Time goes by so quickly, in a blink really! I felt this so much last week as my son, Vincent James, started his first day of second grade! We may feel like we are in a time warp, our cells don’t and as time marches on, our cells undergo a complex series of changes that lead to decreased functionality and increased vulnerability to diseases. One of the key players in this process is cellular senescence, a state in which cells lose their ability to divide and function properly, contributing to chronic inflammation, tissue dysfunction, and age-related diseases. Yes, time marches on and various stressors contribute to the aging process, however, one of the things that I get excited to see is the important role that lifestyle and natural medicine have in combating healing our bodies at a cellular level and helping to slow this aging-process, helping us to age well! Cellular senescence is one of the many topics I had the privilege of learning more about this past spring at Medicines from the Earth in Ashville, North Carolina with the amazing naturopathic doctor and herbalist, Dr. Mary Bove. She shared some of the recent scientific research that have unveiled natural compounds, such as quercetin and fisetin, as powerful senotherapies capable of rejuvenating senescent cells and promoting healthier aging. She also discussed the so-called ‘hit-and-run’ dosing that seems to make these senolytics most effective. Hit and run dosing = less supplements to support well-aging. Interested to learn more, read on!
The Underlying Mechanisms of Cellular Senescence & Zombie Cells
Cellular senescence is a double-edged sword. While it serves as a protective mechanism against cancer by halting the growth of damaged cells, it also contributes to chronic inflammation and tissue deterioration. Senescent cells accumulate over time due to various factors including DNA damage, oxidative stress, and telomere shortening. These cells enter a state of persistent inflammation and release harmful molecules that can negatively impact neighboring cells and tissues, creating what is often referred to as the "senescence-associated secretory phenotype" (SASP). Because they are not yet dead, but not functional, and create havoc in the body, these senescent cells are also know as zombie cells.
Reanimating versus Slaying Zombies
SASP inhibitors (senomorphics) and senolytics are both approaches aimed at addressing aging-related cellular changes, but they work in different ways. Senomorphic agents morph the signals coming from the zombie cells, while senolytic agents directly target and eliminate these problematic aging cells. SASP inhibitors can be thought of agents that help to turn back zombie cells into healthy cells, like in science fiction zombies being reversed or reanimated back into healthy humans, whereas senolytic agents are the zombie slayers in this analogy. Another difference between SASP inhibitors and senolytics is related to how these agents are dosed. Daily dosing seems best for SASP inhibitors, while senolytic agents appear to work best with intermittent or ‘hit-and-run’ dosing.
Hit & Run Dosing
I know, know, zombie cells and ‘hit-and-run’ dosing, what is going on! While I didn’t come up with these terms, I cannot deny they are catchy and on-point. I was particularly excited to learn about how hit and run dosing seems to make these senolytic agents most effective. Hit and run dosing is exactly what it sounds like, using a higher dose of these agents for just a few days and repeating for at least several months in a row. I am always excited to learn about health supportive strategies that are relatively easy to implement and involve less pills!
Slaying the Zombie Cells with Lifestyle & Botanical Agents, Quercetin and Fisetin
Foundational lifestyle measures are pivotal for maintaining cellular health and combating cellular senescence. Regular exercise, a balanced diet, stress reduction, and other healthy practices play a crucial role. Intermittent fasting has garnered attention for its potential impact on cellular rejuvenation. By cycling between eating and fasting periods, intermittent fasting stimulates processes like autophagy, aiding in the removal of damaged cells. This approach shows promise in reducing the presence of senescent cells and supporting prolonged cellular vitality. Two natural compounds that have garnered significant attention as helping to improve cellular heath are quercetin and fisetin, through their actions as both SASP inhibitors and senolytics.
Quercetin
We’ve heard a ton about quercetin in recent years because of its immune supportive and anti-viral benefits. Quercetin is a plant compound called a flavonoid found abundantly in fruits and vegetables and some medicinal herbs (ie elderberry syrup and green tea), quercetin has been extensively studied for its antioxidant and anti-inflammatory properties. Recent research has highlighted its potential as a senolytic agent. By interfering with pathways that promote cell survival in senescent cells, quercetin helps induce apoptosis, or programmed cell death, in these cells. This remarkable action contributes to the removal of senescent cells from tissues, reducing inflammation and potentially delaying age-related diseases.
