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Paul D. ROBBINS, et al.
Fisetin vs Aging








Related: Fisetin & Memory


http://www.wikipedia.org
Fisetin
fisetin

Fisetin, is a plant polyphenol from the flavonoid group. It can be found in many plants, where it serves as a colouring agent. It is also found in many fruits and vegetables, such as strawberries, apples, persimmons, onions and cucumbers.
Molar mass: 286.2363 g/mol
Formula: C15H10O6
Melting point: 626°F (330°C)
ChEMBL Id: 31574
ChemSpider ID: 4444933
PubChem CID: 5281614


https://www.sciencedaily.com/releases/2018/10/181002114024.htm

Researchers have discovered how to slow aging

Natural product found to reduce the level of damaged cells in the body, caused by aging

Summary:    Previous research showed it was possible to reduce the burden of damaged cells, termed senescent cells, and extend lifespan and improve health, even when treatment was initiated late in life.

They now have shown that treatment of aged mice with the natural product Fisetin, found in many fruits and vegetables, also has significant positive effects on health and lifespan.

Previous research published earlier this year in Nature Medicine involving University of Minnesota Medical School faculty Paul D. Robbins and Laura J. Niedernhofer and Mayo Clinic investigators James L.

Kirkland and Tamara Tchkonia, showed it was possible to reduce the burden of damaged cells, termed senescent cells, and extend lifespan and improve health, even when treatment was initiated late in life.

They now have shown that treatment of aged mice with the natural product Fisetin, found in many fruits and vegetables, also has significant positive effects on health and lifespan.

As people age, they accumulate damaged cells. When the cells get to a certain level of damage they go through an aging process of their own, called cellular senescence. The cells also release inflammatory factors that tell the immune system to clear those damaged cells. A younger person's immune system is healthy and is able to clear the damaged cells. But as people age, they aren't cleared as effectively. Thus they begin to accumulate, cause low level inflammation and release enzymes that can degrade the tissue.

Robbins and fellow researchers found a natural product, called Fisetin, reduces the level of these damaged cells in the body. They found this by treating mice towards the end of life with this compound and see improvement in health and lifespan. The paper, "Fisetin is a senotherapeutic that extends health and lifespan," was recently published in EBioMedicine.

"These results suggest that we can extend the period of health, termed healthspan, even towards the end of life," said Robbins. "But there are still many questions to address, including the right dosage, for example."

One question they can now answer, however, is why haven't they done this before? There were always key limitations when it came to figuring out how a drug will act on different tissues, different cells in an aging body. Researchers didn't have a way to identify if a treatment was actually attacking the particular cells that are senescent, until now.

Under the guidance of Edgar Arriaga, a professor in the Department of Chemistry in the College of Science and Engineering at the University of Minnesota, the team used mass cytometry, or CyTOF, technology and applied it for the first time in aging research, which is unique to the University of Minnesota.

"In addition to showing that the drug works, this is the first demonstration that shows the effects of the drug on specific subsets of these damaged cells within a given tissue." Robbins said.


https://linkinghub.elsevier.com/retrieve/pii/S2352396418303736
EBioMedicine, 2018;
DOI: 10.1016/j.ebiom.2018.09.015

Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018; DOI: 10.1016/j.ebiom.2018.09.015
Matthew J. Yousefzadeh, et al.
Abstract
Background

Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.

Methods

A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.

Findings

Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.

Interpretation

The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies.



PATENTS : FISETIN EXTRACTION

Method for extracting fisetin from toxicodendron succedaneum
CN108003125
The invention discloses a method for extracting fisetin from toxicodendron succedaneum. The method comprises the following operation steps: (1) taking toxicodendron succedaneum branches, crushing  the toxicodendron succedaneum branches with a crusher, adding a sodium hydroxide solution, soaking for 1-2 h, taking out the soaked toxicodendron succedaneum branches, performing drying till the water content of the toxicodendron succedaneum branches is 10-15%; (2) adding ethyl alcohol into the dried toxicodendron succedaneum branches; performing heating for a reaction; performing extraction for 1.5-2.5 h at 180-220 DEG C, stopping heating, performing cooling to the room temperature, taking out a substance obtained after the reaction, performing filtration, and taking the filtrate; and (3) concentrating the filtrate obtained in step (2) till the total liquid content of the filtrate is 23-25 wt% to obtain a concentrated solution, adding water into the concentrated solution according to the massratio 1:(1.55-1.59) of the concentrated solution to water, and separating out fisetin. The method can effectively extract fisetin, the extracted fisetin is good in quality and high in purity, and theextraction ratio can be up to 19%; and furthermore, the method is easy and simple to operate, suitable for massive industrial production and safe in extraction process.

