Longevity Wiki - User contributions [en-GB]

Fisetin

2021-08-06T13:21:24Z

MessyMassey: /* Cancer */

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries (160 μg/g), apples (26.9 μg/g), persimmons (10.6 μg/g), lotus roots (5.8 μg/g), onions (4.8 μg/g), grapes (3.9 μg/g), kiwi (2.0 μg/g), peaches (0.6 μg/g), and cucumbers (0.1 μg/g).<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref><ref name=":2">Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin can help inhibit the growth of and expedite the death of cancerous colon cells. It does this in two ways:

# Inhibiting anti-apoptotic B-cell lymphoma 2 (BCL-2) cells. B-cell lymphoma 2 proteins prevent cell death (apoptosis) in both healthy and cancerous cells. By targeting BCL-2, fisetin can help ensure that malignant cells undergo normal programmed cell death.
# Induce pro-apoptotic Caspase-9 and Caspase-3 gene expression in cancerous colon cells. Caspase-9 and Caspase-3 are proteins expressed by the CASP9 and CASP3 genes respectively; both proteins induce apoptosis (cell death) by destroying critical cell infrastructures.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref>
Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity. MMP-1 aids in extracellular matrix (ECM) remodelling and degradation which can occur during neoplastic transformation like uncontrolled cell growth or failed apoptosis. More broadly, this can manifest as tumor growth and metastasis of cancerous cells.<ref name=":2" /> Since MMP-1 promotes ECM remodelling and fisetin inhibits MMP-1 activity, fisetin thus helps to slow the progression of cancer.

ECM remodelling describes the changes that occur in cells when they undergo neoplastic transformation, i.e. when they grow more rapidly than they should, or do not die when they should. More broadly, this can manifest as tumor growth and metastasis of cancerous cells.<ref name=":2" />

Since MMP-1 promotes ECM remodelling and fisetin inhibits MMP-1 activity, fisetin thus helps to slow the progression of cancer.<references />
[[Category:Longevity]]
[[Category:Medication]]
[[Category:Supplement]]

Fisetin

2021-08-06T13:20:29Z

MessyMassey: /* Evidence of lifespan extension */

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries (160 μg/g), apples (26.9 μg/g), persimmons (10.6 μg/g), lotus roots (5.8 μg/g), onions (4.8 μg/g), grapes (3.9 μg/g), kiwi (2.0 μg/g), peaches (0.6 μg/g), and cucumbers (0.1 μg/g).<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref><ref name=":2">Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin can help inhibit the growth of and expedite the death of cancerous colon cells. It does this in two ways:

# Inhibiting anti-apoptotic B-cell lymphoma 2 (BCL-2) cells. B-cell lymphoma 2 proteins prevent cell death (apoptosis) in both healthy and cancerous cells. By targeting BCL-2, fisetin can help ensure that malignant cells undergo normal programmed cell death.
# Induce pro-apoptotic Caspase-9 and Caspase-3 gene expression in cancerous colon cells. Caspase-9 and Caspase-3 are proteins expressed by the CASP9 and CASP3 genes respectively; both proteins induce apoptosis (cell death) by destroying critical cell infrastructures.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref>

Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity. MMP-1 aids in extracellular matrix (ECM) remodelling and degradation which can occur during neoplastic transformation like uncontrolled cell growth or failed apoptosis. More broadly, this can manifest as tumor growth and metastasis of cancerous cells.<ref name=":2" /> Since MMP-1 promotes ECM remodelling and fisetin inhibits MMP-1 activity, fisetin thus helps to slow the progression of cancer.

