Cellular senescence has become a primary target in anti-aging research, and understanding its origins is crucial for developing effective interventions. Fisetin, a plant polyphenol and flavonoid compound, has recently gained attention as a potent anti-aging substance. First isolated in 1833 and structurally defined by the late 1800s, fisetin is a secondary metabolite found in various plants, including their green parts, fruits, bark, and hardwoods, as well as in common foods such as strawberries, apples, persimmons, grapes, onions, and cucumbers.
Imagine strolling through a sun-dappled orchard, plucking a ripe strawberry from the vine. Its sweet juiciness bursts on your tongue, but what if this simple fruit held a secret—a compound that could not only taste delicious but also combat the very mechanisms of aging? In the quest to unlock the fountain of youth, scientists have turned their attention to cellular aging, a process at the core of why our bodies wear down over time. Before we can harness the power to slow aging, we must first understand how cellular aging takes root: as cells accumulate damage, they enter a state of senescence, where they stop dividing yet linger, releasing harmful substances that harm neighboring cells and drive aging-related decline. Enter fisetin—a natural compound hiding in plain sight, emerging as a star player in the fight against aging.
Fisetin, also known as fisetin, is a plant-derived flavonol. It was first extracted from Cotinus coggygria (German: Fisetholz) by Jacob Schmidt in 1886, hence its alternative name "fustin." Since Cotinus coggygria belongs to the Anacardiaceae family, fisetin is also referred to as "sumac flavone." Its chemical formula was first determined by Josef Herzig in 1891. Fisetin is a common plant pigment found in various vegetables and fruits such as strawberries, apples, persimmons, onions, and cucumbers.
Fisetin is present in a wide range of plants. It is found in many eudicotyledons, including legumes such as Acacia greggii and Acacia berlandieri, Butea monosperma, and Gleditsia triacanthos. Additionally, members of the Anacardiaceae family like Quebracho colorado and species of the Rhus genus contain fisetin. In "young fustic," a traditional yellow dye made from the heartwood of Cotinus coggygria, fisetin and myricetin are the main components of its yellow pigment. Fisetin is also found in various fruits and vegetables such as strawberries, apples, and grapes. It can be extracted from fruit juices, wine, and brewed beverages like tea. Monocotyledons such as onions also contain fisetin, as do conifers like Callitropsis nootkatensis.
| Plant Source | Fisetin Content (μg/g) |
|---|---|
| Strawberries | 160 |
| Apples | 26 |
| Persimmons | 10.6 |
| Onions | 4.8 |
| Lotus roots | 5.8 |
| Grapes | 3.9 |
| Kiwis | 2.0 |
| Peaches | 0.6 |
| Cucumbers | 0.1 |
| Tomatoes | 0.1 |
As a flavonoid and thus a polyphenol, fisetin biosynthesis begins with the phenylpropanoid pathway. In this pathway, the amino acid phenylalanine is first converted to 4-coumaroyl-CoA, which then enters the flavonoid biosynthesis pathway. Chalcone synthase, the first enzyme in this pathway, converts 4-coumaroyl-CoA into chalcone, the backbone from which all flavonoids, collectively referred to as chalcones, are derived. Various enzymes such as isomerases and hydroxylases act on chalcones depending on the subclass of the product. Transferases regulate the solubility of flavonoids by catalyzing the addition of methyl groups or sugars, allowing plants to control random variations in physiological activities.
Genes involved in flavonoid synthesis are regulated through interactions between various transcription factors. These genes are expressed at specific times and in different parts of the plant based on the outcomes of these interactions. It has been found that multiple myeloblastosis transcription factors play important roles in regulating the synthesis and accumulation of flavonoids in plants such as strawberries, corn, and Arabidopsis thaliana. Research on these transcription factors is still ongoing, using model plants like corn and Arabidopsis thaliana.
Environmental factors also influence the flavonoid biosynthesis pathway. Short-wavelength light, ranging from blue light to ultraviolet light, stimulates fruits to produce and accumulate more flavonoids. These wavelengths activate enzymes involved in the biosynthesis of polyphenols and flavonoids, prompting them to produce more flavonoids, with the degree of activation varying among different fruits.
How exactly does fisetin work to fight aging? Through extensive animal studies and some initial clinical trials, researchers have identified several key mechanisms by which fisetin may extend lifespan and improve health during aging. These can be broken down into five main areas:
- Fisetin can eliminate senescent cells.
- Fisetin can improve cognitive decline.
- Fisetin can prevent skin wrinkles and redness by inhibiting UVB-induced expressions.
- Fisetin can inhibit cancer cells and halt cancer progression.
- Fisetin is a plant compound beneficial for osteoporosis.
