed that the inflammatory response of senescent cells was amplified in cases of severe acute respiratory syndrome associated with COVID-19. However, when the senescent cells were removed from old mice infected with the virus, mortality was reduced and antiviral antibodies were increased. The result? Survival rate increased by 50%, and researchers gained some possible insight into why older populations struggle with recovery more than younger populations. Researchers used senolytic fisetin to remove the zombie cells, derived from a plant flavanol found in many fruits and vegetables like strawberries, apples, persimmons, onions, and cucumbers.

“Polyphenols like quercetin and fisetin were shown to have senolytic activity in in vitro and preclinical studies,” Yousefzadeh explains. “This means that these compounds were able to selectively remove senescent cells, which can harm the body and shorten healthspan (disease-free survival) and lifespan.”

Fisetin actually has multiple relevant mechanisms of action, he explains. First, it can help shut down the pro-survival pathways that allow senescent cells to persist and produce inflammation. This is a process known as “inflammaging,” during which low-grade chronic inflammation drives the aging process. Second, in some studies⁵, fisetin has been shown to have antioxidant properties, which can induce autophagy, which Yousefzadeh describes as “the cells’ natural recycling program for proteins.”

The interaction of fisetin with senescent cells is at the center of various Mayo Clinic studies, including one ongoing trial⁶ examining how fisetin helps with frailty in older adults, and a separate trial⁷ with older women examining whether using fisetin can remove senescent cells for measurable health benefits. Beyond fisetin, Yousefzadeh says, other compounds of interest when it comes to alleviating the body’s senescent cell burden include apigenin and oleuropein, and may open the doors for further research.

References

1. Boccardi V et al. “The importance of cellular senescence in frailty and cardiovascular diseases.” Advances in Experimental Medicine and Biology (2020); 1216: 79-86
2. Sikora E et al. “Cellular senescence in brain aging.” Frontiers in Aging Neuroscience. Published online February 25, 2021.
3. Lasry A et al. “Senescence-associated inflammatory responses: Aging and cancer perspectives.” Trends in Immunology, vol. 36, no. 4 (April 2015): 217-228
4. Camell CD et al. “Senolytics reduce coronavirus-related mortality in old mice.” Science. Published online June 8, 2021.
5. Khan N et al. “Fisetin: A dietary antioxidant for health promotion.” Antioxidants & Redox Signaling, vol. 19, no. 2 (July 10, 2013): 151-162
6. “Alleviation by fisetin of frailty, inflammation, and related measures in older adults (AFFIRM-LITE).” ClinicalTrials.gov. Identifier NCT03675724
7. “Alleviation by fisetin of frailty, inflammation, and related measures in older women (AFFIRM).” ClinicalTrials.gov Identifier NCT03430037