ECM remodelling describes the changes that occur in cells when they undergo neoplastic transformation, i.e. when they grow more rapidly than they should, or do not die when they should. More broadly, this can manifest as tumor growth and metastasis of cancerous cells.<ref name=":2" />

Since MMP-1 promotes ECM remodelling and fisetin inhibits MMP-1 activity, fisetin thus helps to slow the progression of cancer.<references />
[[Category:Longevity]]
[[Category:Medication]]
[[Category:Supplement]]

Fisetin

2021-07-05T18:03:51Z

MessyMassey: /* Evidence of lifespan extension */

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries (160 μg/g), apples (26.9 μg/g), persimmons (10.6 μg/g), lotus roots (5.8 μg/g), onions (4.8 μg/g), grapes (3.9 μg/g), kiwi (2.0 μg/g), peaches (0.6 μg/g), and cucumbers (0.1 μg/g).<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref><ref name=":2" /> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> In other words, fisetin both inhibits the growth of and promotes the death of cancerous colon cells. Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity, an important enzyme in remodelling and degradation of the extracellular matrix which plays a major role in cancer progression. <ref name=":2">Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> <references />
[[Category:Longevity]]
[[Category:Medication]]
[[Category:Supplement]]

Fisetin

2021-07-04T13:54:55Z

MessyMassey: /* Evidence of lifespan extension */

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries (160 μg/g), apples (26.9 μg/g), persimmons (10.6 μg/g), lotus roots (5.8 μg/g), onions (4.8 μg/g), grapes (3.9 μg/g), kiwi (2.0 μg/g), peaches (0.6 μg/g), and cucumbers (0.1 μg/g).<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref><ref name=":2" /> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> In other words, fisetin both inhibits the growth of and promotes the death of cancerous colon cells. Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity, an important enzyme in remodelling and degradation of the extracellular matrix which plays a major role in cancer progression. <ref name=":2">Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> <references />

Fisetin

2021-07-04T13:52:34Z

MessyMassey: /* Evidence of lifespan extension */

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries (160 μg/g), apples (26.9 μg/g), persimmons (10.6 μg/g), lotus roots (5.8 μg/g), onions (4.8 μg/g), grapes (3.9 μg/g), kiwi (2.0 μg/g), peach (0.6 μg/g), and cucumbers (0.1 μg/g).<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> In other words, fisetin both inhibits the growth of and promotes the death of cancerous colon cells. Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity, an important enzyme in remodelling and degradation of the extracellular matrix which plays a major role in cancer progression. <ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> <references />

Fisetin

2021-07-04T13:47:03Z

MessyMassey: /* Mice */

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries, onions, and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> In other words, fisetin both inhibits the growth of and promotes the death of cancerous colon cells. Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity, an important enzyme in remodelling and degradation of the extracellular matrix which plays a major role in cancer progression. <ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> <references />

Fisetin

2021-07-04T13:45:57Z

MessyMassey: Added some imagery and extended the cancer-parapgraph somewhat.

[[File:Molecular structure of fisetin.png|thumb|216x216px|Molecular structure of fisetin.]]
Fisetin is a potent, plant-based polyphenol compound that has been found to reduce senescence markers (signs of cellular aging) in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries, onions, and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Fisetin has many therapeutic benefits, including anti-inflammatory, cardioprotective, and neuroprotective properties. It is also an antiangiogenic, meaning it can reduce the growth of unwanted blood vessels.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs).

SCs are cells that have accumulated DNA damage or other stressors, which leads to changes in two types of cellular proteins: chromatin, the protein that chromosomes, including RNA and DNA, are made of; and secretome, a general name for the expression profile of proteins secreted by human cells. These changes lead to apoptosis (programmed cell death) which prevents the cell from replicating.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell.

However, SCs can instead develop a senescence-associated secretory phenotype (SASPs) to induce inflammatory immune responses via cytokines, chemokines, and extracellular degrading proteins. Even at low levels, SASPs have been shown to contribute to tissue dysfunction.<ref name=":0" />

SCs are closely linked to age since they usually increase with age in several tissues, including adipose (fat) tissue, skeletal muscle, kidney tissue, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref>

Fisetin appears to be a well-suited treatment to destroy senescent cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Bilde.png|thumb|233x233px|Longevity graph of mice on fisetin diet and control diet. Retrieved from Yousefzadeh et al. (2018) study. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 different flavonoids (a class of plant-based polyphenol compound).<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin.

In vitro, they used Ercc1−/∆ mice and inserted the p16Ink4a-luciferase transgene (bioluminescent foreign gene) to accelerate accumulation of [[Senolytics|senscent cells]]. The mice were then fed a diet from 6-8 to 10-12 weeks of age that included fisetin supplements administered every 500 mg/kg.

