D-galactose is often used by researchers in order to induce aging-like symptoms in mice. It is a damaging compound, provoking oxidative stress, inflammation, and cellular senescence. That in turn produces loss of tissue and organ function in ways that can appear similar to the outcomes of degenerative aging. In today's open access paper, researchers show that injection of fisetin can significantly reduce the harmful outcomes produced by D-galactose, including the loss of cognitive function.
This is of passing interest as fisetin has been shown to have senolytic effects in mice, when ingested at an appropriately high dose. (The injected dose here is much lower, 25 mg/kg versus 100 mg/kg, but one would expect injection to require lower doses than ingestion to be efficacious). Fisetin can selectively destroy significant numbers of senescent cells in aged tissues, leading to rejuvenation. Mice exhibit a reversal of measures of aging, a turning back of age-related conditions. This result occurs because senescent cells accumulate with age, and their secretions actively maintain an inflammatory state of disrupted cell and tissue function. The presence of lingering senescent cells is a major contributing cause of aging. One might hypothesize that benefits in the present study are emerging in large part via destruction of some of the excess senescent cells created by D-galactose.
Chronic administration of D-galactose induces brain aging and accelerates artificial senescence which is used for different anti-aging pharmacological research. D-galactose is a monosaccharide, which exists throughout the body. At higher concentrations, in the presence of galactose oxidase, it converts to hydrogen peroxide and aldose, causing disposition of a superoxide anion, oxygen-derived free radicals, and cellular damage. Chronic administration of d-galactose for 2 months induces cognitive and memory impairment through the accumulated reactive oxygen species (ROS), mitochondrial deficits, neuroinflammation, and neurodegeneration.
Recently, the use of phytonutrients and medicinal herbs have gained a special interest to treat neurological disorders such as Alzheimer's disease. Among the phytonutrients, Fisetin, a natural flavonoid is found in different fruits. Fisetin has shown strong anticarcinogenic, anti-inflammatory, antioxidant, neurotrophic, and neuroprotective effects against different neurodegenerative diseases.
Here, we explore the underlying neuroprotective mechanism of fisetin against d-galactose-induced aging in mice. Normal mice were injected with d-galactose (100 mg/kg/day for 60 days) and fisetin (20 mg/kg/day for 30 days). To elucidate the protective effects of fisetin against d-galactose induced oxidative stress-mediated neuroinflammation, we conducted western blotting, biochemical, behavioral, and immunofluorescence analyses.
According to our findings, d-galactose induced oxidative stress, neuroinflammation, synaptic dysfunctions, and cognitive impairment. Conversely, fisetin prevented the d-galactose-mediated ROS accumulation, by regulating the endogenous anti-oxidant mechanisms, such as Sirt1/Nrf2 signaling, suppressed the activated phosphorylated-JNK/NF-kB pathway, and its downstream targets, such as inflammatory cytokines. Hence, our results together with the previous reports suggest that fisetin may be beneficial in age-related neurological disorders.