1) Eliminating Senescent Cells
As mentioned earlier, senescent cells secrete harmful substances that can damage nearby healthy cells. Another negative impact of senescent cells in the body is their harm to stem cells—the foundational cells responsible for building and repairing the body’s organs and tissues. When stem cells are damaged, the risk of developing life-threatening diseases, particularly cancer, increases significantly.
As mentioned earlier, senescent cells secrete harmful substances that can damage nearby healthy cells. Another negative impact of senescent cells in the body is their harm to stem cells—the foundational cells responsible for building and repairing the body’s organs and tissues. When stem cells are damaged, the risk of developing life-threatening diseases, particularly cancer, increases significantly.
Fisetin’s ability to eliminate senescent cells has shown striking results in mouse studies. Mice that received fisetin over a period of time lived an average of 2.5 months longer than those that did not—an extension of nearly 10% of their lifespan.
2) Improving Cognitive Decline
Another fascinating benefit of fisetin is its ability to reduce cognitive aging in mice. One study found that older mice given fisetin performed better in maze navigation and object recognition tasks, indicating improved cognition and memory. In fact, these elderly mice performed nearly as well as their younger counterparts.
Another fascinating benefit of fisetin is its ability to reduce cognitive aging in mice. One study found that older mice given fisetin performed better in maze navigation and object recognition tasks, indicating improved cognition and memory. In fact, these elderly mice performed nearly as well as their younger counterparts.
Related research suggests that fisetin may extend both median and maximum lifespan in mice, even when administration begins in late life—equivalent to humans in their 50s or 60s. Additionally, in animal models of early-onset Alzheimer’s disease, fisetin has demonstrated the potential to prevent the development of cognitive and memory impairments.
3) Inhibiting UVB-Induced Expressions
Fisetin also offers benefits for skin health, helping to reduce wrinkle formation and strengthen the skin layers. It achieves this by decreasing the number of matrix metalloproteinases (MMPs)—enzymes that break down the extracellular matrix surrounding cells. The extracellular matrix includes collagen, elastin, hyaluronic acid, glycosaminoglycans (GAGs), and many other cell-bound molecules, which are essential for maintaining the firmness of tissues like skin and organs. Excess MMP activity is a known contributor to wrinkle formation, making fisetin a promising ally for skin aging.
Fisetin also offers benefits for skin health, helping to reduce wrinkle formation and strengthen the skin layers. It achieves this by decreasing the number of matrix metalloproteinases (MMPs)—enzymes that break down the extracellular matrix surrounding cells. The extracellular matrix includes collagen, elastin, hyaluronic acid, glycosaminoglycans (GAGs), and many other cell-bound molecules, which are essential for maintaining the firmness of tissues like skin and organs. Excess MMP activity is a known contributor to wrinkle formation, making fisetin a promising ally for skin aging.
4) Inhibiting Cancer Cells
Reports indicate that fisetin can help prevent cancer and limit the growth and spread of existing tumors. It does this by inducing apoptosis, or programmed cell death, in cancer cells, aiding in the removal of tumor cells. Additionally, as an anti-inflammatory agent, fisetin can reduce compounds that exacerbate chronic inflammation—a known driver of cancer progression.
Reports indicate that fisetin can help prevent cancer and limit the growth and spread of existing tumors. It does this by inducing apoptosis, or programmed cell death, in cancer cells, aiding in the removal of tumor cells. Additionally, as an anti-inflammatory agent, fisetin can reduce compounds that exacerbate chronic inflammation—a known driver of cancer progression.
5) A Plant Compound Beneficial for Osteoporosis
Bone fragility is another hallmark of aging, and fisetin has emerged as a plant compound that supports bone health, particularly in combating osteoporosis. Bone health relies on a balance between osteoblasts (cells that form new bone) and osteoclasts (cells that break down old bone). In osteoporosis, osteoclasts become more active than osteoblasts, leading to weakened bones. Studies in rats have shown that fisetin can stimulate osteoblast activity while blocking osteoclast activity, helping to restore this critical balance.
Bone fragility is another hallmark of aging, and fisetin has emerged as a plant compound that supports bone health, particularly in combating osteoporosis. Bone health relies on a balance between osteoblasts (cells that form new bone) and osteoclasts (cells that break down old bone). In osteoporosis, osteoclasts become more active than osteoblasts, leading to weakened bones. Studies in rats have shown that fisetin can stimulate osteoblast activity while blocking osteoclast activity, helping to restore this critical balance.
The potential of fisetin in anti-aging research continues to unfold, with each study revealing new layers of its ability to improve health and reverse signs of aging. As research progresses, this humble plant compound may prove to be a cornerstone in our efforts to live longer, healthier lives.