They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin.

Yousefzadeh et al. (2018) argue that this result demonstrates both that fisetin can destroy senescent cells and that fisetin does not have to be continuously present to successfully suppress senescence.<ref name=":0" />[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. |375x375px]]
=== Humans ===
In preliminary studies in humans, some data has suggested that fisetin can be an effective supplement to clear senescent cells, and therefore affect aging.

=== Mammals ===
Animal studies have shown that it can improve the status of lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> Fibroblast cells normally help with lung architecture, specifically cell scaffolding and injury response. However, when they change in number and phenotype, they can also play a key role in the development of chronic lung conditions like asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Two days following a fisetin treatment, scientists found that an enzyme only found in senescent cells, SA-β-gal, had decreased by 70 percent.

=== Non-mammals ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
[[File:Imagine.png|thumb|362x362px|Illustration from Shanmugam et al. (2018) study showcasing the biological mechanisms of fisetin's cardioprotective qualities against myocardial ischemia reperfusion injury.]]
Similar to [[rapamycin]], fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by suppressing the signaling pathway and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref>

The GSK3''β'' enzyme plays a key role in ischemia reperfusion injury (IRI). IRI describes tissue damage that occurs when blood flow returns to myocardial (heart) tissue after a period of ischemia (lack of oxygen). During an IRI, the mitochondria of the tissue cells are especially susceptible to damage: GSK3''β'' converges in the mitochondria and affects mitochondrial functions, including the determination of cell outcomes.

By inhibiting GSK3''β'', fisetin regulates the mitochondrial ATP-sensitive K+ channels and protects the cell. Specifically, fisetin has been found to reduce oxidative stress markers in other cell structures, lysosomes and microsomes.<ref name=":1" /> Plus, decreasing mitochondrial swelling and less damage from IRI on the K+ channels when fisetin was used.

Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> In other words, fisetin both inhibits the growth of and promotes the death of cancerous colon cells. Fisetin has also been found to be an effective inhibitor of matrix metalloproteinase (MMP)-1 activity, an important enzyme in remodelling and degradation of the extracellular matrix which plays a major role in cancer progression. <ref>Khan, N., Syed, D. N., Ahmad, N., & Mukhtar, H. (2013). Fisetin: a dietary antioxidant fro health promotion. ''Antioxidants & Redox signaling'', ''19''(2), 151-162. http://doi.org/10.1089/ars.2012.4901</ref> <references />

File:Molecular structure of fisetin.png

2021-07-04T11:11:04Z

MessyMassey:

The molecular structure of fisetin

File:Imagine.png

2021-07-04T10:54:24Z

MessyMassey:

File:Bilde.png

2021-07-04T10:48:19Z

MessyMassey:

Longevity graph of Fisetin diet versus control diet in mice.

Aging and depression

2021-06-22T15:07:28Z

MessyMassey: Added some details to the ilSIRENTE study

== Physical characteristics ==
In the ilSIRENTE study, they found significant differences between older adults with and without depression.<ref>Russo, A., Cesari, M., Onder, G., Zamboni, V., Barillaro, C., Pahor, M., ... & Landi, F. (2007). Depression and physical function: results from the aging and longevity study in the Sirente geographic area (ilSIRENTE Study). ''Journal of geriatric psychiatry and neurology'', ''20''(3), 131-137.</ref> They measured the physical attributes of the participants with Short Physical Performance Battery and a 4-meter walking test, muscle strength with hand-grip capacity a

