Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection

Abstract

Like other organs, brain functions diminish with age. Furthermore, for a variety of neurological disorders—including Alzheimer’s disease—age is one of the higher-risk factors. Since in many Western countries the average age is increasing, determining approaches for decreasing the effects of aging on brain function is taking on a new urgency. Neuroinflammation and oxidative stress are two convoluted key factors in brain aging and chronic neurodegenerative diseases. The diverseness of factors, causing an age-related decrease in brain functions, requires identifying small molecules that have multiple biological activities that can affect all these factors. One great source of these small molecules is related to polyphenolic flavonoids. Recently, 3,3′,4′,7-tetrahydroxyflavone (fisetin) has been reported as a potent senotherapeutic capable of extending lifespan by reducing peroxidation levels and enhancing antioxidant cell responses. The neuroprotective effects of fisetin have been shown in several in vitro and in vivo models of neurological disorders due to its actions on multiple pathways associated with different neurological disorders. The present work aims to collect the most recent achievements related to the antioxidant and neuroprotective effects of fisetin. Moreover, in silico pharmacokinetics, pharmacodynamics, and toxicity of fisetin are also comprehensively described along with emerging novel drug delivery strategies for the amelioration of this flavonol bioavailability and chemical stability.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…Different mechanisms of action of senolytics have been reported in the literature: inhibition of the BCL-2 antiapoptotic family, negative modulation of the PI3K/Akt pathway and FOXO regulation [ 28 ]. On the other hand, senomorphics revert or slow down senescence by regulating the SASP [ 29 ].…”

Mannan-Binding Lectin via Interaction With Cell Surface Calreticulin Promotes Senescence of Activated Hepatic Stellate Cells to Limit Liver Fibrosis Progression

“…Although all senolytic drugs appear to clear senescent cells, each drug’s exact roles and mechanisms, especially in different contexts in vivo, still are unclear. 52 , 53 Even though it has been reported that D+Q showed selective cytotoxicity toward senescent HSCs, 26 the study mentioned earlier indicated that fisetin selectively eliminated senescent cholangiocytes, whereas D+Q targeted both proliferating and senescent cholangiocytes. 48 Furthermore, we performed senolytic administration ahead of CCl 4 injection to ensure the depletion of senescent HSCs in the present study, whereas the report mentioned earlier only focused on the senescent cholangiocytes.…”

Single-nucleus profiling identifies accelerated oligodendrocyte precursor cell senescence in a mouse model of Down Syndrome

“…SCAPs can be targeted by small molecule senolytic compounds to selectively clear senescent cells from pathological tissues 125 . Fisetin, a natural flavonoid, has senolytic properties and can be added to the diet as a supplement with minimal adverse effects 126 . We fed Ts65Dn mice a diet supplemented with 500ppm Fisetin, as previously described 127 (Methods).…”