Research Progress on the Anti-Aging Mechanisms of Fisetin
With the acceleration of global population aging, the prevention of age-related diseases and the intervention in the aging process have become major focuses in biomedical research. Fisetin, a naturally occurring flavonoid widely distributed in fruits, vegetables, and other plants, has attracted increasing attention due to its diverse biological activities and potential applications in the field of anti-aging. This review summarizes the current understanding of the anti-aging mechanisms of fisetin at multiple levels, discusses its potential applications, and highlights future research directions. The aim is to provide valuable insights for the further exploration and utilization of fisetin in anti-aging strategies.
Keywords: Fisetin; Anti-aging; Antioxidant; Tissue repair; Cell cycle
1. Introduction
Aging is a complex biological process characterized by the progressive decline of physiological functions across multiple systems, and it is closely associated with an increased risk of various age-related diseases, including cardiovascular disorders, neurodegenerative conditions, and osteoarthritis. Developing safe and effective anti-aging interventions is of great importance for improving the health status of the elderly population and reducing the burden on public health systems. Among the wide range of anti-aging candidates, natural compounds have attracted significant attention due to their abundant biological sources and favorable safety profiles. Fisetin, a flavonol widely distributed in fruits and vegetables, has emerged as a promising compound. Recent studies have demonstrated that fisetin exerts anti-aging effects through multiple mechanisms, including the attenuation of oxidative stress, suppression of inflammatory responses, and regulation of the cell cycle, thereby showing protective potential at cellular, tissue, and organismal levels.
2. Fundamental Properties of Fisetin
Fisetin is a naturally occurring flavonol characterized by multiple hydroxyl groups in its molecular structure, which confer unique chemical properties and strong biological activities. Following oral administration, fisetin undergoes hydrolysis by intestinal β-glucosidases to release the aglycone form, with an estimated bioavailability of only about 5–10%. It is subsequently metabolized in the liver, primarily through glucuronidation and sulfation pathways mediated by enzymes such as UGT1A9 and SULT1A1. The plasma half-life of fisetin is approximately 2–4 hours, and excretion occurs mainly via the biliary route. Notably, nano-formulations of fisetin have been shown to markedly improve its bioavailability, thereby enhancing its efficacy, particularly in exerting potent antioxidant effects.
3. Cellular Mechanisms of Fisetin in Anti-Aging
3.1 Antioxidant Activity
During cellular metabolism, various reactive oxygen species (ROS) are generated, which can attack DNA, proteins, and lipids, thereby accelerating cellular damage and aging. The hydroxyl groups in the fisetin molecule act as hydrogen donors, neutralizing free radicals and converting them into stable molecules, effectively interrupting oxidative chain reactions. In skin cells exposed to ultraviolet (UV) radiation, fisetin has been shown to efficiently scavenge ROS, protecting collagen and elastin fibers from oxidative damage, preserving the structural and functional integrity of skin cells, and ultimately delaying skin aging.
In addition to its direct radical-scavenging activity, fisetin enhances the endogenous antioxidant defense system. Studies have demonstrated that fisetin can upregulate key antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), which play pivotal roles in maintaining cellular redox balance. By activating relevant signaling pathways or directly modulating enzyme activity, fisetin significantly boosts SOD and GSH-Px activities, strengthens cellular antioxidant defenses, reduces the accumulation of oxidative by-products, and markedly lowers oxidative stress levels. Through these mechanisms, fisetin contributes to the delay of cellular aging processes.
3.2 Regulation of Cell Cycle and Proliferation
The orderly progression of the cell cycle is essential for maintaining normal cellular functions and tissue homeostasis. Fisetin has been shown to regulate key proteins involved in cell division, thereby supporting stable proliferation in normal cells. At the same time, it can suppress abnormal growth in precancerous or dysregulated cells, preventing excessive proliferation and reducing the risk of malignant transformation. Through this dual action—maintaining normal cell cycle control while inhibiting aberrant proliferation—fisetin not only contributes to tumor prevention but may also slow cellular senescence, highlighting its unique role in cell cycle regulation and health maintenance.
Stem cells, with their capacity for self-renewal and differentiation into multiple cell types, are fundamental to tissue repair and regeneration. Evidence suggests that fisetin can activate several critical signaling pathways, enhancing the self-renewal ability of stem cells while directing their differentiation toward specific functional lineages, such as promoting the osteogenic differentiation of bone marrow mesenchymal stem cells. These properties indicate that fisetin holds significant potential in facilitating tissue regeneration, supporting skeletal health, and delaying aging, thereby offering novel insights for stem cell–based therapies and anti-aging strategies.