Fisetin

2021-06-22T14:35:54Z

MessyMassey: /* Evidence of lifespan extension */

Fisetin is a potent flavonol plant based compound called polyphenol, found to reduce [[Senolytics|senescence]] markers in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries, onions, and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Among the therapeutic advantages of fisetin are anti-inflammatory, antiangiogenic, cardioprotective, and neuroprotective benefits.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs). These cells have accumulated DNA damage or other stressors, and this leads to changes in chromatin and secretome protein levels, which prevents the cell from replicating or apoptosis.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell; however, SCs can instead develop senescence-associated secretory phenotypes (SASPs) which induce inflammatory cytokines, chemokines, and extracellular degrading proteins. This is problematic because, even with low levels of SCs, it can cause tissue dysfunction.<ref name=":0" /> These cells are closely linked to age since they usually increase in abundance with age in several tissues, such as adipose tissue, skeletal muscle, kidney, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref> Fisetin is a well-suited treatment option to destroy such cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. |351x351px]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. |375x375px]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 flavonoids.<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin. In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to evoke accelerating accumulation of senscent cells. The mice were then living on a diet from 6-8 to 10-12 weeks of age, with fisetin supplements adiminstered in every 500 mg/kg. They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin. Yousefzadeh et al. (2018) argue that this is consistent with the idea that fisetin can destroy senescent cells, but is not required to be continuously present to suppress senescence.<ref name=":0" />

=== Humans ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> After two days following the fisetin treatment, they found that the enzyme only found in senescent cells called SA-β-gal, had decreased by 70 percent.

=== Other vertebrates ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
Similar to [[Rapamycin]], Fisetin is believed to inhibit the effects of the glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by inhibiting the compound and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref> GSK3''β'' is targeted and inhibited because it normally converges in the mitochondria, which is the area of dysfunction in damaged myocardial tissue that results from ischemia reperfusion injury (IRI). By inhibiting GSK3''β'', fisetin modulates the mitochondrial ATP-sensitive K+ channels and provides cardioprotection to the cell. Specifically, fisetin has been found to reduce oxidative stress markers in lysosomes and microsomes.<ref name=":1" /> Furthermore, mitochondrial swelling and K+ channels were less damaged by the IRI when combined with fisetin. Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> <references />

Fisetin

2021-06-15T15:23:30Z

MessyMassey: Added more content on the biological mechanisms of fisetin in cardioprotection and preventing the spread of cancer cells.

Fisetin is a potent flavonol plant based compound called polyphenol, found to reduce [[Senolytics|senescence]] markers in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries, onions, and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Among the therapeutic advantages of fisetin are anti-inflammatory, antiangiogenic, cardioprotective, and neuroprotective benefits.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs). These cells have accumulated DNA damage or other stressors, and this leads to changes in chromatin and secretome protein levels, which prevents the cell from replicating or apoptosis.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell; however, SCs can instead develop senescence-associated secretory phenotypes (SASPs) which induce inflammatory cytokines, chemokines, and extracellular degrading proteins. This is problematic because, even with low levels of SCs, it can cause tissue dysfunction.<ref name=":0" /> These cells are closely linked to age since they usually increase in abundance with age in several tissues, such as adipose tissue, skeletal muscle, kidney, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref> Fisetin is a well-suited treatment option to destroy such cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. |351x351px]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. |375x375px]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 flavonoids.<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin. In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to evoke accelerating accumulation of senscent cells. The mice were then living on a diet from 6-8 to 10-12 weeks of age, with fisetin supplements adiminstered in every 500 mg/kg. They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin. Yousefzadeh et al. (2018) argue that this is consistent with the idea that fisetin can destroy senescent cells, but is not required to be continuously present to suppress senescence.<ref name=":0" />

=== Humans ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> After two days following the fisetin treatment, they found that the enzyme only found in senescent cells called SA-β-gal, had decreased by 70 percent.

=== Other vertebrates ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref>

== Biological mechanism ==

=== Cardioprotective ===
Similar to [[Rapamycin]], Fisetin is believed to inhibit the effects of glycogen synthase kinase 3''β'' (GSK3''β)'' enzyme by inhibiting the compound and reversing mitochondrial dysfunction.<ref name=":1">Shanmugam, K., Ravindran, S., Kurian, G. A., & Rajesh, M. (2018). Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. ''Oxidative medicine and cellular longevity'', ''2018''.</ref> GSK3''β'' is targeted and inhibited because it normally converges in the mitochondria, which is the area of dysfunction in damaged myocardial tissue that results from ischemia reperfusion injury (IRI). By inhibiting GSK3''β'', fisetin modulates the mitochondrial ATP-sensitive K+ channels and provides cardioprotection to the cell. Specifically, fisetin has been found to reduce oxidative stress markers in lysosomes and microsomes.<ref name=":1" /> Furthermore, mitochondrial swelling and K+ channels were less damaged by the IRI when combined with fisetin. Interestingly, fisetin can also "blunt" IRI-induced apoptosis in damaged myocardial tissues.

