The term “hallmarks of aging” refers to the biological processes that drive aging. When first introduced into the scientific literature in 2013,1 nine hallmarks of aging were identified. This framework was updated in 20232 to include a total of 12 hallmarks, which describe interconnected biological processes that together drive aging across tissues and organ systems. In simplified terms, aging occurs because cells progressively accumulate damage, lose their ability to repair and maintain themselves, communicate less effectively, and exist in an increasingly inflammatory environment—ultimately leading to declining function of the whole organism. The two hallmarks of aging discussed in this article—and the role that natural fisetin plays in helping to address them—are cellular senescence and chronic inflammation.
Cellular Senescence
Cells sometimes respond to severe stress or damage by permanently stopping division, a process known as cellular senescence. Initially, this response is protective, helping prevent damaged cells from becoming cancerous.
Over time, however, the body becomes less efficient at clearing these senescent, or “zombie,” cells. As they accumulate, they secrete a mix of harmful signaling molecules, including inflammatory factors and tissue remodeling enzymes, collectively referred to as the senescence-associated secretory phenotype (SASP). These signals disrupt nearby healthy cells and tissues, impair regeneration and maintenance, and ultimately accelerate aging.
In short, senescence is cellular deterioration with age. In fact, senescence contributes to chronic disease and aging.3 Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21. Luckily, there are senolytic agents (i.e., compounds able to destroy senescent cells) that have been shown to extend lifespan and reduce tissue injury.4
Chronic Inflammation
Inflammation plays a central role in the aging process. As we grow older, the balance between pro inflammatory and anti-inflammatory signals shifts toward a persistent, low-grade inflammatory state.
This chronic inflammation aggravates other hallmarks of aging. It can impair protein maintenance systems, damage mitochondria, increase DNA stress, reinforce cellular senescence and disrupt tissue repair.
Even more problematic, chronic inflammation tends to become self perpetuating: inflammation damages cells and tissues, and that damage triggers even more inflammation. This vicious cycle, often referred to as “inflammaging,” accelerates biological aging and increases the risk of cardiovascular disease, neurodegeneration, cancer, frailty and other age-related conditions.
Because chronic inflammation intersects with so many hallmarks of aging, it represents a particularly attractive target for evidence-based nutraceutical interventions. Addressing inflammation may yield broader anti aging benefits than targeting individual hallmarks in isolation.
Introduction to Fisetin
Flavonoids are a broadly distributed class of compounds regularly consumed in the diet. One such flavonoid, fisetin (3,3’,4’,7-tetrahydroxyflavone), has been reported to have neurotrophic, anticarcinogenic, anti-inflammatory and other beneficial health effects, including that as a senolytic agent.5 Fisetin is found in various fruits and vegetables, such as strawberry, apple, persimmon, grape, onion and cucumber. As a dietary supplement ingredient, it is frequently extracted from the wood and branches of the smoke tree (Cotinus coggygria) shrub. It can also be produced synthetically.
Fisetin and Synolysis
In one study,6 a panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. Other studies7-9 have shown similar senolytic results with fisetin.
Fisetin and Synolysis in Human Research
In a recent cohort study,10,11 a sub-analysis of healthy participants (n=10) reporting daily self-dosing of 100 mg/day fisetin showed a decrease in serum levels of SASP factors (MMP-3, MMP-9, platelet-derived growth factor AA [PDGF-AA], IL-6 and ‐8, monocyte chemoattractant protein-1 [MCP-1], and GDF11 and ‐15) between the baseline and a follow-up visit. The study also reported a decrease in the percentage of senescent (C12FDG++ bright, co-expressing uPAR) peripheral blood mononuclear cells (PBMCs).