COSMETIC SKIN WHITENING COMPOSITIONS CONTAINING EXTRACTS DERIVED FROM IN VITRO PROPAGATED HYPERICUM HIRSUTUM
EP3135341
The present invention relates to extract containing active substances and use of extract as active ingredient for skin whitening cosmetic formulations. A skin whitening cosmetic active ingredient based on extract derived from in vitro cultivated Hypericum hirsutum by 50% ethanol extraction is proposed. Invention relates specifically to the plant material derived from in vitro shoot cultures with no growth regulators added. The offered ingredient contains Kaempferol-3-O-glucoside, Kaempferol-7-O-glucoside, Fisetin, Chlorogenic acid, 3-Caffeoylquinic acid and Umbelliferone. Invention proposes use of extract, which exhibits anti-proliferative effect on melanocytes and is not highly cytotoxic in concentration range of 1 -3 %, as active ingredient in skin whitening cosmetic formulations. The proposed concentration range for use in cosmetic formulations is 0.5-2% (v/v)

Method for extracting fisetin from boxwood
CN102924419
The invention provides a method for extracting fisetin from boxwood. The method comprises that boxwood as a raw material is subjected to crushing, extraction and crystallization to produce fisetin crystals. The method has the advantages that processes are simple and easy; equipment requirements are low and only simple extraction condensation equipment is adopted; extracted fisetin has the purity of 98%; a fisetin yield is greatly improved and 15 to 20kg of fisetin can be extracted from 1T of the raw material having the content of 1 to 2%; an active ingredient loss is less in the processes; and compared with the prior art, the method can improve a yield about 4-5 times.

Vernonia anthelmintica flavone components, preparation method and application thereof
CN102526153
The invention relates to vernonia anthelmintica flavone components, a preparation method and application thereof. The flavone components are fisetin, butein, 7,8,3',4'-tetrahydroxy flavone, 5,7,8,3',4'-pentahydroxy chalcone, 6,8,3',5'-tetrahydroxy-dihydroflavone, liquiritigenin and isoliquiritigenin, which are prepared from plant vernonia anthelmintica through extraction, separation and purification. Application of each flavone component in preparation of a medicament for treating leucoderma provides a new medicament choice for treating leucoderma.

Fisetin extraction method
CN102442987
The invention relates to a fisetin extraction method. The process method comprises the following steps: crushing dried branches and leaves of smoke trees; adding 10-20 times of saturated limewater solution, and soaking and extracting at normal temperature; filtering the extracting solution, regulating the pH value to 7, and adding a macroporous resin column for adsorption; eluting with a 60-70% ethanol solution; recovering ethanol in the eluent while depressurizing, standing for crystallization, and filtering out coarse crystals; dissolving in a 5% sodium carbonate solution; sequentially leaching with n-butyl alcohol and ethyl acetate; removing the organic phase, regulating the water phase with hydrochloric acid until the pH value is 4-5, and standing for precipitation; and recrystallizing the precipitate, and drying to obtain the product. The fisetin extraction method has the advantages of easy acquisition of raw materials, simple process operation and low production cost, and is applicable to industrial production.



https://www.ncbi.nlm.nih.gov/pubmed/28575152
J Gerontol A Biol Sci Med Sci. 2018 Mar 2;73(3):299-307. doi: 10.1093/gerona/glx104.

Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse.
Currais A, Farrokhi C, Dargusch R, Armando A, Quehenberger O, Schubert D, Maher P.

Abstract
Alzheimer's disease (AD) is rarely addressed in the context of aging even though there is an overlap in pathology. We previously used a phenotypic screening platform based on old age-associated brain toxicities to identify the flavonol fisetin as a potential therapeutic for AD and other age-related neurodegenerative diseases. Based on earlier results with fisetin in transgenic AD mice, we hypothesized that fisetin would be effective against brain aging and cognitive dysfunction in rapidly aging senescence-accelerated prone 8 (SAMP8) mice, a model for sporadic AD and dementia. An integrative approach was used to correlate protein expression and metabolite levels in the brain with cognition. It was found that fisetin reduced cognitive deficits in old SAMP8 mice while restoring multiple markers associated with impaired synaptic function, stress, and inflammation. These results provide further evidence for the potential benefits of fisetin for the treatment of age-related neurodegenerative diseases.



Aging (Albany NY). 2017 Mar 8;9(3):955-963. doi: 10.18632/aging.101202.

New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463.

Zhu Y1, Doornebal EJ1,2, Pirtskhalava T1, Giorgadze N1, Wentworth M3, Fuhrmann-Stroissnigg H4, Niedernhofer LJ4, Robbins PD4, Tchkonia T1, Kirkland JL1.

Abstract
Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XL inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin 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. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.


https://www.selfhacked.com/blog/15-science-based-health-benefits-fisetin-1-favorite/

15 Science-Based Fisetin Health Benefits + Natural Sources

Health Benefits of Fisetin
1) Fisetin is Good For Your Brain..  Encourages New Brain Growth... Fisetin Improves Memory... Protects Against Brain Degeneration... Decreases Brain Damage After Stroke... Fisetin Minimizes Brain Damage From Injury... Fisetin is Neuroprotective
2) Fisetin May Treat Depression
3) Fisetin Has Anti-Inflammatory Properties
4) Fisetin May Prevent and Treat Cancer
5) Fisetin Improves Blood Flow & Lowers Blood Pressure
6) Fisetin May Help Treat Diabetes
7) Fisetin May Extend Lifespan
8) Fisetin May Lower Body Weight
9) Fisetin Lowers Pain
10) Fisetin Protects Bone
11) Fisetin Protects Skin From Sun Damage
12) Fisetin Prevents Toxicity
13) Fisetin Helps Maintain Energy Levels
14) Fisetin Can Treat Infections
15) Fisetin is a Mast Cell Inhibitor and Can Help Histamine Intolerance




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