4. Anti-Aging Effects of Fisetin at the Organ and System Level
4.1 Skin-Specific Anti-Aging Effects
Fisetin delays skin aging through multiple mechanisms. Its potent antioxidant activity scavenges excessive free radicals, thereby reducing damage to collagen and elastin fibers. At the same time, fisetin promotes fibroblast-mediated synthesis of collagen, elastin, and other dermal extracellular matrix components, strengthening the structural support of the skin. In addition, it inhibits the activity of matrix metalloproteinases (MMPs), preventing excessive degradation of the dermal matrix. These combined actions enhance skin elasticity, reduce fine lines, and improve overall texture, contributing to the maintenance of healthy and youthful skin.
Fisetin also exhibits significant effects on skin pigmentation. It can reduce melanin accumulation by inhibiting tyrosinase activity and modulating melanogenesis pathways, thereby lightening age spots and promoting a more even and radiant complexion. Furthermore, its antioxidant properties help prevent new pigmentation caused by ultraviolet (UV) exposure and free radical damage, offering natural support for improving skin brightness and overall appearance.
4.2 Anti-Aging Effects on the Cardiovascular System
Fisetin exerts protective effects on vascular endothelial cells through both antioxidant and anti-inflammatory mechanisms. Its free radical-scavenging capacity helps prevent oxidative stress–induced damage and preserves endothelial structural integrity. In addition, fisetin inhibits the release of pro-inflammatory mediators, reducing inflammatory cell infiltration and vascular injury, thereby alleviating the oxidative and inflammatory burden associated with atherosclerosis. Furthermore, fisetin improves endothelial function, maintains vascular elasticity, and supports stable blood flow. These coordinated actions collectively slow cardiovascular aging, highlighting fisetin’s potential as a preventive and therapeutic agent for cardiovascular diseases.
4.3 Anti-Aging Effects on the Nervous System
Fisetin exhibits pronounced neuroprotective effects and plays a significant role in delaying nervous system aging. Studies indicate that it can effectively reduce neuroinflammation and oxidative stress, thereby protecting neurons from damage and improving neural function. Fisetin also activates key regulatory pathways, including SIRT1 and Nrf2, enhancing antioxidant defenses, scavenging excessive free radicals, and suppressing the release of inflammatory mediators. Through these coordinated mechanisms, fisetin helps maintain neuronal homeostasis and functional integrity. Such multifaceted actions may slow the onset and progression of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, highlighting its potential for promoting brain health and mitigating nervous system aging.
5. Systematic Evaluation of Fisetin Safety
Current studies and systematic evaluations indicate that fisetin exhibits a favorable safety profile within the commonly used dosage range (≤500 mg/day). Animal studies have shown that its median lethal dose (LD₅₀) exceeds 2000 mg/kg, and 90-day subchronic toxicity tests revealed no significant organ damage. Reported adverse effects in clinical trials are generally mild, primarily involving gastrointestinal discomfort, while high doses may occasionally induce diarrhea or nausea, all of which are reversible upon discontinuation. In vitro genotoxicity assays have consistently yielded negative results, showing no mutagenic risk. However, the safety of long-term administration at high doses still requires further clinical investigation.
6. Applications of Fisetin in Anti-Aging Products and Health Management
Owing to its multifunctional effects—including antioxidant activity, promotion of collagen synthesis, and inhibition of melanin production—fisetin has broad applications in the anti-aging industry. In cosmetics, it can serve as a key active ingredient in creams, serums, and other skincare products, improving wrinkles and enhancing skin elasticity. It may also be incorporated into sunscreens as a complementary component, working synergistically with traditional UV filters to mitigate photoaging by scavenging UV-induced free radicals. In the nutraceutical sector, fisetin can be formulated into capsules, tablets, or other oral dosage forms to provide systemic anti-aging protection through redox regulation and tissue repair. Additionally, increasing the intake of fisetin-rich foods, such as strawberries and onions, or fortifying functional foods with fisetin, offers consumers a comprehensive anti-aging strategy that spans topical care, dietary supplementation, and everyday nutrition.
7. Conclusion and Outlook
Fisetin, as a promising natural anti-aging compound, has garnered significant research attention. Numerous studies have demonstrated its potent antioxidant activity, effectively scavenging free radicals and mitigating oxidative stress, while exerting anti-aging effects through mechanisms such as cell cycle regulation. Evidence from cellular and animal models indicates that fisetin can improve skin aging, protect cardiovascular function, and enhance stem cell activity, among other benefits. Although clinical data in humans remain limited, existing research provides a solid foundation for its potential therapeutic applications. With further elucidation of its molecular mechanisms and advancements in delivery technologies, fisetin holds considerable promise as a next-generation, safe, and effective anti-aging intervention.
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