Although present in strawberries, the fisetin is a relatively rare nutrient found only in minute quantities in the plant kingdom. It has been shown to maintain levels of
Its exceptional capacity to ward off age-related cognitive decline through the modulation of multiple neuronal (nerve cell-related) pathways has drawn the most intense scientific interest. Fisetin also exerts multimodal effects common to known caloric restriction mimetics.
"We had already shown that in normal animals, fisetin can improve memory," says Pamela Maher, a senior staff scientist in Salk's Cellular Neurobiology Laboratory who led the new study. "What we showed here is that it also can have an effect on animals prone to Alzheimer's."
More than a decade ago, Maher discovered that fisetin helps protect neurons in the brain from the effects of aging. She and her colleagues have since--in both isolated cell cultures and mouse studies--probed how the compound has both antioxidant and anti-inflammatory effects on cells in the brain. Most recently, they found that fisetin turns on a cellular pathway known to be involved in memory.
"What we realized is that fisetin has a number of properties that we thought might be beneficial when it comes to Alzheimer's," says Maher.
So Maher--who works with Dave Schubert, the head of the Cellular Neurobiology Lab--turned to a strain of mice that have mutations in two genes linked to Alzheimer's disease. The researchers took a subset of these mice and, when they were only three months old, began adding fisetin to their food. As the mice aged, the researchers tested their memory and learning skills with water mazes. By nine months of age, mice that hadn't received fisetin began performing more poorly in the mazes. Mice that had gotten a daily dose of the compound, however, performed as well as normal mice, at both nine months and a year old.
"Even as the disease would have been progressing, the fisetin was able to continue preventing symptoms," Maher says.
Fisetin's antioxidant potency is comparable to quercetin. Alone among the polyphenols, fisetin induces genetic expression of a powerful cellular antioxidant system called quinone reductase or QR, which is vital in preventing oxidant-induced carcinogenesis. The antioxidant action of fisetin has been shown to significantly extend the life span of C. elegans--a benchmark indicator of CR mimesis (simulation). Its proven ability to inhibit oxidation of harmful LDL cholesterol also indicates fisetin's potential in preventing cardiovascular disease.
Laboratory studies show that fisetin inhibits glycation (destructive binding of sugar molecules to functional proteins) in human hemoglobin, protecting red blood cells from long-term damage. It interacts beneficially with other human proteins and with DNA. These effects likely account for its specific ability to protect brain and nerve tissues. Studies show that advanced glycation end-products (AGEs) and their receptors are closely linked to conditions such as Alzheimer's disease and other forms of cognitive decline.
Fisetin ranks very high among flavonoids at preventing DNA damage. Low doses of fisetin offer superior protection against DNA strand rupture induced by hydrogen peroxide, a potent free radical. These effects also place fisetin high on the list of potentially effective cancer-preventing agents.
Fisetin suppresses inflammatory cytokine production by diverse mechanisms. It downregulates the master inflammatory modulator NF-kB, which may reduce inflammatory responses, cancer-related cell proliferation, and metastatic alterations through a unique set of cellular mechanisms.
Fisetin has been shown to protect mitochondria against repeated oxidative stress. Cells treated with fisetin are able to maintain mitochondrial-dependent levels of adenosine triphosphate or ATP--the body's primary "energy currency"--in the presence of powerful mitochondrial toxins. In live animal studies, researchers found that fisetin could significantly improve behavioral outcomes when administered fiveĀ minutes after the initiation of an embolic stroke. Strokes impose a huge metabolic burden on brain tissue, and destruction of mitochondria is one reason for the neurological deficits observed after such events. Fisetin was shown to reduce the amount and volume of brain damage following induction of stroke in animal models.
Protection of Vital Cellular Components
Fisetin consistently increases activity of a vital cellular waste excretion unit called the proteasome, to such an extent that it promotes nerve cell survival following withdrawal of otherwise vital growth factors. Proteasome activity is decreased in a variety of age-associated neurological disorders including Alzheimer’s and Parkinson’s diseases.
Maher and her colleagues found that fisetin promotes long-term potentiation of brain neurons, thereby enhancing memory in two pre-clinical models of aging.
In collaboration with scientists at the University of California, San Diego, Maher's team next tested the levels of different molecules in the brains of mice that had received doses of fisetin and those that hadn't. In mice with Alzheimer's symptoms, they found, pathways involved in cellular inflammation were turned on. In the animals that had taken fisetin, those pathways were dampened and anti-inflammatory molecules were present instead. One protein in particular -- -known as p35 -- -was blocked from being cleaved into a shorter version when fisetin was taken. The shortened version of p35 is known to turn on and off many other molecular pathways.
Studies on isolated tissue had hinted that fisetin might also decrease the number of amyloid plaques in Alzheimer's affected brains. However, that observation didn't hold up in the mice studies. "Fisetin didn't affect the plaques," says Maher. "It seems to act on other pathways that haven't been seriously investigated in the past as therapeutic targets."
Next, Maher's team hopes to understand more of the molecular details on how fisetin affects memory, including whether there are targets other than p35.
"It may be that compounds like this that have more than one target are most effective at treating Alzheimer's disease," says Maher, "because it's a complex disease where there are a lot of things going wrong."
They also aim to develop new studies to look at how the timing of fisetin doses affect its influence on Alzheimer's.
"The model that we used here was a preventive model," explains Maher. "We started the mice on the drugs before they had any memory loss. But obviously human patients don't go to the doctor until they are already having memory problems." So the next step in moving the discovery toward the clinic, she says, is to test whether fisetin can reverse declines in memory once they have already appeared.