Fisetin for Inflammation
Fisetin has been shown to reduce senescent cell burden, indirectly reducing senescence-driven inflammation.12 More significant is a randomized, controlled trial (RCT) involving stroke patients in which 100 mg/day fisetin dramatically improved stroke outcomes. This was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum.13 These biomarkers are associated with inflammation. In another RCT, 100 mg/day of fisetin reduced the inflammatory markers IL-8 and hs-CRP and suppressed MMP-7 levels in colorectal cancer patients.14
A 12-week parallel group randomized controlled trial15 examined whether fisetin supplementation augments the effects of concurrent interval resistance-aerobic training on Maresin 1 (MaR1, a specialized pro resolving mediator, plays a critical role in terminating inflammation and supporting metabolic homeostasis), pro inflammatory markers and insulin resistance in 44 obese adult males. Subjects completed one of four interventions: control-placebo (CP), fisetin (F) (200 mg/day), training-placebo (TP), or training-fisetin (TF). Training comprised eight resistance exercises at 60 percent 1RM with active rest followed by progressive aerobic bouts (50 percent-70 percent HRmax). Anthropometric and biochemical parameters, including plasma Maresin 1, the inflammatory markers interleukin-6 (IL 6) and tumor necrosis factor-alpha (TNF α), as well as fasting blood glucose (FBS), insulin, and HOMA IR (a measure of insulin resistance), were assessed pre and post intervention. Results were that significant group × time interactions were observed for Maresin 1 (p = 0.034), IL 6 (p = 0.001), TNF α (p = 0.001), FBS (p = 0.001), insulin (p = 0.001), and HOMA IR (p = 0.001). Maresin 1 increased in the TP (p = 0.001) and TF (p = 0.001) groups. IL 6 decreased in T (p = 0.006), TF (p = 0.001), and F (p = 0.013) groups. TNF α decreased in all intervention groups (F, TP, and TF) (p = 0.002). FBS, insulin and HOMA IR decreased significantly in all active arms (p = 0.003), with the greatest reductions in the TF group. In conclusion, 12 weeks of concurrent interval resistance-aerobic training, especially when combined with fisetin, improved inflammatory resolution and metabolic control in obese men. The synergy between exercise induced adaptations and fisetin’s anti-inflammatory properties offers a promising non pharmacological strategy for mitigating obesity related metabolic risk.
Bioavailability of Fisetin
Unfortunately, fisetin has relatively low bioavailability (44.1 percent), poor water solubility (10.45 g/mL), and high lipophilicity (logP 3.2).16 Two potential methods of addressing this issue are the use of fisetin liposomes and micellar/hydrogel fisetin.
In one study,17 liposomal fisetin resulted in a 47-fold increase in relative bioavailability compared to free fisetin. A 2026 review18 also reported the enhanced bioavailability of liposomal fisetin. It should be noted, however, that—to-date—the liposomal data on fisetin is from animal studies, not human.
Conversely, the strongest human evidence for improving fisetin bioavailability comes from a randomized crossover pharmacokinetic study19 in healthy volunteers using a fisetin formulation consisting of lecithin-based micelles embedded in a fenugreek galactomannan hydrogel matrix (Hybrid-FENUMAT). Specifically:
• Plasma AUC (overall exposure) was 26.9-fold higher than unformulated fisetin.
• Peak plasma concentration (Cmax) was 23.9-fold higher than unformulated fisetin.
• The formulation significantly improved systemic absorption without reported adverse events.
Sustainability Issues and Other Concerns
As it currently stands, smoke tree appears to be the primary commercial source of natural fisetin. It should be noted that fisetin occurs at its highest concentrations in the heartwood, bark, stems, and branches of smoke tree. From a sustainability standpoint, harvesting these tissues is inherently more destructive than collecting leaves or fruits.20 It has been posited that the risks associated with increased demand of smoke tree as a source of fisetin include overharvesting of wild populations, habitat degradation, loss of genetic diversity, insufficient cultivation programs, and pressure on native ecosystems. These concerns are especially relevant when extraction relies on roots, bark, or wood rather than renewable aerial tissues.21
Another commercial source for natural fisetin is Toxicodendron succedaneum (syn. Rhus succedanea),22 commonly known as wax tree or Japanese wax tree. Unfortunately, fisetin is likewise derived from the heartwood of this plant,23 and so faces the same stability issues.
While there are other food sources of fisetin, such as apples, the levels are significantly lower than that of smoke tree extracts.24 Nevertheless, some nutraceutical ingredient companies are working on developing new natural sources.
Despite these issues, I personally prefer natural source fisetin over synthetic fisetin. In fact, you should be aware of the risk that some ingredient companies offering natural fisetin may adulterate it with some of the synthetic material—so choose your supplier carefully.
Conclusion
In conclusion, as a nutraceutical, fisetin offers an effective strategy for helping to destroy senescent cells and reduce inflammation—thereby impacting two of primary hallmarks of aging. Due to its low bioavailability, the use of liposomal or micellar/hydrogel delivery systems are recommended.
References:
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Gene Bruno, DBM, MHS, Professor Emeritus of Nutraceutical Science, is a writer, educator and a nutraceutical scientist with more than 45 years of experience educating natural product retailers and health care professionals and formulating natural products for dozens of dietary supplement companies. He has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. Dr. Bruno also hosts “The Vitamin Professor Podcast” brought to you by VRM Media. He can be reached at [email protected].