Fisetin
Another flavonoid and senolytic agent, found to help our bodies as well , not as well know by the general public is fisetin, found in foods like strawberries, apples, grapes, onions, cucumbers, and in higher amounts in the many trees such as various Morus species (Mulberry leaf), Cotinus coggygria (Smoke Tree) and Rhus succedanea fruit wax (the fruit of a sumac tree native to Japan). The fruit of North American species of sumac also contains fisetin, but have not been as well studied - yet. Fisetin, through its ability to modulate the senescence signaling pathways research suggests it can help our cellular ‘powerhouses’ or mitochondria function despite stress, combats aging in brain clean-up cells called microglia by increasing the production of the important antioxidant called glutathione and thus decreasing inflammation. All these actions work together to slow down age related changes in our aging bodies and brains!
The effects of quercetin and fisetin as senolytics are profound. Not only do these natural compounds aid in the elimination of senescent cells, but they also exhibit the potential to rejuvenate surrounding cells and tissues. As senescent cells are cleared away, inflammation decreases, and the tissue microenvironment becomes more conducive to healthy cellular function. What I find so exciting is that when dosed regularly in lower doses quercetin and fisetin can help to manage inflammation and cellular damage, but at when dosed intermittently and in higher doses the so called ‘hit-and-run’ dosing they act as senolytics, slaying the zombie cells that contribute to our aging.
Beyond Cellular Senescence
The implications of quercetin, fisetin and other botanical senolytics (ie gingerenone A from ginger and piperlongumine from black pepper) extend beyond their senolytic properties. Those of you who have worked with me for years, likely already know how much I appreciate natural therapeutics that are “multi-fers”, a term I’ve lovingly coined for natural agents that have multiple health promoting properties. I’ve long appreciated quercetin for being one of these agents. Both quercetin and fisetin have been studied for their potential in reducing the risk of chronic diseases such as cardiovascular disorders, neurodegenerative conditions, and cancer and research on botanically derived senotherapeutics is on the horizon. Their antioxidant and anti-inflammatory actions may contribute to overall wellness and longevity.
Conclusion
The discovery of natural senolytics such as quercetin and fisetin represents an important advancement in the field of aging research. By targeting and removing senescent cells, these compounds offer a unique opportunity to rejuvenate aging tissues and potentially delay the onset of age-related diseases and are with a relatively low side-effect profile compared to the pharmaceutically based senolytics. The potential for healthier aging through a well-aging lifestyle and the application of these natural therapeutics is good news for those of us who want to both optimize our health and age as well as we can.
Dr. Sarah Giardenelli is a naturopathic doctor, acupuncturist, herbalist, owner of Collective Health Center. She is passionate about optimizing patients’ health, including strategies to age well. If you are interested in aging-well with lifestyle, natural medicine, and personalized supplements, including senotheropeutic and senolytic agents, please feel free to schedule or reach out to her office.
References
Bove, Mary. Sencescene, Senolytics, and Aging. Medicines from the Earth Herb Symposium Conference Proceeding Notes, 2023. https://www.botanicalmedicine.org/
Chaib S, Tchkonia T, Kirkland JL. Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022 Aug;28(8):1556-1568. doi: 10.1038/s41591-022-01923-y. Epub 2022 Aug 11. PMID: 35953721; PMCID: PMC9599677.
Liu X, Wang Y, Zhang X, Gao Z, Zhang S, Shi P, Zhang X, Song L, Hendrickson H, Zhou D, Zheng G. Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation. Bioorg Med Chem. 2018 Aug 7;26(14):3925-3938. doi: 10.1016/j.bmc.2018.06.013. Epub 2018 Jun 18. PMID: 29925484; PMCID: PMC6087492.
Moaddel R, Rossi M, Rodriguez S, Munk R, Khadeer M, Abdelmohsen K, Gorospe M, Ferrucci L. Identification of gingerenone A as a novel senolytic compound. PLoS One. 2022 Mar 29;17(3):e0266135. doi: 10.1371/journal.pone.0266135. PMID: 35349590; PMCID: PMC8963586.
Rayne S, Mazza G. Biological activities of extracts from sumac (Rhus spp.): a review. Plant Foods Hum Nutr. 2007 Dec;62(4):165-75. doi: 10.1007/s11130-007-0058-4. Epub 2007 Oct 2. PMID: 17909971.
Tsurudome N, Minami Y, Kajiya K. Fisetin, a major component derived from mulberry (Morus australis Poir.) leaves, prevents vascular abnormal contraction. Biofactors. 2022 Jan;48(1):56-66. doi: 10.1002/biof.1798. Epub 2021 Oct 23. PMID: 34687255; PMCID: PMC9298084.