M.J. Yousefzadeh et al, 2017. New agentsthat target senescent cells: the flavone, fisetin, and the BCL-XLinhibitors, A1331852 and A1155463. AGING  Vol. 9, No. 3; 955-963. 7

Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. This study report that fisetin, a naturally‐

occurring flavone with low toxicity,  are senolytic.

To assess if fisetin is senolytic, the research cultured primary human preadipocytes, HUVECs, and IMR90 cells and exposed these cells to 10Gy radiation (senescent cells) or sham-irradiated them (control cells). Proliferating or senescent cells were exposed to different

concentrations of fisetin for 3 days.

Result: The study found that fisetin is  indeed senolytic in senescent HUVECs, it selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not

senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes.

Conclusion: Fisetin may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.

Kim, S. C., et al, 2015. Fisetin induces Sirt1 expression while inhibiting early adipogenesis in 3T3-L1 cells. Biochem. Biophys. Res. Commun. 467 (4), 638–644

As a polyphenol, fisetin can counteract oxidative stress and mediate immune response via AMPK/SIRT1 and Nfr2 pathways. Fisetin was shown to increase SIRT1 expression and enhance SIRT1-mediated PPAR and FOXO1 deacetylation in 3T3L1 cells.

Fisetin counteract oxidative stress via AMPK/SIRT1 and Nfr2 pathways

Result: Fisetin inhibits lipid accumulation and suppresses the expression of PPARγ in 3T3-L1 cells. Fisetin suppressed early stages of preadipocyte differentiation, and induced expression of Sirt1. Depletion of Sirt1 abolished the inhibitory effects of fisetin on intracellular lipid accumulation and on PPARγ expression. Mechanistically, fisetin facilitated Sirt1-mediated deacetylation of PPARγ and FoxO1, and enhanced the association of Sirt1 with the PPARγ promoter, leading to suppression of PPARγ transcriptional activity, thereby repressing adipogenesis. Lowering Sirt1 levels reversed the effects of fisetin on deacetylation of PPARγ and increased PPARγ transactivation.

Conclusion: The results suggest the effects of fisetin in increasing Sirt1 expression and in epigenetic control of early adipogenesis.

Syed DN, et al, 2014. Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol,14; 89:349-60.

It is now accepted that mTOR inhibition increases lifespan,  mTORC1 inhibition may not delay aging itself, but may delay age-related diseases. Aging is generally characterized by a progressive loss of physiological integrity, which leads to impaired functions, and therefore increases vulnerability to death thus limiting lifespan. The mTOR network is known to regulate some of these aging hallmarks. Ultimately, the prominence of mTORC1 signaling in aging likely reflects its exceptional capacity to regulate such a wide variety of key cellular functions.

mTOR network regulate aging hallmarks
Fisetin inhibits mTOR

Result : Fisetin inhibits multiple signaling kinases, including the PI3K/mTOR pathway and is considered a natural dual inhibitor of PI3K/Akt and mTOR signaling. Fisetin inhibits the mTOR pathway both indirectly and directly by binding to mTOR and its downstream target, p70S6K. Fisetin causes death of cancer cells, which is associated with mTOR inhibition. Fisetin exerts multiple rapamycin-like effects in animals. It prevents cardiac hypertrophy by inhibiting mTOR. Fisetin inhibits Akt, S6K1 and mTORC1, S6K1 in adipose tissue and prevents adipocyte differentiation and obesity in HFD-fed mice.

Sandeep Singh et al, 2022. Fisetin, a potential caloric restriction mimetic, modulates ionic homeostasis in senescence induced and naturally aged rats. Arch Physiol Biochem. Feb,128(1):51-58

Fisetin as a caloric restriction mimetic (CRM) exerts numerous beneficial effects on different aging model systems. Male Wistar rats were used for natural and D-galactose (D-gal) induced aging model. After supplementation with fisetin, the activities of different membrane transporters and biomarkers of oxidative stress were evaluated.

Results: Fisetin modulated membrane transporters such as calcium-ATPase, sodium potassium-ATPase and sodium hydrogen exchanger during senescence-induced as well as in natural aging. Fisetin also protected oxidative modifications in rat aging.Conclusion: Fisetin supplementation improves the ionic homeostasis, a factor that is involved in the aetiology of several age-associated diseases, in naturally old as well as D-gal induced aged rats.

Sandeep Singh et al, 2018. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Ar Life Sci. Jan 15;193:171-179

The study investigated the antioxidative and protective potential of fisetin in a rat model. Young rats, aged D-gal-induced rats and naturally aged D-gal-induced rats were supplemented with fisetin (15 mg/kg, orally) for 6 weeks.

Result: Supplementation with fisetin suppresses aging-induced increases in the levels of reactive oxygen species, eryptosis, lipid peroxidation, and protein oxidation. Data show that fisetin significantly increases the levels of antioxidants and activates the plasma membrane redox system.

Conclusion: Fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and a fisetin-rich diet could be an anti-aging intervention strategy.

