Feisty Fisetin: A Formidable Flavonoid Warding Off Aging Foes

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Feisty Fisetin: A Formidable Flavonoid Warding Off Aging Foes

The search for agents that promote healthy aging and extend lifespan is a tale as old as time. Even predating modern science, natural products have been some of the most popularly investigated agents for millennia. Recently, naturally derived non-toxic biomolecules from the diet have received utmost attention to support healthy aging.

One natural product in the limelight of the aging field (geroscience) is called fisetin. This naturally occurring compound has garnered a wide range of health-endorsing perspectives. This small, plant-based, orally-active biomolecule can target multiple proteins and cellular pathways, has antioxidant properties, and has health-supporting effects on the brain and immune system.

Where Does Fisetin Come From?

Fisetin is a flavonoid — a broad category of plant-derived pigments. Flavonoids are consumed as part of our diets and are abundantly present in several plants, making them easily accessible. The broad therapeutic potential of flavonoids makes them one of the prospective tools to address challenges prevalent in the health sector. Moreover, there is a growing interest in these plant-derived flavonoids because they reap immense health benefits with minimal adverse effects even in chronic consumption.

In the vast pool of flavonoids, fisetin is one molecule that has grabbed the attention of researchers owing to its potential spanning several dimensions. The first record of fisetin dates back to 1833, when it was isolated from Venetian sumach. About half a century later, the essential chemical characteristics of fisetin were provided in 1886. We now know that fisetin is found in barks, hardwood, and the green parts of vegetables like onions and kale. It is also found in several fruits: strawberries, apples, persimmons, grapes, and kiwi. However, in fruits and vegetables, fisetin naturally occurs in low concentrations. For this reason, nutritional supplements are also prepared with fisetin by using higher concentrations. 

We now know that fisetin is found in barks, hardwood, and the green parts of vegetables like onions and kale. It is also found in several fruits: strawberries, apples, persimmons, grapes, and kiwi.

How Does Fisetin Work?

Natural products, in some cases, have widespread targeting pathways often greater than synthetic drugs. Fisetin shows promising activity in a wide variety of cell functions. So, targeting such interwoven pathways is a massive task that may be better suited for a compound like fisetin than a synthetic product with very limited targets.

Fisetin has antioxidant properties

Studies have shown that fisetin can help cells fight off oxidative stress, the buildup of harmful compounds called reactive oxygen species (ROS), making this plant-based compound an antioxidant. Fisetin not only has direct antioxidant activity but can also increase the intracellular levels of glutathione, one of the body’s major antioxidants. This is important because glutathione levels can be decreased by about 30% in elderly subjects.

This finding is of particular relevance concerning the alterations in cognition with aging and brain health because multiple studies have shown that transient decreases in glutathione levels can temporarily impair cognitive function, even in young animals. Together these studies suggest that acute reductions in glutathione levels can impact aspects of both learning and memory.

Fisetin has senolytic potential

Perhaps the most promising of the documented fisetin biological activities reside in the anticipated possibility of targeting fundamental aging mechanisms. Nearly six decades ago, the phenomenon of senescence — the finite proliferation capacity of cells — was discovered. This led to a period of extensive studies on cell growth arrest mechanisms, particularly in connection to the causes of the aging process. Although senescent cells resist death through upregulation of the prosurvival pathways, some pharmacological agents, such as fisetin, can overcome this resistance.

What Is Fisetin Good for?

Healthy aging is mediated by complex cellular pathways that are known, yet many hidden mechanisms operate that geroscientists have yet to decipher. 

Fisetin supports brain health

Fisetin can yield beneficial health effects in humans and animal models of brain health, and its role in treating age-related changes in brain structure and function is well documented. The brain’s immune response is central to brain health. There is data showing that during aging, fisetin supports a healthy immune response in the brain. Fisetin also has shown effects on age-related changes in the brain by triggering signaling pathways that promote brain cell growth and health.

The way brain cells transmit information is through structures called synapses. These information bridges are the basis for cognitive functions, and dysfunction of synapses has proven to have a detrimental impact on neuronal connectivity and the functioning of the nervous system. Changes in synaptic transmission are evident with normal aging and change in brain health. Dysregulation of synaptic proteins in neurons can have adverse effects on brain health. This makes modulation of synaptic function one of the interventions to support brain health.

Regarding synapses, fisetin has been shown to prevent the decrease in synaptic proteins in the brains of aging mice, leading to a remarkable reduction in synaptic dysfunction. Fisetin can also maintain the forms of these proteins, which supports neuronal integrity. Fisetin can also modulate the proteasome’s activity, a molecular complex essential for recycling damaged proteins to maintain cell health, including brain cells. 

Fisetin supports brain health

Fisetin and the Immune System

A few studies have examined the effects of fisetin on the immune system, finding that fisetin can support immune health. In particular, fisetin is able to clear senescent immune cells and reduce downstream effects of senescence on immune system responses. More work is needed to determine whether fisetin could be a viable option in humans to rejuvenate an aged immune system.

Fisetin and Aging

Experiments with laboratory organisms, from yeast to flies to vertebrate animals, clearly demonstrate that fisetin can extend the lifespan of investigated organisms of both sexes. Fisetin extends the replicative lifespan of yeast by 55% and the lifespan of flies by 23%. Chronic exposure to fisetin improves healthspan and extends the median and maximum lifespan of mice.

As a result of these findings, Dr. James L. Kirkland's team at the Mayo Clinic has recently designed and begun a clinical trial aimed at the “Alleviation by Fisetin of Frailty, Inflammation, and Related Measures in Older Adults” (AFFIRM-LITE) with fisetin administered orally in doses up to 20 mg per kilogram of patient body weight.

Fisetin can also affect the levels of the aging-related compound nicotinamide adenine dinucleotide (NAD+), a key coenzyme for catalyzing countless biological reactions integral to cell health, function, and survival. Studies published recently unraveled the relationship between the cellular concentration of NAD+ concerning aging, metabolism, and brain health. When NAD+-consuming enzymes are over-activated, NAD+ levels can drop considerably and lead to adverse health consequences. However, fisetin can reverse these effects.

fisetin supports healthy aging

Fisetin modulates the microbiome

Some of the beneficial effects of fisetin may be mediated by alterations to the gut microbiota. ​​The gut microbiome has come under increasing attention as a potential contributor to human health. There is strong evidence that gut microbiota is important for normal development and health maintenance. Fisetin can alter the distribution and diversity of the gut microbiome in mice as well as the metabolic pathways associated with the microbiome.

The Future of Fisetin

The growing body of preclinical data, along with fisetin’s ability to modulate a large number of pathways associated with brain and immune health as well as its senolytic potential, strongly suggest that it would be worthwhile to pursue its effects in humans. These characteristics indicate the feasibility of translation to human clinical studies. Specific research work is required to further explore its toxicity and interaction with current agents and potential efficacy in a clinical setting. Evidence of clinical data is critical for better understanding and proving the effective strategy of fisetin against aging-related conditions. Given the known safety profile of fisetin in humans, human studies are beginning to test if fisetin can be used effectively to reduce senescent cell burden and support healthy aging in elderly subjects.

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