=== Cancer ===
Fisetin has been found to inhibit anti-apoptotic Bcl-2 cells and induce pro-apoptotic Caspase-9 and Caspase-3 expression in cancerous colon cells.<ref>Fan, Q., Wang, X., Chinnathambi, A., Alharbi, S. A., & Wang, Q. (2020). Fisetin suppresses 1, 2-dimethylhydrazine-induced colon tumorigenesis in Wistar rats via enhancing the apoptotic signaling pathway. ''Journal of King Saud University-Science'', ''32''(3), 1959-1964.</ref> <references />

Fisetin

2021-06-11T10:27:10Z

MessyMassey: /* Evidence of life span extension */

Fisetin is a potent flavonol polyphenol compound found to reduce [[Senolytics|senescence]] markers in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits like strawberries, onions and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. <nowiki>https://doi.org/10.1155/2012/639469</nowiki></ref> Among the therapeutic advantages of fisetin is anti-inflammatory, antiangiogenic, cardioprotective and neuroprotective.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs). These cells have accumulated DNA damage or other stressors, and this leads to changes in chromatin and secretome protein levels which prevents the cell from replicating or apoptosis.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell, however SCs can instead develop secretory phenotypes (i.e. SASPs) that induce inflammatory cytokines, chemokines and extracellular degrading proteins. This is problematic because even with low levels of SCs, it can cause tissue dysfunction.<ref name=":0" /> These cells are closely linked to age since they usually increase in abundance with age in several tissues like adipose tissue, skeletal muscle, kidney, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257.</ref> Fisetin is a well-suited treatment option to destroy such cells and this has thus been investigated in mice and humans.

=== Mice ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. ]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 flavonoids.<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin. In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to evoke accelerating accumulation of senscent cells. The mice were then living on a diet from 6-8 to 10-12 weeks of age with fisetin supplements adiminstered in every 500 mg/kg. They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that in the following weeks the fisetin-treated mice had lower p16Ink4a expression levels when the mice did not receive more fisetin. Yousefzadeh et al. (2018) argue that this is consistent with the idea that fisetin can destroy senescent cells, but is not required to be continuously present to suppress senescence.<ref name=":0" />

=== Humans ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> After two days following the fisetin treatment, they found that the enzyme only found in senescent cells called SA-β-gal, had decreased by 70 percent.

=== Other vertebrates ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref> <references />

Fisetin

2021-06-11T10:18:29Z

MessyMassey: /* Mice studies */

Fisetin is a potent flavonol polyphenol compound found to reduce [[Senolytics|senescence]] markers in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits like strawberries, onions and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. <nowiki>https://doi.org/10.1155/2012/639469</nowiki></ref> Among the therapeutic advantages of fisetin is anti-inflammatory, antiangiogenic, cardioprotective and neuroprotective.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of life span extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs). These cells have accumulated DNA damage or other stressors, and this leads to changes in chromatin and secretome protein levels which prevents the cell from replicating or apoptosis.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell, however SCs can instead develop secretory phenotypes (i.e. SASPs) that induce inflammatory cytokines, chemokines and extracellular degrading proteins. This is problematic because even with low levels of SCs, it can cause tissue dysfunction.<ref name=":0" /> These cells are closely linked to age since they usually increase in abundance with age in several tissues like adipose tissue, skeletal muscle, kidney, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257.</ref> Fisetin is a well-suited treatment option to destroy such cells and this has thus been investigated in mice and humans.

=== Mice ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. ]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 flavonoids.<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin. In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to evoke accelerating accumulation of senscent cells. The mice were then living on a diet from 6-8 to 10-12 weeks of age with fisetin supplements adiminstered in every 500 mg/kg. They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that in the following weeks the fisetin-treated mice had lower p16Ink4a expression levels when the mice did not receive more fisetin. Yousefzadeh et al. (2018) argue that this is consistent with the idea that fisetin can destroy senescent cells, but is not required to be continuously present to suppress senescence.<ref name=":0" />

=== Humans ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> After two days following the fisetin treatment, they found that the enzyme only found in senescent cells called SA-β-gal, had decreased by 70 percent.