Jng Cui, et al, 2021. Neuroprotective potential of fisetin in an experimental model of spinal cord injury: via modulation of NF-κB/IκBα pathway. Neuroreport,Mar 3;32(4):296-305.11

In order to evaluate neuroprotective efficacy of fisetin against the experimental model of spinal cord injury (SCI), SCI was induced in male Sprague-Dawley rats by placing an aneurysm clip extradurally. Rats were treated either with vehicle or fisetin for 28 days after SCI.

Results: Treatment with fisetin significantly attenuated SCI-induced alternations in mechano-tactile and thermal allodynia, hyperalgesia and nerve conduction velocities.  Spinal nuclear factor kappa B and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha protein levels were also significantly downregulated by fisetin. Hematoxylin and eosin staining of spinal cord suggested that fisetin significantly ameliorated histological aberrations such as neuronal degeneration, necrosis and inflammatory infiltration induced in it.

Conclusion: Fisetin exerts neuroprotection via modulation of nuclear factor kappa B/nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-alpha pathway by inhibiting release of inflammatory mediators , proinflammatory cytokines, apoptotic mediators.

Limin Wang, et al, 2021. Fisetin Prolongs Therapy Window of Brain Ischemic Stroke Using Tissue Plasminogen Activator: A Double-Blind Randomized Placebo-Controlled Clinical Trial. Clinical and Applied Thrombosis/Hemostasis, Volume 25: 1-8

Recombinant tissue plasminogen activator (rt-PA) can be utilized to treat ischemic stroke with safety and effectiveness but limited by a narrow therapeutic window. In the present clinical trial among patients with stroke, we sought to evaluate the potential of fisetin to extend the therapeutic window of rt-PA treatment.

Result: Fisetin dramatically improved the treatment outcomes of the patients with stroke in the delayed OTT strata, as revealed by lower NIHSS scores. The beneficial effect of fisetin was likely attributable to reduced levels of MMP-2, MMP-9, and CRP in the serum, as evidenced by strong linear correlations between serum levels of such markers with the NIHSS scores in all enrolled patients.

In conclusion, the present randomized double-blind and placebo-controlled trial has provided the first clinical evidence on the role of fisetin as a supplement in rt-PA reperfusion therapy against acute brain ischemic stroke. Fisetin, when administered simultaneously with rt-PA, extended the otherwise narrow effective window of rt-PA treatment and dramatically improved the treatment outcome of this widely used stroke therapy.

Zhen, L., et al, 2012. The antidepressant-like effect of fisetin involves the serotonergic and noradrenergic system. Behavioural Brain Research, 228(2), 359-366

The study aimed to investigate the antidepressant potential of fisetin and its possible mechanism.

Two mouse models of despair tests were used to evaluate the antidepressant-like effect of fisetin. The results suggested that fisetin (10 and 20mg/kg, p.o.) dose dependently inhibited the immobility time in both behavioral tests, while the doses that affected the immobile response did not affect locomotor activity.

Result: The higher dose of fisetin was found to effectively antagonize the hypothermia, but not ptosis, induced by reserpine. Pre-treatment with PCPA abolished the anti-immobility effect of fisetin in the forced swimming and tail suspension tests. Moreover, neurochemical assays showed that fisetin produced an increase in serotonin and noradrenaline levels in the frontal cortex and hippocampus. Monoamine oxidase (MAO) activity in the mouse brain was inhibited by 14.7% after treatment with fisetin, while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of fisetin involves the regulation of the central serotonin and noradrenaline levels.

Conclusion: The study provided evidence that fisetin exerts antidepressant-like effects in the tail suspension and forced swim tests. This positive effect is likely mediated, at least in part, via the central serotonergic and noradrenergic system by inhibiting the MAO activity. Our results therefore suggest that fisetin could serve as a novel natural antidepressant agent.

Maher, P. et al, 2006. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proceedings of the National Academy of Sciences, 103(44), 16568–16573.

Small molecules that activate signaling pathways used by neurotrophic factors could be useful for treating CNS disorders. The study show that fisetin activates ERK and induces cAMP response element-binding protein phosphorylation in rat hippocampal slices, facilitates long-term potentiation in rat hippocampal slices, and enhances object recognition in mice.

Conclusion:The data demonstrate that the natural product fisetin can facilitate long-term memory, and therefore it may be useful for treating patients with memory disorders

Ehren JL, 2013. Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. Biochem Pharmacol.  85:1816-1826

The research  showed that the flavonoid fisetin not only increases basal levels of GSH but also maintains GSH levels under oxidative stress conditions and the mechanisms underlying these effects have been investigated.

Studies indicate the major two transcription factors that regulates GSH metabolism is the ubiquitously expressed protein NF-E2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4).

 And the result of study shows that fisetin was able to increases the levels of both Nrf2 and ATF4 in nerve cells in a dose- and time-dependent manner, and  fisetin was able to increase the half-lives of both of these proteins about 2-fold. Both Nrf2 and ATF4 were essential for the effect of fisetin on GSH levels.

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