=== Other vertebrates ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref> <references />

Fisetin

2021-06-11T10:14:00Z

MessyMassey: Extended the mice-studies section, as well as some on the human studies and other vertebrates part.

Fisetin is a potent flavonol polyphenol compound found to reduce [[Senolytics|senescence]] markers in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits like strawberries, onions and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. <nowiki>https://doi.org/10.1155/2012/639469</nowiki></ref> Among the therapeutic advantages of fisetin is anti-inflammatory, antiangiogenic, cardioprotective and neuroprotective.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of life span extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs). These cells have accumulated DNA damage or other stressors, and this leads to changes in chromatin and secretome protein levels which prevents the cell from replicating or apoptosis.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell, however SCs can instead develop secretory phenotypes (i.e. SASPs) that induce inflammatory cytokines, chemokines and extracellular degrading proteins. This is problematic because even with low levels of SCs, it can cause tissue dysfunction.<ref name=":0" /> These cells are closely linked to age since they usually increase in abundance with age in several tissues like adipose tissue, skeletal muscle, kidney, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257.</ref> Fisetin is a well-suited treatment option to destroy such cells and this has thus been investigated in mice and humans.

=== Mice studies ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. ]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 flavonoids.<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin. In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to evoke accelerating accumulation of senscent cells. The mice were then living on a diet from 6-8 to 10-12 weeks of age with fisetin supplements adiminstered in every 500 mg/kg. They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that in the following weeks the fisetin-treated mice had lower p16Ink4a expression levels when the mice did not receive more fisetin. Yousefzadeh et al. (2018) argue that this is consistent with the idea that fisetin can destroy senescent cells, but is not required to be continuously present to suppress senescence.<ref name=":0" />

=== Human studies ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> After two days following the fisetin treatment, they found that the enzyme only found in senescent cells called SA-β-gal, had decreased by 70 percent.

=== Other vertebrate studies ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref> <references />

File:FisetinDietAdvantage.jpg

2021-06-11T09:27:29Z

MessyMassey:

These graphs illustrate the effectiveness of the fisetin treatment. Every illustration has been collected from Yousefzadeh et al. (2018).

Senolytics

2021-06-08T10:20:43Z

MessyMassey: /* Fisetin */

Senolytics are a novel class of drugs that clear senescent cells (SCs) from the body, thereby removing this specific type of cell that accumulates with aging. SCs are responsible for generating the senescence-associated secretory phenotype (SASP), which have been shown to drive tissue dysfunction in a large range of organ systems.

== Types of senolytics ==

Senolytics are a novel class of drugs that clear senescent cells (SCs) from the body that are implicated in aging. SCs not only accumulate with aging, but also play a fundamental role in aging and age-related diseases; removal of such cells confers substantial benefit in healthspan and lifespan in animal models of premature aging and normal aging.

SCs are responsible for generating the senescence-associated secretory phenotype (SASP), which have been shown to drive tissue dysfunction in a large range of organ systems.

=== Dasatinib + Quercetin ===
Dasatinib and Quercertin are a specific combination of medicines (D+Q) used for senescent cell clearance, which began from research in the Mayo Clinic.

=== Fisetin ===
[[Fisetin]] is a naturally-occurring flavonoid that is rich in certain fruits and vegetables, such as strawberries, grapes, apples, cucumbers, and onions. It has known antioxidant activity and is a supplement that is regarded as safe, even at high doses.

https://www.thelancet.com/article/S2352-3964(18)30373-6/fulltext

Fisetin

2021-06-08T10:10:52Z

MessyMassey: Written more details on mice-research and added a table to illustrate the effectiveness of fisetin treatment.

File:Yousefzadeh et al. (2018) results.jpg

2021-06-08T10:06:36Z

MessyMassey:

The table illustrates the difference between fisetin and the other ten flovanoids.